chemotherapy and diagnostic toxicology

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RATIONAL ANTIMICROBIAL THERAPY IN DOMESTIC ANIMALS

A.G.REDDY

The choice of antimicrobial agent in the clinical practice should be based upon susceptibility of the infecting organism to the drug concentrations achieved in the tissue and pharmacokinetic characteristics of the drug and its dosing protocol. Although, several class of antimicrobials are readily available, the clinical cure may not be always successful and its partially attributable to lack of culture and sensitivity tests under field conditions. Therefore, atleast, one can bank upon certain pharmacokinetic principles in the routine clinical practice as well as in serious infections like meningitis, endocarditis and in immuno-compromised hosts.

Pharmacokinetics:

Pharmacokinetics deals with absorption, distribution, metabolism and excretory pattern of a given therapeutic agent. Selection of antimicrobial agent based on its pharmacokinetic characteristics aid in achieving optimal concentration at the desired site. For example, the location of infection can have a major influence on the drug concentration achieved there, as some sites (eg: CNS) are protected by barriers to drug penetration, while others (eg. mammary gland, urinary tract) local pH may favour drug accumulation. Knowledge of pharmacokinetic data is also useful to avoid possible toxicity in a given species as well to take necessary precautions during physiological stress (eg. pregnancy, lactation) or pathological conditions (eg: hepatic failure, renal dysfunction). The probable antimicrobial agent that can be employed in the clinical practice should be selected after giving due considerations to following issues:

i.organ/s is/are involved ii.Most likely pathogen iii. Antibiotic likely to be effectiveiv. Drug concentrations at the site of infection v. Drug/route likely to achieve that concentration

Absorption: The absorption and disposition of antimicrobial agents in the body arelargely governed by their chemistry and certain physiochemical properties as well as status of the animal (Fig.1). The various antimicrobials are basically grouped into weak organic electrolytes (acids/bases), amphoteric or neutral compounds. The absorption is primarily dependent on extent of lipid solubility and degree of ionization,

KVC Sponsored CVE training programme on “Chemotherapy and Diagnostic Toxicology” organized by the Dept.of Pharmacology &Toxicology,Veterinary College,Bidar,from 23rd to 28th November 2009

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which are determined by pKa of the drug and pH of the biological fluid in question. These factors also determine the extent of distribution and elimination process for antimicrobials. Only non-ionized forms of drugs are passively diffuses across GIT or can pass across blood-brain or blood-milk barrier. For acidic drugs, a fall in 1 pH unit results in a 10 fold increase in the concentration of the non-ionized form and converse applies for organic bases.

Distribution and elimination: Some of the lipophilic antimicrobials listed below enter most tissues of the body and penetrate cellular barriers and can generally reach infection foci. Chloramphenicol,Trimethoprim,Erythromycin,Metronidazole,3rd

generation cephalosporins like moxalactam,Fluoroquinolones:Enrofloxacin, Pefloxacin, Ofloxacin, Norfloxacin.These antimicrobials are eliminated mainly by hepatic metabolism and/or carrier mediated biliary exertion. This rate of elimination varies with species, but obeys first order kinetics when therapeutic doses are administered.

Tetracyclins: The lipid solubility of tetracyclins varies with the compound but enter most tissues and body fluids except CSF. The more lipophilic number, minocycline attain effective concentration at relatively inaccessible infection site, such as the prostate. As a result of chelation with calcium, tetracyclins become bound at active sites of ossification and in developing teeth. Long acting tetracyclins (doxycyline, minocycline) undergo biliary excretion and may adversely affect indigenous microbes in the caecum/colon of horses. However, they are suited for biliary and upper intestinal tract infection in farm animals. Oxytretracyclin in 2-PVP base (IM only) exert long duration of action over propylene glycol base. Because of poor water solubility, oxytetracyclin dihydrade must be given in much higher dose (50 mg/kg) than the hydrochloride salt to produce equivalent tissue concentration.

Sulfonamides: Most of the sulfonamides predominantly non-ionized in biological fluid of pH below their pKa value (sulfisoxzole = 5; sulfonilamide = 10.4). Commonly used compounds like sulfamethazine (pka = 7.4) and sulfadimethoxin (pKa = 6.1) enter most tissues of the body and eliminated by a combination of metabolic reactions (acetylation) and renal exertion (filteration and pH - dependent passive tubular reabsorption). Cats are poor acetylators and therefore sulfonamides are contraindicated. Sulfisoxazole (pKa = 5.0) is more ionized in the plasma and widely distributed and eliminated mainly by glomerular filtration (best suited for UTI), but their exerction is dependent on urinary pH.

Penicillins: Distributions of penicillin are limited due to high ionization and they attain low concentration in cells and do not penetrate well into transcellular fluids. Protein binding varies among penicillin over a wide range (80%-cloxacillin, 22%-ampicillin) and this is


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responsible for low extra-vascular distribution. However, penicillin and/or in combination with streptomycin is best suited for lower respiratory tract infection (unknown pathogen) with exudation. Penicillins are rapidly eliminated by kidney. Probencid compete with their excretion (for tubular excretion) and delays penicillins excretion.

Antibiotic Desired environment for optimal action

Penicillins,Hexamine(only UTI)

Nitrofurazones,Cephalosporins

Acidic pH

Tetracyclins,Fluoroquinalones,Aminoglycosides

Alkaline pH

Ampicillin, amoxicillin and naficillin undergoes enterohepatic circulation and therefore their half-lives are longer than penicillin-G. Penicillins and cephalosporins (beta-lactams) are highly active during logarithmic phase of bacterial growth (time dependent action). Dosing of beta-lactams should be aimed to keep serum concentration over MIC to prevent regrowth. Penicillins retains their activity even in the presence of fibrin and abscess formation.

Antibiotic Factors decrease their action

Sulfonamides Pus, blood clot

Penicillin,Cephalosporins,Aminoglycosides Intracellular organisms

Gentamicin,Polymyxin Pus

Aminoglycosides DecreasedpH,anaerobiasis, hyperosmalarity

Aminoglycosides :

Aminoglycosides does not attain therapeutic levels in CSF and ocular fluid. Poor diffusibility is attributed to this low degree of lipid solubility. Hafl-lives are short (1-2 hr) in domestic animals. Inspite of limited distribution, selective binding to renal tissue (cortex) occurs. Their bacteriocidal action is rapid but killing of Gm-ve aerobes is concentration dependent and produce a prolonged post-antibiotic effect. Due to this biphasic mode of action, serum concentration continuously exceeding MIC are not required unlike penicillins. Loop diuretics and impaired renal function delays their renal excretion and it is necessary to adjust maintenance dosage to prevent ototoxicity and nephrotoxicity. One should not administer large IV dose or multiple injections in dehydration or ureamic conditions. Intravenous eg: neomycin) must be restricted to


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one or two occasions only. Systemic administration does not give satisfactory levels in milk and therefore local (intramammary) route should be employed in mastitis cows.

Chloramphenicol: In pre-ruminant calves, chloromphenicol is well absorbed from GIT following systemic administration. The drug readily pass through cellular barriers and attain sustained concentration in CSF and aqueous humor. The drug can readily cross placenta. Penetration of the blood: prostate barrier is relatively poor. Due to lipophilic nature, the apparent volume of distribution is large (> 1L/kg) in all species and its distribution is independent of pH. It possess short half-lives in most species except cat (poor in conjugation with glucoronic acid). Due to short of half-life chloromphenicol (sodium succinate) at the rate of 50 mg/kg (priming dose) followed by maintenance doses of 25 mg/kg at 8-12 interval is suggested in ruminants.

Fluoroquinolones:

These are amphoteric compounds and having low degree of ionization. Therefore, their distribution is widespread and even penetrate well into CSF (>50% serum levels in meningitis), bronchial secretions, bone and cartilage and prostatic tissue. Partially metabolised in liver and bile concentrations are 2-10 times the serum levels and even enterohepatic circulation may occur. Plasma half-lives varies with species and urinary concentration exceed serum concentration by several hundred times and remain high for 24 hr after administration. Clearance of certain drugs like theophylline get reduced leading to adverse effects and one should not administer concurrently. They have affinity for weight bearing cartilages and therefore do not administer to puppies (before 8 months of age) or foals (below 1 year of age). Reduction of dosage is required in animals with impaired renal function.

Antimicrobial combinations and their effect

Bacteriostatic (systemic) + bacteriocidal (systemic) Antagonistic

Bacteriostatic (local) + bacteriocidal (systemic) Antagonistic

Bacteriocidal (local) + bacteriostatic (systemic) Antagonistic

Chloramphenicol + Aminoglycosides Antagonistic

Macrolid + Chloramphenicol Antagonistic

Conclusion:

The antimicrobial chemotherapy particularly in the absence of antibiotic sensitivity testing facility under field conditions is a difficult task. In the routine clinical practice as well as in the absence of microbial sensitivity pattern, one can adopt certain


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pharmacological principles discussed here so as to obtain clinical and/or bacterological cure. The veterinarian must update their knowledge pertaing toclinical pharmacology of newer antimicrobials released in to market.

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CLINICAL ASPECT OF ANTIMICROBIAL THERAPY IN RUMINANTS

N.A.PATIL

Drug passage through the ruminant gastrointestinal tract is much different than that of mono-gastric animals. The drug residence time in rumino-reticulum, that greatly alters drug blood level profiles as compared to those observed in monogastric. A drug reaches, the intestine at a rate primarily determined by the rate of rumen emptying. The drug is then absorbed and enters the general circulation or passes out the faces.

Although the rumen is lined with stratified squamous epithelium, the nonionized form of weak organic acids and passes passively diffuses through the mucosa and intraruminal drug administration provides low blood levels and greatly extended duration when compared to monogastric animals. This is caused by slow rate of rumen emptying. In ruminants long times (3-5 days) are needed to achieve steady-state blood levels during multiple oral dosing. But in some cases, extended duration of activity caused by slow rumen emptying is advantageous for prolonging blood levels. This principle contributes greatly to the long-lasting properties of many sulfa drugs in ruminants. Chronic oral dosage with a broad spectrum antimicrobial agent can suppress activity of ruminal microflora, there by interferes with carbohydrate digestion. The ruminal microflora also can activate drugs by hydrolytic or reductive reactions (Trimethoprim).

Sick animals may demonstrate decreased rumen activity. This inturn will result in a greatly increased rumen mean residence time, which will result in even longer duration and lower peak blood levels. For example, lower will be peak sulfamethazine blood levels in diseased cattle compared to normal animals. Decreased rumen motility of a sick or starved animal may result in subtherapeutic blood levels, even while therapeutic levels are obtained with the same dose in normal animals. On the other hand, increasing the dose sufficiently to sick animals can result in therapeutic blood


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levels for a much longer duration than that observed in normal animals. In this case depressed rumen motility enhances therapy.

Antimicrobial therapy: Stability towards chemical and metabolic inactivation within the reticulo-rumen and abomasum of ruminant species determines the amount of oral dose which is potentially available for absorption.

Erythromycin is a valuable antibiotic for use against a variety of gram positive bacterial pathogens. Recent reports indicate that high proportions of pasturella haemolytica isolates are sensitive to erythromycin in vitro. IM route of administration is the only acceptable route in cattle at the dose rate of 15 mg / kg body weight. Apart from the adverse effects like diarrhea there is little reason to use erythromycin orally in ruminants because of negligible drug absorption. Uses of erythromycin in preruminant calves require higher dosage due to the limitations in absorption. Serious adverse gastrointestinal effects associated with the oral administration may occure with parentral administration since a high proportion of erythromycin apparently is eliminated by biliary secretion.

Tetracyclines will interfere with bacterial flora in the rumen, so they should not be given to ruminants. The use of intramuscular and intraabdominal sodium ampicillin is suitable during abdominal surgery in calves. Ampicillin will appear in milk and urine for at least 48 hours post administration. Trimethoprim will be metabolized by the microflora in the gastrointestinal tract of ruminants within 48 minutes; thus oral dosing is not effective.

Chloramphenicol in ruminants will be inactivated by a reductive reaction in the rumen. Since the rumen takes 8-12 weeks to develop and become functional, the bioavailable profile of drugs administered orally to neonatal valves is similar to that obtained in monogastric species. So the chloramphenicol administered as oral solution is well absorbed in neonatal calves and oral dosage (26 mg /kg at 12 hour intervals) will maintain therepeutical effective plasma concentrations. The half life of chloramphenicol which is 14 hours in one day old calf, decrease to 4.2 hours in 10-12 weeks old calves. This decrease is caused partly by increasing drug “trapping” in the developing rumen and partly by development of metabolic capacity. Similar changes noticed in the case of Trimethoprim therapy of goats.

However Furaltadone @10 mg/kg body weight twice daily orally is found to be effective for simple indigestion, ruminal simple impaction, acid indigestion and enteritis. Long acting parenteral preparations are most convenient dosage form in farm


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animals. A single dose of (25,000 units/kg body weight) of procaine penicillin-G (in buffered aqueous suspension) injected either intramuscularly or subcutaneously can maintain effective levels of penicillin-G for 24 hours although the half life of penicillin-Gis less than an hour.

Passage of antimicrobial agents into milk: In milk weak acids (Benzyl penicillin, ampicillin, cephalosporin, sulfamethazine and cloxacillin) produces ratios of milk ultra-filtrate concentration to plasma ultrafiltrate concentration that are less than or equal to unity and organic bases (Erythromycin, Tylocin, Lincomycin, Trimethoprim) excluding aminoglycoside antibiotics (which are) polar attain concentration ratios greater than one.

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ANTIMICROBIAL THERAPY OF PROTOZOAL AND RICKETTSIAL INFECTIONS

B.G. RAVINDRA

Protozoan and Rickettsial diseases are responsible for considerable mortality and morbidity in animals leading to devastating losses. Protozoan parasites are unicellular, eukaryotic organisms present in blood cells, tissues, skin and intestines. The Rickettsial organisms are minute, lack cytoplasm and are present in blood cells. Attempts to develop vaccines aginst these have been greatly handicapped due to complexity of different parasitic stages and their life cycle. Few vaccines are available against these diseases. Drugs currently available are effective, if they are used specifically with proper dose, route and course of treatment. Integrated method of control is very important by using vaccines, drugs and other managemental practices.

PROTOZOAL DISEASES

BABESIOSIS (PIROPLASMOSIS, RED WATER FEVER): The viable protozoa are present in blood stream of animals only in active stages of infection. Ticks (Boophilus spp.) are natural vectors in which transovarial transmission occurs.Contaminated needles and surgical instruments can physically transmit the infection.

Clinicla signs: acute syndrome- high fever (up to 106oF), anorexia, depression, weakness, suspension of rumination, decrease in milk yield, increased heart and respiration rates. Conjuctiva brick red but soon changes to extreme pale due to severe


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anaemia. In terminal stages, severe jaundice, urine dark red/ brownish and produces stable froath. Many severely affected animals die after 24 hours and which survive febrile reaction last for week; pregnant animals often abort, course of disease is 3 weeks. In subacute infection- mild fever, hemoglobinuria absent .B. bigemina- cerebral babesiosis- incoordination, posterior paralysis, mania, convulsions and coma. High mortality inspite of treatment in cerebral form.B. divergens- additional sign is spasm of anal sphincter and feces expelled with greater force in long thin stream referred to as “pipe-stem feces”.Dogs: Signs vary from mild fever lasting for several days to sudden high fever, marked anemia, hemoglobinuria and jaundice.There may be cerebral form (hyperexcitability), alimentary form (stomatitis, gastritis, enteritis), respiratory form (dyspnea), circulatory form (edema), ocular form (keratitis, iritis) and muscular form (muscular weakness).Therapy: a) Quinoronium sulphate derivatives- Acaprin (@ 1ml/50 Kg BW s/c, maximum dose 6ml otherwise salivation, panting, diarrhoea), Babesan, Piroparv, Piroplasmin. b) Acridine derivatives- Acriflavin (50-100ml i/v as 1% solution), Gonacrine, Trypan blue, Euflavine c) Aromatic diamidines- Diminazine aceturate (Berenil- 0.8-1.6 gm/100 Kg BW deep i/m), Stilbamidine, Propamidine, Phenamidine. d) Imidocarbs- Imizole @ 1mg/Kg BW s/c. (Imidocarb hydrochloride and Imidocarb dipropionate)

In horses- Berenil @ 11mg/Kg BW deep i/m.; Imidocarb- most favoured drug. B.equi- @ 4mg/Kg BW four IM injections of 10% solution at 72 hour interval. B.caballi- @ 2mg/Kg BW two injections at 24 hour interval. In donkeys- maximum @ 2mg/Kg BW.; Buparvaquone @ 4-6mg/Kg BW to control B.equi infection.In sheep- Berenil @ 3.5mg/Kg BW on two successive days or 12mg/Kg single dose. Supportive treatment- blood transfusion, Vitamin B complex.

THEILIEROISIS: Theileria parva, T. annulata- tropical theileriosis, T. mutans- less pathogenic, T. ovis, T. hirci- sheep and goat.T. camelensis- camel. Mainly transmitted by Hyalomma spp ticks; the organism pass trans-stadially through stages of larva, nymph and adult. No transovarian transmission.

Clinical signs: Initial sign- enlargement of superficial lymph nodes (prescapular, prefemoral, parotid) within 7-10 days of tick attachment. After 1-2 days, fever (105-106oF), depression, anorexia and decrease in milk yield. In later stages- nasal and ocular discharges, dyspnea, generalized lymph node enlargement and splenomegaly. In severe cases- emaciation, weakness and recumbency followed by death due to asphyxia. Ocassional cerebral theileriosis- circling, tremors, convulsions, profuse


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salivation and head pressing. T. annulata infection- additional signs of anemia and jaundice.

Treatment: a) Halofuginone lactate- coccidiostat but also has schizonticidal effect @ 1.2-2.0 mg/Kg orally for two days. Higher doses may be toxic- salivation, diarrhea, conjunctivitis, subnormal temperature and even death. b) Parvaquone @ 10 mg/Kg, may be repeated after 48 hours. c) Buparvaquone (Butalex) @ 2.5 mg/Kg i/m, may be repeated after 48 hours. d) Tetracyclines, Nivaquine act only on the piroplasm stages. e) Supportive treatment- blood transfusion, liver tonics, diuretics (to check pulmonary edema).

TRYPANOSOMIASIS (SURRA): Trypanosoma evansi- highly pathogenic, produce surra/ murrina/ mal de caders affect cattle, buffalo, sheep, goat, horse, camel and dogs. Horses and dogs most commonly affected, camel are carriers (chronic disease- Tibersa in camels- 3 year sickness). Transmission is through biting flies- Tabanus, Stomoxys, Lyperosia, Glossina, Hematopota even vampire bats help in transmission from one animal to other.Dogs may contract disease by eating infected meat (after 20 days of eating placenta of affected cattle).

Clinical signs: i) Peracute form- sudden death within 2-3 hours, animal dies showing some convulsions. Ii) Acute- Intermittant fever (103-105oF), animal dull and depressed, eyes are starring and wide open, breathing hard and noisy, staggering gait, circling movements, cattle stretches the rope to which it is tied, animal strikes head against wall or manger, stamping of feet, apparent blindness, frequent micturition, profuse salivation, muscular twitching followed by stage of comma and death within 6-12 hours. iii) Subacute/chronic- dullness, lacrimation, animal show progressive emaciation, rapid pulse, intermittent fever, edema of legs, wasting of muscles, loss of weight, occasionally diarrhea, some animal remain standing with neck extended even throughout the day. Dogs: may be acute form of disease, intermittent fever, anemia, edema and corneal opacity.

Camel: in chronic form and may last for 3 years, first sign is weakness of all quarters, eyes dull, alopecia, mucus membranes pale and show petechial hemorrhages, edema of legs, abortion common, mange is frequently seen in surra affected cases.

Treatment: a) Quinapyramine sulphate (Antrycide) curative @ 5mg/Kg BW; Quinapyramine sulphate and chloride (Antrycide prosalt); prophylactic @7.4 mg/Kg BW. In horses- give injection at 2-3 sites, in weak animals there may be salivation, restlessness and muscular tremors. b) Suramin @ 10mg/Kg BW i/v as 10% solution in horses and camels. c) Diminazine aceturate- against T.vivax and T.congolense @ 3.5-


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7.0 mg/Kg, toxic to horses and camels. d) Homidium- bromide and chloride salts @ 1mg/Kg BW. e) Isometamidium @ 0.25-1.0mg/Kg BW. f) Pyrithidium bromide @ 2mg/Kg BW.

COCCIDIOSIS: Eimeria bovis and Eimeria zurnii are the common species, transmited by Feco-Oral route .Sub-clinical coccidiosis occur in 95% of the cases of ruminants. The other 5% are clinical cases.Anorexia, Diarrhoea (may or may not contain blood), dehydration, weakness, depression, weight loss, cachexia, Anaemia and death, Nervous coccidiosis-muscle tremors, staggering, convulsions and occasionally blind nes.

Amprolium @ 10 mg/Kg BW for five days, 1.25% crumble, 9.6%solution, 20% soluable powder ; Sulphaquinoxaline @ 8-70 mg/ kg BW for five days, as soluable powder or feed alternative; Monensin @ 1 mg/ kg daily for 30 days, as feed additive is effective.

GIARDIOSIS: It is a chronic protozoal disease, common in dogs caused by Giardia canis and characterized by diarrhea, dysentery and abdominal pain. Treatment is with: Chloroquin or Metronidazole 250 mg/kg for 10 days are effective.

BALANTIDIOSIS: Balantidium coli exist as a commensal in the large intestine of pigs. Infection of cattle occurs by ingestion of the cysts. The organisms cause ulceration of the mucosa and diarrhea. Diagnosis is based on the detection of cysts/trophozoites in the faeces. Tetracyclines and Metronidazole are effective.

TOXOPLASMOSIS: It is contagious disease of all species including man and is manifested by abortions and stillbirths in ewes and in all species characterized by encephalitis, pneumonia and neonatal mortality.

Clinical signs: cattle: in acute form marked by fever, dyspnoea, ataxia, hyperexcitability in early stages followed by extreme lethargy, stillborn or weak calves die soon after birth. The parasite plays no significant role in bovine abortion. Congenitally affected calves show fever, dyspnoea, sneezing, coughing, nasal discharge, clonic convulsions and grinding of teeth. The death may occur after 2-6 days.; Pigs: highly susceptible, all ages affected. Adults show debility, weakness, incoordination, coughing, tremors and diarrhea but no fever. In young pigs, high fever, diarrhoea, dyspnoea, coughing and ataxia. The pregnant sows abort and piglets are premature or stillborn; Sheep: abortion at last 4 week of gestation and neonatal death. is fever, dyspnoea and generalized tremors whereas lambs show fever and dyspnoea. Goats: abortion and stillbirths; Horses- mainly nervous signs including ataxia, circling


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movement, paresis, myeloencephalitis that may be positive factor for Wobbler syndrome.

Treatment: a) A combination of sulpha drugs @200 mg/Kg BW i/v for 3-5 days (sulphadiazine, sulphadimidine, sulphamerazine, sulphapyrazine) and pyrimethamine @ 1-2 mg/Kg BW orally is quite effective b) Sulfomoyl diamino diphenyl sulphon (SDDS) tried in pigs only @ 5 mg/Kg BW, not used clinically.c) Linomycin and Clindamycin are reported to be quite effective. D) Treatment of anemia as there is blood loss.

BOVINE TRICHOMINIASIS: It is a non-febrile protozoal disease of cattle leading to irregular estrus intervals, early fetal deaths and cases of pyometra.Trichomonas (Tritrichomonas) fetus, the etiological agent. Clinical signs: The parasite normally persists for 3 months in female genital tract after infection and a mild vaginitis is seen after the infective coitusThere is death of fetus within 2-4 months of conception leading to cases of repeat breeding and infertility.Abortions are usually not detected and main feature is failure of animals to hold to service.In bulls, infection is confined to penile and prepucial surface and cause mild inflammatory response.

Treatment: a) The majority of infected cows recover and clear the infection within 3 months so not normally treated. In bulls- douches of prepuce and penis with acriflavin. Dimetridazole @ 50 mg/Kg/day orally for five days is quite affective. Ipronidazole can be administered IM but priorl, bulls should be treated with broad spectrum antibiotic to reduce preputial commensal bacteria which might inactivate the ipronidazole.

RICKETTSIAL DISEASES

ANAPLASMOSIS (GALL SICKNESS) : A non-contagious disease of ruminants caused by obligate intraerythrocytic parasites: Anaplasma marginale, A. centrale, A. ovis. Mainly transmitted by ticks: Boophilus spp., Dermacentor spp, tabanid flies; infected hypodermic needles, blood transfusions

Clinical signs: Subacute (in younger ones): Temperature rises slowly up to 105oF- remain elevated or fluctuate, partial anorexia, animal may die at this stage or survive in an emaciated condition- mucous membranes become pale, urine may be brown but no haemoglobinuria. Peracute cases: sudden onset of high fever, anemia, jaundice, severe dyspnea and death within 24 hours; animals become hyperexcited and may attack pregnant animals may abort. Recovered bulls- testicular function depressed for several months. Sheep and Goat- usually subclinical infection but sometime severe anaemia in goats.


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Treatment: a) Oxytetracycline @ 6-10 mg/Kg BW for three days or single injection of long acting oxytetracycline @ 20 mg/Kg BW i/m. b) Imidocarb @ 3 mg/Kg BW s/c. The problem of carriers can be avoided by using tetracycline @ 10-30 mg/Kg BW i/m daily for 10-15 days or 22 mg/Kg BW i/v daily for 5 days or long acting tetracycline @ 20 mg/Kg BW i/m weekly for 2-4 times or two injections of imidocarb @ 5 mg/Kg BW i/m or s/c. The oral use of chlortetracycline @ 11 mg/Kg BW for 30-60 days or 1.1 mg/Kg BW for 120 days also eliminates carrier animals . c) Supportive treatment- blood transfusion if PCV less than 15%.

EHRLICHIOSIS: Ehrlichia canis, Ehrlichia bovis are the etiological agents, commonly transmitted by ticks: Rhipicephalus sanguineus. Clinical signs: Anorexia, fever, incordination and enlargement of lymphnodes. The disease is of low significance in indigenous cattle, however it is serious problem in imported and newly introduced cattle. In dogs: Anorexia, fever, respiratory distress, Limb oedema, enlargement of lymphnodes, bleeding tendacy (epistaxis, hematuria), and petichial haemorrhages on mucus membrane, Progressive weight loss and Neurological disorder may be seen.

Treatment: Doxcycline @ 5-10 mg/Kg BW per oral for about 10-14 days for four days ; Oxytetracycline @ 5-10 mg/Kg BW for four days ; Chloromphenicol, @ 5 mg/Kg BW for four days, Enrofloxacin @ 2.5-5 mg/Kg BW for four days may also be effective

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ANTIMICROBIAL THERAPY OF IMPORTANT DISEASES OF ZOONOTIC IMPORTANCE

PRADEEPKUMAR

The antimicrobial therapy of important diseases of zoonotic importance are

discussed in brief in this article.

ANTHRAX:Penicillin, the drug of choice for years other drugs from penicillin family

such as amoxicillin should be equally effective. Doxycycline, one of the tetracyclines,

most recently listed as the drug of choice in treating anthrax. Ciprofloxacin, one of the

quinolone antibiotics and is also effective. is recommended as the first drug to use until

the sensitivities of the organisms are known Lung infections may be treated with IV

antibiotics.If untreated, cutaneous anthrax may result in death. Untreated inhalation

anthrax always results in death.

BRUCELLOSIS: Use of surgical hand gloves is recommended during vaccination and

yhe vaccine should be handled properly. Vials, syringes, needles and gloves used

during vaccination should be discarded by suitably disinfecting them.Streptomycin is

the drug of choice. Doxycycline (per oral dosage) is also effective. Flouroquinolones

can also be used.

TUBERCULOSIS:Tuberculosis is curable only with a combination of chemotherapy,

in which a medley of three or four anti-tubercular drugs is administered. The first line

drugs are Isoniazid, Rifampicin, Ethambutal, Pyrizinamite, and Streptomycin. The

treatment is streamlined over a period of 6-9 months.Azithromycin, clarithromycin,

ciprofloxacin are the second line agents, used in cases of resistance and toxicity tio first

line drugs.


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TOXOPLASMOSIS:From acute maternal infection during pregnancy;

incidence/severity related to trimester of infection; may cause abortion, stillbirth, and

premature birth. Manifestations varied: if not evident at birth, usually develop in later

life (85%) and may include: microcephaly, hydrocephaly, neurologic disease/mental

retardation, ocular disease, pneumonitis, hepatomegaly, splenomegaly, icterus, anemia,

thrombocytopenia. Clindamycin; sulfa trimethoprim; monitor for evidence of bone

marrow suppression. Do not feed raw or undercooked meat to cats, keep cats inside and

do not let them hunt.

PLAGUE (BUBONIC, PNEUMONIC, SEPTICEMIC) : The etiological agent

is: Yersinia pestis (gram-negative coccobacillus); Rodents (dog, ground squirrel, rock

squirrel) are the major reservoirs. Bubonic form (most common; 80 - 90% of cases):

enlarged, painful lymph nodes (axillary, cervical, inguinal), fever, chills, weakness, GI

signs, headache, myalgia. Septicemic: septic shock, meningitis,

coma, .Pneumonic (least common: severe pneumonia, fever, dyspnea, and hemoptysis).

Aminoglycosides, fluoroquinolones, are effective agents with supportive care.Insect

repellent, appropriate clothing, flea control for pets and environment, rodent control.

Avoid contact of cats with reservoir hosts.

RINGWORM: Patchy pruritic dermatitis that may be multifocal. Many possible

etiologies in people (zoophilic, geophilic, anthrophilic dermatophytes); M. canis most

common zoophilic dermatophyte and infections are from cats. Keeping the affected part

of the body dry and clean and antifungal agents like griseofulvin, terbinafine,

miconazole, ketoconazole are used.

CRYPTOSPORIDIOSIS : Cattle, rodents, dogs, cats, birds, raccoons are the

reservoirs. Immunocompetent ones: Self-limited acute watery diarrhea, epigastric pain,

nausea, anorexia requiring fluid therapy. Immunocompromised: chronic profuse watery

diarrhea, fever, epigastric pain, nausea, anorexia. Gall bladder infection possible.

Respiratory tract infection may occur. Azithromycin may be effective. Evaluate for


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concurrent immunosuppressive conditions if prolonged treatment needed. Clean and

disinfect environment (100% ethanol or 50% bleach with 30 minutes of contact

effective after removal of organic matter)

Q-FEVER : Coxiella burnetii is the etiological agent. Cattle, sheep, and goats are the

primary reservoirs. Inhalation of organisms from air that contains airborne barnyard

dust contaminated by dried placental material, birth fluids, and excreta of infected herd

animals. Outbreaks occur mainly from occupational exposure involving veterinarians,

meat processing plant workers, sheep and dairy workers, livestock farmers, and

researchers at facilities housing sheep.

Acute: high fever (up to 104-105° F), severe headache, general malaise, malign,

confusion, sore throat, chills, sweats, non-productive cough, nausea, vomiting, diarrhea,

abdominal pain, hepatitis and chest pain. 1-2% mortality in humans. Chronic:

Endocarditis, generally involving the aortic heart valves, less ommonly the mitral

valve. Patients who recover can develop lifelong immunity. Incubation period: 2-3

weeks. Doxycycline is the treatment of choice for acute Q fever. Antibiotic treatment is

most effective when initiated within the first 3 days of illness. A dose of 100 mg of

doxycycline taken orally twice daily for 15-21 days is a frequently prescribed therapy.

Quinolone antibiotics have demonstrated good in vitro activity against C. burnetii and

may be considered.

INFLUENZA : Two antiviral agents: zanamivir (TN: Relenza) and oseltamivir (TN:

Tamiflu) are used to prevent or reduce influenza A and B symptoms. These should not

be used indiscriminately, because viral resistance to them can and has occurred. Also,

they are not recommended if the flu symptoms already have been present for 48 hours

or more. Severe infections in some patients may require additional supportive measures

such as ventilation support and treatment of other infections like pneumonia that can

occur in patients with a severe flu infection.

General precautions to prevent zoonotic infections:


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Hand hygiene: Consistent thorough hand hand washing with plain (nonantimicrobial)

soap and running water mechanically removes organic material and reduces the number

of transient organisms on the skin, whereas antimicrobial soap kills or inhibits growth

of transient and resident flora.To reduce the opportunity for cross-contamination, liquid

or foam soap products should be selected rather than bar soaps. Hands should be

washed between animal contacts and after contact with feces, blood, body fluids, and

exudates. Alcohol-based hand rubs are highly effective against bacteria and enveloped

viruses and may be used if hands are not visibly soiled.

Use of gloves and sleeves: reduce the risk of pathogen transmission by providing

barrier protection; though, wearing gloves is not a substitute for hand washing. Gloves

are available in a variety of materials. Choice of gloves depends on their intended use.

If allergic reactions to latex are a concern, acceptable alternatives include nitrile or

vinyl gloves.

Facial protection: prevents exposure of mucous membranes of eyes, nose, and mouth

to infectious materials. Whenever exposures to splashes or sprays are likely to occur,

such as those generated during lancing of abscesses, flushing wounds, dentistry,

suctioning, lavage, and necropsy, facial protection- surgical mask worn with goggles or

a face shield is used..

Respiratory tract protection: designed to protect the airways of the wearer from

infectious agents that are transmitted via inhalation of small particles.It may be

appropriate in certain situations, such as during investigations of abortion storms in

small ruminants (Q fever), high mortality rates among poultry (avian

influenza),positive herd (bovine tuberculosis), and avian chlamydiosis. Disposable

particulate respirators often resemble surgical or dust masks but fit closely to the

wearer’s face and are designed to filter smaller particles (surgical masks are not

designed to prevent inhalation of small particles).

Protective outerwear: a. Nonsterile gowns: Gowns provide better barrier protection

than laboratory coats. Permeable gowns- used for general care of animals in isolation.

Impermeable gowns should be used when splashes or large quantities of body fluids are


76

present or anticipated.. b. Footwear: Footwear should be suitable for the specific

working conditions (eg, rubber boots for farm work) and should protect personnel from

exposure to infectious material as well as from trauma. Recommendations include

shoes or boots with thick soles and closed-toe construction that are impermeable to

liquid and easy to clean.. d. Head covers: Disposable head covers provide a barrier

when gross contamination of the hair and scalp is expected. Bite and other animal-

related injury prevention: Use of physical restraints, bite-resistant gloves, muzzles,

sedation or anesthesia, and reliance on experienced veterinary personnel rather than

owners to restrain animals

*****

RATIONAL USE OF HORMONES IN ANIMAL REPRODUCTION

M.K.TANDLE

The following is a brief description of various harmones used in animal reproductive disorders

1. Oxytocin: The effect of oxytocin on uterus is to change the weak, spontaneous and irregular contractions. Physiologically oxytocin has shorter half-life

(about 2 minutes) due to its cleavage in plasma by oxytocinase. Therapeutic response to oxytocin is always better when administered as slow intravenous drip rather than given as a single bolus dose. The binding of oxytocin to specific receptors present in mammary gland and myometrium.stimulates smooth muscle contractions promoting uterine motility and milk let down. The efficacy of exogenously administered oxytocin is more in estrogen-sensitized uterus and the response to oxytocin is greatest when circulatory estrogen levels are high.

Indications: Induction of parturition ( only in case of sufficient cervical dilation), expulsion of last fetus in polytocous animal, post caesarian section- to speed up involution and control bleeding after removal of fetus , as local infiltration, expulsion of placental debris, uterine inertia and post repositioned uterine prolapse ( to reduce enlargement and facilitate contraction ).Dosage : Mare 75-125


76

IU ; Cow 75-100 IU ;Sow, Ewe 30-50 IU ;Bitch 5-25 IU;cat 5-10 IU. Route IM or IV

Precautions: Generally oxytocin preparations contain sodium sulfite as a preservative therefore it should not be infused with solutions containing higher concentration of dextrose to overcome possible drug interaction. Administration of oxytocin in dystocia without sufficient cervical dilation is contraindicated. Intravenous administration may be done by diluting oxytocin with distilled water in 1:10 ratio.Products: Inj. Pitocin (Parke –Davis) 5 IU / 0.5 ml , Inj. Syntocinon (Novartis) 5 IU / ml

2. Prostaglandins :

a. Cloprostenol sodium (PGF2 α analogue) : It has potent luteolytic action that brings about regression of corpus luteum (CL) and induces fertile estrus following luteolysis.

Indications: Cow, buffalo: sub estrum, luteal cyst, synchronized breeding, removal of mummified fetus, chronic endometritis, pyometra and induction of parturition

Dosage: IM, IV, SC; Cattle, Buffalo: 2 ml IM, SC; 1.3 ml IV. Contra indicated in pregnancy except for termination of pregnancy.Keep away from pregnant woman veterinarian, persons suffering with asthma or other diseases of respiratory tract Products: Inj. Juramate 263 µg / ml,2 ml (Vetcare); Inj. Synchromate 263 µg / ml, 4 ml (Prima Vetcare), Inj Cyclix, Intervet, 2 mL and 20 mL vials ; Inj Clostenol, Sarabhai Zydus. 2 mL

b. Luprostiol (PGF2α analogue) -Dosage: Cow 15 mg, heifer and Horse 7.5 mg;Products: Inj. Prosolvin 7.5 mg / ml 2 ml, 10 ml, 20 ml (Intervet)

c. Tiaprost (PGF2α analogue)-Products: Inj. Iliren 0.196 mg / ml, 10 ml (Intervet); Dosage:Bovine 3.5 ml IV, 5 ml SC IM, Equine 3 ml IV, Caprine 1-1.5 ml SC

d. Dinoprost (PGF2 α analogue) : Dosage: Pyometra, chronic endometritis: Cattle 5 ml IM’; Induction of parturition: Cattle 3.5 ml IV, Horse 3 ml IM, Pig 2-4 ml IM; MTP: Cattle 3.5 ml IV .Products : Inj. Hormo P2α 5 mg / ml, 5 ml(BCAHP) ; Inj. Lutalyse 5 mg / ml10 ml (Novartis)

3. Estrogens: Natural estrogens include oestradiol, estrone and oestriols. They have low bioavailability following postoperative administration. Simple esters of steroidal estrogens such as benzoates or valerate are used in therapeutics as they release parent


76

molecule on hydrolysis. Potency of estrogen is enhanced adding ethinyl groups to the molecule.

Indications: Misalliance, urinary incontinence in old, spayed bitches, uterine infections, anal adenoma and to induce estrus in bitches. Dosage: Dog 1-3 mg daily orally / 0.5 – 1 ml, IM. Precautions: Polydypsia, polyuria, GI upsets, suppression of red cell production, chronic use may lead to hypogonadism and cystic ovary in females. Products:Tab Evalon,30s (Infar); TabProgynon-C30’s ;Inj. Progynon Depot 1 ml amp. (German Remedies)

4. Conjugated estrogens: To prevent conception in small animal (misalliance) as it delays transport of zygote from oviduct into the uterus. In uterine infections,

estrogens facilitate uterine drainage through cervix provided cervix is dilated. Indications: Misalliance (within one week following breeding), urinary incontinence in spayed / old bitches, anal adenoma, lactation, suppression and uterine infections . Precaution: Pregnancy, feminization in male and large doses may cause aplastic anemia. Products: Premarin (Wyeth lederle) Dosage: Dog, Cat 3 tabs daily for 3 days, 1 ml IM , Tab 0.625 mg; Inj. 25 mg / ml)

II. Hormones used to treat reproductive disorders :The choice of hormones and drugs acting on reproductive system are important as therapeutic agents during reproductive disorders like anoestrus, metritis, pyometra, repeat breeder, retention of fetal membranes, delayed puberty, ovarian disorders etc. The dosage, route, frequency and indications of hormones acting on reproductive system are mentioned in tabular form as below.

Note: Trade names mentioned by the authors are only examples and in any form the author is not promoting or recommending any pharmaceutical products for treatment.

Particulars Indications Dosage and

route in cow

and buffalo

Commercial preparations

DRUGS ACTING ON FEMALE GENITAL SYSTEM-OVARIES

Buserelin-GnRH analogue

Anoestrus, 2.5 mL, IM, IV Inj Receptal, Intervet


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stimulates follicular development, estrus and ovulation by enhancing release of FSH and LH

Delayed ovulation 0.0042 mg/mL,

10 mL vialTrueanoestrus,Follicular cyst

5mL, IM, IV

Gonadorelin-GnRH analogue

stimulates follicular development, estrus and ovulation by enhancing release of FSH and LH

Cystic ovarian disease 100 mcg IM, IV Inj Cystorelin, BCAHP,50 mcg/ml,

2 mL, 10 mL vialsDelayed ovulation,Repeat breeder,Improvement of post partum fertility

250 mcg IM, IV

PITUITARY GONADOTROPINS

Follicle stimulating hormone

FSH induces folliculogenesis in mature female ovaries

Superovulation in ETT 50 mg BID for 4 days

Inj Folltropin-V, Vetrepharm Inc400 mg/vial + 20 mL diluent

Luteinizing hormone

induces maturation, estrogen production and finally ovulation of Graafian follicles and also the growth of CL

Anovulation

Delayed ovulation

Cystic ovaries,Repeat breeding

25 mg, IV Inj Lutropin-V, Vetrepharm Inc,25 mg vial + 5 mL diluent

NON-PITUITARY GONADOTROPHINS

Human chorionic gonadotrophin

mimics the effect of pituitary LH causing ovulation.

Repeat breeding 1500-3000 IU, IM Inj Chorulon, Intervet,1500 IU vial

Inj Coriogan, Intervet,250 IU/mL

Cystic ovaries 1500-3000 IU, IV

Delayed ovulation 1500-3000 IU, IM


76

It promotes the formation and maintenance of CL

repeat on day 8 1000 IU, 2000 IU vials

Inj Corion,Win Medicare,1000 IU,

2000 IU, 5000 IU vials

Post partum lactation failure 1500-3000 IU, IM , q 24 h with synthetic oxytocin

Early abortion 1500-3000 IU / week for 4 weeks as IM

Pregnant mare serum gonadotrophin (FSH like action) induce follicular growth in inactive ovaries of mature animals

Superovulation in ETT 1500-3000 IU

IM, IV

Inj Folligon, Intervet1000 IU vl; Inj Synchro part 400, 500, 600, 700, 6000 IU,BCAHP

Other combinations

FSH 0.48 mg/9 mL, LH 0.42 mg/3mL

To improve quality and yield of superovulation in ETT n bovines

Day 1, 6 mL BID ;Day 2, 5 mL BID;Day 3, 3 mL BID;Day 4, 2 mL BID

Inj Ovaset, BCAHP

9 mL vial FSH + 3 mL vial LH +12 mL diluent

hCG 3000 IU, Progesterone 125mg/ vial

Cystic ovarian syndrome 1 vial as slow IV Inj Nymfalon, Intervet;hCG 3000 IU, Progesterone 125 mg/ vial

Ovarian steroids

Hydroxy-Progesterone caproate

Stimulates luteal action and cause quieting of myometrium, enhances endometrial glandular secretions, thus favour in maintenance of pregnancy. At

Delayed ovulation,Post partum anoestrus

500 mg, IM Inj Duraprogen, Unichem;Inj Proluton Depot, German Remedies

Inj Uniprogestin Depot, Foreva;Inj Vetaprogen, Prima Vet care;Inj P-Depot, Sarabhai Zydus;Inj Dinolutin, ;Alved250 mg/ mL, 2 mL ampoule

Cystic ovarian disease 500 mg, IM

Habitual abortion (late) 500 mg for 3 days followed by 500 mg/week, IM

Habitual abortions (early) 500 mg after 11/2 monthpregnancy, repeat every 10 days, IM


76

lower doses it induces ovulation by its indirect effects on LH release

Progestagen Norgestomet- Synthetic Progestagen

Administered as ear implant to control/induce/ synchronize ovulation in normal healthy animals. In conjunction with estradiol act as a strong negative feed back complex on hypothalamic hypophyseal system preventing final growth and maturation of follicles. Sudden withdrawal of Progestagen releasing implant lead to an increase of LH pulse frequency resulting in estrus and ovulation within 2-3 days

Control/ induce/synchronize ovulation in normal healthy animals

3 mg implant SC on ear (to be kept for 9 days) + 2 mL Inj IM

Crestar implant, Intervet

(Norgestomet 3 mg + (estradiol valerate 5 mg, Norgestomet 3 mg) per mL)

6 mg implant SC on ear (to be kept for 9

days) + 2 mL Inj IM

Synchromate-B implant, BCAHP

(Norgestomet 6 mg + (estradiol valerate 5 mg, Norgestomet 3 mg) per mL)

Prostaglandins

Dinoprost- PGF2α analogue

Potent luteolytic action by constriction of utero-ovarian vessels. It enhances cervical dilation

Sub-estrum

Luteal cyst

Timing and synchronization of estrus

5 mL, IM Inj Hormo P2α, BCAHP5mg/mL,

5 mL vial;Inj Lutalyse, Novartis5mg/mL, 10 mL vial


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and also has selective spasmogenic action.

Luprostiol- PGF2α analogue

It causes regression of CL followed by follicle growth, estrus and ovulation in sub-estrus and anoestrus.

Sub-estrus,Anoestrus,

Luteal cystPersistent CL,Estrus synchronization

15 mg, IM Inj Prosolvin, Intervet.7.5mg/mL,2 mL, 10 mL,

20 mL vials

Tiaprost- PGF2α analogue

Luteolytic activity; enhances cervical dilation and has selective spasmogenic action.

Sub-estrus,Luteal cyst

Estrus synchronization

3.5 mL, IV or

5 mL SC/IM

Inj Iliren, Intervet

0.196 mg/mL, 10 mL vial

Estrogens

Natural steroidal estrogens- estradiol, estrone, estriols. Low oral activity, Potency is enhanced adding Ethinyl groups to the molecules

Induction of estrus

Induction of parturition,Pyometra,RFM

1.5 mL on day1 and 1.5 mL after 3

3 mL

Inj Progynon Depot, Zydus Cadila,1 mL amp,Inj Heatreg ,(di-ethyl stilboestrol 10 mg/mL), Novitech ,3 mL ampoule

Hydroxy Progesterone caproate

Progesterone acts on the endometrium inhibiting myometrial activity and thus quieting uterus

Pre partum uterine/ vaginal prolapse

500 mg,alternate days for 3 times, IM

Inj Duraprogen, Unichem

Inj Proluton Depot, German Remedies

Inj Uniprogestin Depot, Foreva

Inj Vetaprogen, Prima Vet care

Post partum prolapse 500 mg for 3 days ; 500 mg/week for 3 weeks, IM

Prolapse due to pronounced heat

500 mg for 2 days, repeat on 3rd


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day, IM Inj P-Depot,

Zydus AHL

250 mg/ mL,

2 mL ampoule

Habitual pronounced heat 500 mg at the beginning of estrus, IM

Miscellaneous drugs / products

Eazi Breed CIDR Post partum and suckling anoestrus

Cystic ovaries

Silent estrus

Estrus synchronization

Inserted for 7 days;

Inserted for 12 days

Inserted for 10 days along with estradiol benzoate cap 10 mg or insert for 7 days and administer PGF2α on 6th day or at the time of removal

Eazi Breed CIDR, Saideep,

10,s

*****


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THERAPEUTIC CONSIDERATIONS IN HELMINTHIC INFECTIONS OF FARM ANIMALS

P.M.THIMMAREDDY

Chemicals/Drugs used to treat helminthic infections are called Anthelmintics; are classified in to antitrematodal, anticestodal and antinematodals. The Ideal drug should be active against all stages, least toxic to host, have wide therapeutic index, economical and environment friendly. The principle sites of drug action in parasite include neuromuscular system, biochemical reactions involved in energy metabolism and those related to reproduction.

A. Antitrematodal drugs: Drugs used against liver flukes, rumen flukes, lung flukes and Blood flukes

1. Carbon tetrachloride : Effective against mature Fasciola hepatica but not against Dicrocoelium dentriticum. Sheep – 3 ml P.o or S.c. Cattle 20 ml S.c. or 5 ml P.o. This drug is hepatotoxic. Hyperaesthesia, convulsions and coma may occur. More toxicity in hypocalcemic animals. In toxicity, give calcium compounds and reduce the protein intake.

2. Hexachlorethane: Effective against mature Fasciola sp Haemonchus sp and Trichostrongylus sp. The dose is 20 gm/100 kg. Monthly dosing in areas of repeated infestations.

3. Hexachlorphene : 10 mg/kg 4. Triclabendazole : Acting on both mature and immature liver flukes. Cattle –

12mg / kg, Sheep and goat 10 mg/kg.5. Nitroxynil : Active against mature and immature stages (4 to 6 wks) of Fasciola

sp and gape worms in birds. Reaction at the infection site is common. Induce yellow staining of the skin and wool. It is not used in lactating cows.

6. Rafaxanide : Effective against mature and immature flukes, oetsum ovis larva and Haemonchus contortus. 10 mg/kg P.o. Toxicity rare but not used lactating cows.

7. Oxyclozanide : 10 mg/kg. P.o. Safe for lactating, young and pregnant animals. Toxicity: Transient diarrhoea and hypogalactia. Others from this group for subacute and chronic fascioliasis are brotianide (22.5 mg+ thiophanate 200


76

mg/ml) closantel – 5 mg/kg I. M or 15 mg /kg. P.o. Effective against flukes, Haemonchus sp, larval flies & ticks.

8. Diamphenithide : 180 mg/ml susp. 100 mg/kg against mature and immature flukes

9. Bithiona : 50 mg/kg in divided doses on alternate days for 3 or 4 weeks is effective against paragonimiasis, fascioliasis and clonorchiasis, taeniosis and Diphyllobothrium latum

10. Chlorsulon : A sulphonamide 100 mg + Ivermectin 10 mg/ml inj. S.c. Good for biliary fascioliasis in lactating cattle

11. Resorantel : 65 mg/kg P.o. in cattle and sheep against only intestinal paramphistomes.

12. Albendazole : 7.5 mg/kg in cattle, sheep and goat, for the control of Fasciola sp 15 mg/kg b.wt for the treatment of Dicrocoelium dentriticum in sheep.

13. Lithium Antimony thiomalate 6%. Cattle 15-20 ml i.m 2-3 doses at weekly intervals against nasal schistosomiosis.

14. Praziquantel : used in human schistosomiosis, clonorchis sinsensis and opisthorchis viveroni.

B. Anticestodals

1. Natural compounds : The earliest anticestodal drugs used were of plant origin, like minced pumpkin seeds, powdered rhyzome of male fern, kamala and Arecholine

2. Inorganic Compounds : a) Tin compounds were used against human, dog and poultry tapeworms. Stannous chloride – man, dog-0.5 gm daily for 8 days. b) Di-n-butyl tin dilaurate : 1ml for poultry c) Lead arsenate : used for treating Moneizia in lambs and calves.

3. Synthetic organic compounds : i). Hexachlorophene : 100 mg tab

ii). Bunamidine hydrochloride : Used against Echinococcus granulosus : second dose after 6 weeks to eliminates those which were immature, Also, effective against Dipylidium caninum and moniezia expansa.

iii) Dichlorophen : Dogs : 300 mg/kg ,Cats : 100-200 mg/kg

iv) Niclosamide : Dogs & cats: 100-157 mg/kg ,Cattle : 50 mg/kg ,Sheep, Goat, rabbit and monkey : 100 mg/kg

v). Paramomycin Sulphate :


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vi) Praziquantel : 2.5 to 7.5 mg/kg P.o or S.c against Diphyllobothrium latum, Hymenolepis nana, Taenia saginata etc. Dipylidium caninum, Taenia sp, E. granulosus Spirometra, Side effects: Malaise, dizziness, headache, abdominal discomfort with or without nausea. Not used in puppies or kittens younger than 4 wks.

vii). Nitroscanate : 50 mg/kg used against Dipyllidium caninum, Taenia

viii) Benzimidazoles : a) Mebendazole b) Albendazole c) Fenbendazole d) Oxfendazoel e) Febantel etc are effective against

tapeworms.

C. Antinematodals

1. Phenothiazine : 10 gm/45kg used in strongyles, Triodontophorus, Haemonchus, Ostertagia and Trichonema. On exposure to light, it causes photosensitization keratitis manifested by ulceration of the cornea. So, avoid sun for 2-3 days.

(a) Piperazine : 75 mg/kg P.o. for mammals ,3g/bird in water for 3d in poultry

(b) Bephenium hydroxynaphthoate : irritant and poor absorption from the gut. 80%. Cure of Trichostrongylus in man, Ancylostoma in man and dogs and nematodirus in ruminants.

(c). n-Butyl chloride : 90% effective against ascarids and 60% against hookworms.

(d) Toluene : 0.2 ml/kg P.o. 98% effective in ascarids and hookworms in dogs and cats, Emesis, tremors and ataxia in pups and kitten.

(e) Tetrachloroethylene : Removes 90% hookworms. To prevent toxicity give fat free diet 48h before dosing. It is hepatotoxic, causes dizziness, inco-ordination and death. Contraindicated in tapeworm infection as the tapeworms may ball up due to irritation and occlude the intestinal passage.

(f) Methyridine : 200 mg/kg P.o., S.c, or I.P. Twice the normal dose is toxic. Diethylcarbamazine potentiates toxicity.

(g) Diethyl Carbamazine citrate: 6 mg/kg P.o or S.c in dogs in Spirocerca lupi, human wucheria bancrofti or Loa loa, onchocerca volvulus, cutaneous larva migrans and tropical eosinophilia. 22 mg/kg i.m for 3 days in early cases of Dictyocaulus viviparous infection in cattle, 5mg/kg daily or alternate day commencing before exposure and continuing 60 days after exposure.


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(h) Disophenol : 10 mg/kg P.o., S.c. or i.m. Effective against hookworms and spirocerca lupi of dogs, syngamus trachea in turkeys. It causes pyrexia, tachycardia, polypnoea, corneal and lens opacity in dogs which regress within 7 days. Non blood sucking and histotropic parasites are unaffected, orally administered drug is more toxic.

(i) Phtholofyne : 200 mg/kg for whip worm. 24hour fast followed by light meal after dosing. Toxicity leads to emesis, ataxia, and death.

(j) Hygromycin-B : An antibiotic in feed for swine and poultry against ascarids, capillaria, oesophagostomum and Heterakis gallinarum. Feed 6 weeks prior to farrowing in swine.

3. Tertrahydropyrimidines : Less active against larval stages and have minimal action on hypobiotic larvae. Not ovicidal.

a) Morantel citrate : Not effective against adult lung worms. 10 mg/kg P.o in cattle & sheep

b) Pyrantel pamoate : used for round worms in horses, dog and man. Due to mutual antagonism, piperazine and pyrantel compounds should not be combined.

c) Oxantel : Specific single dose treatment of Trichuriasis in dog at 55 mg/kg.4. Benzimidazoles :Benzimidazoles have a high therapeutic index, but not to be used in the first month of pregnancy (teratogenic).

a) Thiabendazole : Not widely used now b) Mebendazole : Generally not used in cattle, sheep and horse 10 mg/kg. 25-50

mg/kg twice daily for 5 days for round worms and tapeworms in dogs.c) Parbendazole : 30 mg/kg P.od) Albendazole : It is used in the treatment of roundworms, tapeworms and

flukes. 5 mg/kg for roundworms and 7.5 mg/kg for flukes in sheep and goats .7.5 mg/kg for round worms and 10 mg/kg for flukes in cattle. 5 mg/kg in horses

e) Fenbendazole : In addition to important roundworms, it is effective against hypobiotic larva and also on tapeworms in sheep, Goat and dogs.

f) Oxfendazole : Active against round worms, their inhibited larva and tapeworms 4.5 mg/kg P.o as a single dose to cattle, sheep and pig. 10mg/kg daily for 3 days in horses and dogs

g) Oxibendazole : Effective against roundworms and lung worms in horses 10 mg/kg P.o.


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h) Flubendazole : 5 mg/kg P.o. mainly used in pigs against round worms i) Luxabendazole : Effective against round worms and flukes .7.5 mg/kg for

round worms5. Benzimidazole pro-drugs.These are converted in vivo to benzimidazoles. The drugs are ovicidal, larvicidal and affect adults including some tape worms (Taenia sp)

a) Febantel : Converted to fenbendazole and oxfendazole, 7.5 mg/kg in cattle and 5 mg/kg in sheep

b) Thiophanate : Converted to lobendazole 50 mg/kg c) Netobin : Converted to albendazole 7.5 mg/kg P.o in cattle & sheep

6. Imidazothiazoles :

a) di-Tetramisole b) Levamisole (1-Tertramisole) : Effective against larvae (but not hypobiotic and not ovicidal) and adults. anthelmithic dose is immunostimulant. The drug is non-teratogenic and hence can be used in pregnant animals. The dose is 7.5 mg/kg Antidote is Atropine

7. Macrolides (macrocyclic lactones)

a) Ivermectin : 0.2mg/kg single oral or P.o.Effective against nematodes and ectoparasites. Used at 6 ug/kg at one month intervals for prevention of Dirofilaria immitis infestation in dogs. Other macrolides includes Doramectin, milbomycin-D, milbomycin oxime, Eprinomectin, Moxidectin and selamectin.

8. Organophosphorus compounds : The use is restricted to the treatment of round worms of dogs, cats, pigs and especially horses where they also control the stomach bots.

a) Dichlorovos : 20 -40 mg/kg in horses ,30-40 mg/kg in pigs,27-33 mg/kg in Dogs. They may be incorporated into polyvinyl chloride resin pellets for slow release and safety

b) Coumaphos : 2 mg/kg/day for 6 days in feed c) Trichlorofon : A prodrug of dichlorvos used in horses at 40 mg/kgd) Napthalofos : Narrow margin of safetye) Crufomate: used for warble fly control.

Broad Spectrum Combinations

1. Clorsulon and Ivermectin : For use in cattle 1 ml/50 kg. S.C.2. Dichlorophene and Toluene: used in dogs against cestodes and nematodes


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3. Diethylcarbamazine and oxibendazole : used in dogs for prevention of infection with D. immitis and A. caninum, and for the removal of T. canis and T.vulpis

4. Febantel, praziquantel, and pyrautel: A single dose is given to dogs to remove D. caninum, T. pisiformis, E.granulosus, A. caninum, U. stenocephala, T. canis, T. vulpis

5. Milbemycin oxime and Lufenuron :This is given once every mouth to remove G I worms and control of flea population

6. Praziquantel and pyrantel : A single dose is given to cats and kittens to remove D. caninum, Taenia sp Ancylostoma sp and T. cati

7. Ivermectin and pyrantel pamoate : This is given orally to dogs every 30 days to prevent D. immitis and for the treatment & control of T. canis, T. leonina,

*****


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CLINICAL PROTOCOLS IN ANTINEOPLASTIC THERAPY OF SMALL ANIMALS

D.DILIP KUMAR

The effectiveness of a chemotherapeutic agent is measured in terms of concentration and exposure time. Routes of administration and absorption may influence the efficacy of an administered drug.The chemotherapeutic agents can be administered orally, subcutaneously, intramuscularly and intravenously for systemic effects.Local effects can be obtained by topical,intrapleural/peritoneal ,intra cystic/intrathecal into the CSF.All the chemotherapeutic agents can not be given by each and every route hence proper selection of route of administration can maximize the efficacy . Biotransformation of the drug also should be taken into consideration in chemotherapy.Prednisone used in chemotherapy has to be converted into prednisolone by the liver to be effective. Distribution of drugs partially determines its effectiveness. If the drug donot reach to the tumour,the exposure of tumour cells to chemotherapeutic agent will be nil. Some drugs will be effective during first time administration while they may not be so effective during their subsequent administration Drug resistance may develop by several means such as acquired resistance of the tumour may occur owing to decreased activation or increased deactivation of drug reducing its effective contact time..Toxicity: GI toxicity, bonemarrow suppression and immunosuppression.

Principles of combinations of chemotherapy: 1. Effective single agent used. 2. Two drugs with different mechanisms of actions should be used. 3. Intermittent treatment schedule

Guidelines for chemotherapy: Thorough clinical examination, history collection and appropriate data base are necessary for chemotherapy.

1. Histological diagnosis of tumour is must to know whether it is begnin or malignant

2. Biological behavior of tumors should be understood

3. Drug toxicities,dose level ,species limitations should be understood.

4. Monitoring of toxicities is essential.

5. Therapy should be undertaken with properly explaining the pros and cons to the owners.


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Chemotherapeutic agents can be classified as : 1. Alkalyting agent’s 2.Antimetabolites 3.Plant alkaloids 4. Antibiotics 5.Hormones 6.Miscelaneous

1. Alkalyting agents: These are the compounds that substitute an alkyl radical (R-CH2-CH2

+) for hydrogen atom on some organic compounds. These agents interfere with DNA replication and RNA transcription.There are five class of alkylating agents

a) Nitrogen mustard derivatives: Methchloethamine,Cyclophosphamide,Chlorambucil and Melphalan; b) Ethenimine derivatives:Triethylenethiophospharamide; c)Alkyl Sulfonate:Busulfan d) Triazene derivatives:Dacarbazine; e) Nitrosoureas: Carmustine, Lomustine, and Somustine

Cyclophosphamide is the most commonly used alkylating agent in Veterinary practice.It is used for lymphoreticular neoplasms,carcinomas,mast cell tumour,TVT,Cyclophophamide requires activation to its active metabolite 4-hydroxy Cyclophosphamide by liver.Dose 50mg/ M2 per orally or weekly once for four times intravenously. Chlorambucil is used in canine lymphosarcoma.Dose rate is 2mg/ M2

Per orally or at weekly intervals for two to four weeks.

2. Antimetabolites: The antimetabolites are structural analogues of normal metabolite required for cell function and replication.They damage cells by interacting with cell enzymes (1).By substituting for a metabolite needed in key molecule,rendering it functionally abnormal (2.)By competing successfully with a normal metabolite that acts at an enzyme regulatory site to alter the catalytic rate of a key enzyme.

The important antimetabolite drugs are Methotrixate, 6-Mercaptopurine,)5-Flurouracil and Cytosine Arabinoside. The antimetabolite drugs are S-phase specific.

Methotrixate acts in S-phase to inhibit dihydroxy foliate reductase compitatively and interferes with both DNA and RNA synthesis.The folic acid antagonists are used in the treatment of lymphoreticular neoplasms,myeloproliferative disorders,transitional metastatic cell tumours,TVT,sertoli cell tumour and ostesarcoma.Methotrixate dose 2.5mg/ M2 per orally daily until response or toxicity.

3.Plant alkaloids: Vincristine and Vinblastine are the alkaloids extracted from the periwinkle plant.Vinca Rosea.They act specifically in M phase by binding with microtubular protein tubulin and blocking mitosis by interfering with chromosomal separation in metaphase.Both the drugs are used in the treatment of lymphoreticular neoplasms Vincristine is the treatment of choice for TVT and has been used for the treatment of carcinomas and mast cell tumour.


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4.Antibiotics : They are derived from soil fungus( Streptomyces).They are cell cycle non –specific drugs.They damage the DNA.Inhibit DNA or RNA synthesis.Doxorubicin is a cytotoxic drug.Vomiting,diarrhea,myelosuprression,cardiac toxicity are the side effects.Doxorubicin must be given slowly when given intravenously.Pretreatment with histamine helps in avoiding complications.Dose:30mg/ M2 at three week interval for TVT,lymphosarcoma,carcinoma.

5.Hormones: Peptide hormones convert ATP to c-AMP(cyclic AMP).c-AMP is a secondary messenger to deliver and amplify signals to intracellular site.Steroid hormones enter cell and bind to specific receptor protein. “Transformation” (activation) of this newly formed complex allows it to pass the nuclear membranes where it binds to DNA.This binding alters transcription of cell messenger RNA,resulting in synthesis of new protein.Steroid induced increase in fatty acids may cause dissolution of the nuclear membrane,leading to cell death.

Adrenal corticoids are used for treatment of lymphosarcomas and mast cell tumours.Sex hormones are used in the treatment of mammary ,prostate and perineal gland tumours.Hormones have valuable role in replacement therapy following abalation surgery,in the management of some metastatic problems.Prednisolone 60 to20mg/ M2 per orally every 48 hours used in Lymphoreticular tumors mast cell tumour,and CNS tumours.Diethyl Stilbestrol 1.1mg/kg (not more than 25mg)- used for perianal adenomas, prostatic tumours.

6. Miscellaneous agents: examples: L-Asparginase o,p-DDD. L-Asparginase enzyme preparation is derived from the bacteria.L-asparginase deprives the neoplastic cells that lack the ability to synthesise L-asparginase of extracellular source there by inhibiting protein synthesis.L-asparginase acts against cells in G1 phase.Used for the treatment of lymphoreticular neoplasms @20,000units/ M2 intraperitoneally.Side effects are anaphylaxis and leukaemia. o,p-DDD: Directly suppresses normal and neoplastic adrenocortical cells,used in adrenocortical insufficiency @50mg /kg PO, to effect.

Drugs used in Chemotherapy:Chemotherapeutic agents dose is expressed in terms of mg per square meters of body surface area.This is physiologically more accurate method of determining the dose.Weight in grams is converted to body surface

area(meter square) as follows: M2 = Km xW2/3 / 104; wherein: M2 - Body surface area

in square meters; W-Weight in grams; Km- Species specific constant (10 for cats and 10.1 for dogs).The relation of body weight to surface area in square meters for dogs is given in this table:


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Kgm2

Kg

m2

kg m2 Kg

m2

kg m2

0.5 0.06 6 0.33 12 0.52 18 0.69 24 0.83

1 0.10 7 0.36 13 0.55 19 0.71 25 0.85

2 0.15 8 0.40 14 0.58 20 0.74 26 0.88

3 0.20 9 0.43 15 0.60 21 0.76 27 0.90

4 0.25 10 0.46 16 0.63 22 0.78 28 0.92

5 0.29 11 0.49 17 0.66 23 0.81 29 0.94

DRUGS MAJOR INDICATIONS Dose& Route of Admn.

Cyclophosphamide Lymphoma, sarcomas, mammary adenocarcinoma,lymphocytic leukemia

60mg/kgBW daily oral

Melphalan Multiple myeloma 150mcg/kgBW/day or 250mcg/kgBW daily 4 weeks oral

Chlorambucil Chronic lymphocyticleukemia, lymphoma

100mcg/kgBW daily oral

Carboplastin CNS neoplasm,GI carcinomas 300-360mg/m2 BSA by IV

Dacarbazine Lymphoma 2-4.5mg/kgBW for 10 days IV10-15mg/day for 4-8days oral

Busulfan Chronic myelogenous leukemia, polycythemia vera

60mcg/kg BW daily oral

Methotrexate Lymphoma, Sertoli cell tumor, osteosarcoma, metastatic TVT

10-15mg/day for 4-8 days oral

Fluorouracil GI, lung, liver, and mammary carcinomas (systemic); cutaneous carcinomas (topical)

15mg/kgBW once a week oral15mg/kgBW in 500ml DNS


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Dactinomycin (Actinomycin D)

Choriocarcinoma, testicular carcinoma, rhabdomyosarcoma, lymphoma

15mcg/kgBW per day or400-600 mcg/m2 BSA IV

Doxorubicin Lymphoma, acute lymphocytic granulocyticleukemia, sarcomas carcinomas,

60-75mg/ m2 BSA IV

Bleomycin Carcinomas (testicular, squamous cell –head,neck,seminoma,malignant teratoma

15,000IU thrice a week IM/IV

Vinblastine Lymphoma and leukemias, mastocytoma

0.1-0.5mg/kgBW IV

Vincristine TVTs, lymphoma and leukemias,CNS tumors, mammary carcinoma

25-75 mcg/kg or 1.4mg/m2

IV

Cisplatin Osteosarcoma, carcinomas (transitional cell, testicular, squamous cell of head and neck, ovarian, cervical, bladder

50-120mg/m2 BSA with % NS, IV

L-Asparaginase Acute lymphocytic and lymphoblastic leukemia and lymphoma

1000units/kg BW/10days with NSor Dextrose 5%

Hydroxyurea Polycythemia vera, mastocytoma, granulocytic and basophilic leukemia, thrombocythemia

20-30 mg/kgBW oral

Prednisolone Lymphoma, mast cell tumors, palliative treatment of brain tumors

60mg/m2 IM,IV

Tamoxifen Estrogen-receptor-positive mammary carcinomas

20mg/day single dose oral

Flutamide Testosterone-receptor-positive prostatic tumors; surgical castration preferred

250mg TID oral

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ANTIMICROBIAL THERAPY IN HEPATIC IMPAIREMENTS

M. VIJAY KUMAR

Liver has very complicated functions and one of the most important function is the detoxification of drugs such as antibiotics and its metabolites. Some antibiotics can cause allergic reactions while others can cause direct damage to their liver, which can be quite severe in patients with chronic liver disease. For patients with a pre-existing liver disorder, the detoxification function of the liver is already compromised and substances that would normally be metabolized could actually accumulate in the liver or in the bloodstream.Liver disease may have a variable effect on drug clearance. There are no tests for hepatic function that will reliably predict drug clearance.

Antibiotics that accumulate in this manner could become toxic to the body and its functions can change drastically from its original purpose. For the most part in treating patients with preexisting liver disease who develop infections outside the liver, one should use caution in prescribing drugs known to be dependent on liver for inactivation or excretion. Usually a safer substitute drug can be found. If a potentially toxic drug must be used, blood levels can be useful in monitoring the dose to within safe limits. One should also take care to avoid use of hepatotoxic non-antibiotic drugs concomitantly. On the other hand, drugs metabolized and/or excreted by the liver are theoretically ideal for treatment of acute infections of liver and biliary tract. Each one of the ollowing antibiotic is ordered according to their potential harmful effects on the liver, the top group being the most potentially harmful and the last group being the least.

Tetracyclines: Used in larger doses, cause jaundice, fever, and fatty liver. Hepatitis patients should not be administered with these agents. All tetracyclines are concentrated in liver and excreted via bile into intestine, where they are reabsorbed. Variable amounts of each member of this drug family are thereafter eliminated in urine.; have prolonged half-lives in the serum because of slower renal clearance than that of tetracycline or oxytetracycline. With excess parenteral dose, liver toxicity progresses to acidosis, shock, coma and death.Other organs which may suffer simultaneous toxicity are pancreas, kidneys and brain. Pregnancy and chronic renal


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disease seem to predispose patients to this type of hepatotoxicity. Dosage adjustment is necessary, avoid exceeding a blood level of 10mcg/ml. Tetracyclines have adverse effects on several hepatic enzymes. Inactivated chlortetracycline causes same toxic hepatic changes as the active drug, so hepatic toxicity appears not related to antibacterial activity; thus to be avoided completely in liver disease

Macrolides : Erythromycin: It causes damage to the liver via cholestasis (bile retention) and jaundice. The harmful effects usually start to show after 10 to 14 days use and the incidence rate is approximately 5 to 10%. Clinically, patients may develop abdominal pain, nausea, vomiting, jaundice, and elevation of liver enzymes. These conditions are often considered allergic reactions since the incidence rate is not very high Liver toxicity is caused by only estolate form. Avoid estolate form in liver disease and other forms in usual dosage. Estolate-induced hepatitis is a dose dependent. hypersensitivity reaction.

Lincosasmides: Lincomycin: is excreted and re-excreted via enterohepatic circulation. Bile levels are high upto 10-20x the serum level. Occasional jaundice and/or abnormal liver function tests which clear rapidly, sometimes even while drug is continued. Half-life of drug is doubled in liver disease accordingly drug dose should be reduced, or drug avoided entirely.

Kanamycin : Not Metabolised by liver.No change in dose in case of parenteral liver disease.in case of oral dose kanamycin at 8 Gm/day eventually builds serum levels to therapeutic range. This effect is even greater with hepatic disease and azotemia. Accordingly, such patients on gut sterilization with kanamycin should be watched for deafness and increasing nephropathy. Neomycin: Not metabolised by liver. No more than 6 Gm P.o in liver disease for gut sterilization. If azotemia also present,kanamycin is preferred.

Chloramphenicol: When metabolized in the liver, they combined with glucoronic acid and lose their anti-microbial effects. This combination of antibiotics and glucoronic acid can accumulate in the bloodstream, which can cause bone marrow inhibition. As a result, WBC and RBC counts can drop and patients with hepatitis should try to avoid this group if they can. Metabolism by liver. 85-95% is conjugated in liver to monoglucuronide and 3% is further converted to aryl amines and aryl nitro derivatives.Most of above is secreted then by kidney tubules. Significant concentration in liver tissue levels and average bile levels,that of plasma. Liver toxicity is rare. Use with caution in liver disease. If ascites or jaundice is present, use under 25 mg/kg/ day


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or another drug. Newborns are vulnerable to "grey syndrome"due to immature hepatic and renal function.

Penicillins: These antibiotics cause the least liver damage and only patients who are allergic may experience some side effects. Generally, antibiotics in the penicillin family are the most "liver friendly" and safe for chronic hepatitis patients to use.

Penicillin G: . Metabolism by liver: Only minor fraction is ordinarily handled by liver, but in impaired renal function the liver may be a major excretion route via bile. Attains significant liver tissue levels and also bile levels.Liver toxicity is rare, as part of a generalized hypersensitivity reaction. No change in dose in liver diseases if renal function is good and reduce dose in circumstances of combined kidney and liver disease.

Generally the information for penicillin G applies also for Alpha-phenoxy-peniclllins Methicillin., Oxacillin methicillin. Cloxacillin and broad spectrum penicillins: ampicillin, hetacillin, carbenicillin and nafcillin.

Streptomycin and Dihydrostreptomycin: Metabolism by liver.Small fraction is secreted into bile. Bile levels up to 10-20mcg/ ml on high doses. Liver toxicity is rare and also may aggravate existing liver disease. No change in dose in liver disease.

Cephalosporins: Cephalothin: Metabolism by liver, 70-80% usually excreted unchanged in urine. However, it can be inactivated by deacetylation (presumably in liver), then excreted in urine. Advisable to decrease in presence of combined renal-hepatic disease.

Nitrofurantoin: Metabolism by liver: 50-60% is metabolized at unknown site. Rarely, causes a hypersensitivity hepatitis with cholestasis, focal necrosis, infiltrates,eosinophils.

Sulphonamides: Metabolism is significantly, but not solely by liver (acetylation, glucuronidation, and/or oxidation), then excreted into urine. Not influenced by dose: direct hepatotoxicity and hypersensitivity. Either may go on to acute yellow atrophy. Best to avoid dose in liver disease. Pre-existing nutritional liver disease may predispose to sulfonamide hepatotoxicity. Kidneys appear to be more susceptible to damage by sulfas in patients with chronic liver disease.Neonate require less dose for therapeutic blood levels.

Metronidazole and related drugs (tinidazole, ronidazole): are sometimes used in patients with hepatic disease because of the anaerobic spectrum. The most serious


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problem caused by high dose of metronidazole has been attributed to CNS toxicity and include seizures, ataxia, nystagmus, tremors, and rigidity.4 These signs have been attributed to inferring with the inhibitory neurotransmitter GABA. Because animals with hepatic disease also may be prone to CNS disorders that also share these clinical signs, veterinarians should understand the risks of metronidazole, and become familiar with the signs associated with toxicity.

Fluoroquinolones: The fluoroquinolones (enrofloxacin, marbofloxacin, orbifloxacin, difloxacin) have had a good safety record and increased risk of toxicity in animals with hepatic disease has not been documented. Although some of these drugs are metabolized, the clearance is low and probably not affected unless there is substantial loss of hepatic function. These drugs are also cleared by the kidneys

A common dilemma for veterinarians is which nonsteroidal antiinflammatory drug (NSAID) to administer to a patient with hepatic disease. The six approved NSAIDs for dogs: carprofen, etodolac, Meloxicam (cats), tepoxalin, deracoxib, and firoxixib. Because studies have not been conducted in animals with hepatic disease, there is no single drug shown to be safer than another. However, All NSAIDs have the potential to: (1) induce liver injury. (2) Pre-existing elevations in liver enzymes has not been shown to increase an animal’s risk for NSAID-induced liver injury, but a sharp increase in liver enzymes and/or bilirubin after instituting NSAID therapy is cause for alarm. (3) cause gastrointestinal injury, including erosions, ulcers, and bleeding. Patients with hepatic disease have an increased risk of these problems. (4) There is no NSAID yet to be shown safe for long-term administration for cats and hepatic reactions have been one of the problems associated with NSAID administration in cats. Tramadol and opiate analgesic drugs have high clearance and their metabolism is not likely to be affected by a loss in hepatic function or changes in hepatic enzymes. These drugs have a high safety margin and can be used safely in patients with hepatic disease.

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ANTIMICROBIAL THERAPY OF OCULAR INFECTIONS

M.VIJAY KUMAR

Ocular antimicrobial therapy differs from treating infections in other tissues because drugs can be administered directly to the eye, achieving high drug concentrations. However,owing to the limited number of veterinary ophthalmic preparations available for topical ophthalmic use, practitioners need to make rational antimicrobial choice and extralabel drug use for successful therapy.practitioners should avoid using the antimicorbials to treat noninfectious ocular conditions such as uveitis or allergic conjunctivitis.unwarranted antimicrobials have no affect on an antiiflammatory disease process and encourage antimicrobial resistance. Common bacterias affecting eye include Staphylococcus intermdius, Streptococcus spp.( Dogs), Chlamydophilia felis, Mycoplasma felis(cats), ,Streptococcus zooepidemicus, Pseudomonas spp., Aspergillus spp., Fusarium spp (Equines), Moraxella bovis (Cattle), Mycoplasma conjunctivae Branhamella ovis(Goats) and Chlamydophilia pecorum ,Branhamella spp (Sheep).

Routes of drug administration : The 3 primary methods of delivery of ocular medications to the eye are : Topical, Local ocular (ie, subconjunctival, intravitreal, retrobulbar, intracameral) and Systemic. The most appropriate method of administration depends on the area of the eye to be medicated - extraocular structures, cornea, anterior segment (anterior chamber and iris), posterior segment (ciliary body, retina, vitreous), and retrobulbar or orbital tissues. The conjunctiva, cornea, anterior chamber, and iris are usually best treated with topical therapy. In contrast, the eyelids can be treated with topical therapy but more frequently require systemic therapy. The posterior segment always requires systemic therapy, as most topical medications do not penetrate to the posterior segment.

1. Topical-most common route of administration :Degree of penetration of topically applied medications depends on integrity of normal defense mechanisms of the eye. Drug absorption is greatly enhanced by ocular inflammation. Medications put in the conjunctival sac can penetrate the cornea, conjunctiva, or be absorbed systemically via the nasolacrimal system It is also affected by the Vehicle, molecular size of the drug, drug concentration, pH, electrolyte composition and preservatives.

Corneal epithelium is the main site of resistance to drug penetration.. As a result, the epithelium and endothelium are relatively impermeable to electrolytes but are readily


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penetrated by fat-soluble substances. Drugs that have the ability to exist in equilibrium in solution as ionized (water soluble; polar) and unionized (lipid soluble;nonpolar) forms are ideal for topical use, i.e., chloramphenicol, fluoroquinolones. Topical administration is used for treatment of eyelids, conjunctiva, cornea, iris, and anterior uvea. Following which , up to 80% of the applied drug(s) is absorbed systemically across the highly vascularized nasopharyngeal mucosa. Because absorption via this route bypasses the liver, there is no large first-pass metabolism seen after administration PO.

2. Subconjunctival (bulbar conjunctiva): This technique requires only topical anesthesia and a tuberculin syringe with a 25- or 27-gauge needle. Volumes should not exceed 0.25 ml in cats and dogs and 1.0 ml in horses and cows. Subconjunctival medication reaches the cornea by slowly leaking out of the injection site. Intraocular drug levels are attained by diffusion through the cornea and sclera. This is used for diseases of the cornea, anterior, uvea, anterior vitreous, and sclera.Drugs with low solubility such as corticosteroids may provide a repository of drug lasting days to weeks. Appropriate amounts must be used, as large amounts, especially of long-acting salts, can cause a significant inflammatory reaction. For sub-Tenon’s injections, 0.5 ml/site is usually safe and effective in small animals and ≤1 ml in large animals such as the horse and cow.

3.Retrobulbar medications:are used infrequently for therapeutics. In cattle, the retrobulbar tissues can be anaesthetized with local anesthetic (lidocaine) for enucleations. Whenever any medication is placed into the orbit, extreme care must be taken to ensure that the medication is not inadvertently injected into a blood vessel, the optic nerve, or one of the orbital foramen. Retrobulbar injection has a high risk of adverse effects and should not be used unless the clinician is experienced and the animal is appropriately restrained.

4. Intravitreal-used infrequently: Antibiotics,antifungal drugs have been effectively used in microgram dosages. Generally injected at the pars plana for infectious endophthalmitis.

5. Systemic-P.O., I.V. or I.M: Systemic administration is required for treatment of diseases of the retina, optic nerve, and vitreous., for posterior segment therapy and to complement topical therapy for the anterior segment. The blood-ocular barriers can limit absorption of less lipophilic drugs, but inflammation initially allows greater drug concentrations to reach the site. As the eye starts to heal, these barriers become more effective and can limit further drug penetration. This should be considered when


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treating posterior segment disease, eg, blastomycosis in small animals with hydrophilic drugs such as itraconazole.

Ocular dosage forms : Topical ophthalmic drugs are formulated as ointments, suspensions and solutions. Deciding which formulations to be used depends on the several practical considerations.Ocular contact time of ointment is longer than solutions or suspensions,so they are more practical when the owner cannot follow a frequent administration regimen.avoid ointments on penetrating wounds or descemetocele,and prior to intraocular surgery,as their petroleum base elicits severe granulomatous reaction when in direct contact with intraocular tissue. The frequency of topical application depends on disease and formulation.One drop of an antimicrobial solution applied four times daily is usally sufficient in uncomplicated corneal ulcers and bacterial conjunctivitis.When ointment is used a , 5mm strip is applied to the conjunctiva a minimum of three times a day. If more than one drug is involved in the therapeutic regimen,then 3 to 5 minutes should be allowed between application of each medication to avoid dilution or chemical incompatability.antimicrobial therapy is typically continued for seven days or until the ocular infection is resolved.

Antibacterial ocular drug therapy

Topical antibiotics are indicated for the treatment of corneal ulcers, corneal perforations, conjunctivitis,and blepharitis.. Ideal choice of appropriate therapy begins with identification of the organism and its sensitivity. Culture or cytologic examination of material from the affected area is necessary.Minor bacterial conjunctivitis infection may not justify routine culture and may be amendable to initial therapy with broad spectrum antibiotics. Normal ocular flora is predominantly gram positive;a predominance of gram negative organisms is indicative of an abnormal condition.

Chloramphenicol: Broad spectrum, bacteriostatic. Soluble in both water and fat so it penetrates intact cornea with topical administration-thus may be considered for initial treatment of intraocular infections (penetrates the cornea).it is good first choice antimicrobial for corneal ulcers and bacterial conjunctivitis.it is having poor efficacy against gram negative bacteria and pseudomonas spp.Frequency of administration- q4 hours for full therapeutic levels. Toxicity- risk of aplastic anemia

Aminoglycosides: a.. Neomycin: Usually found in combination with other antibiotics. Broad spectrum-bacteriocidal impairs protein synthesis.Frequency of administration-BID-TID. Toxicity- Topical-localized sensitivity; conjunctival irritant.Systemic-ototoxicity-possible head tilt. b. Gentamicin: Broad spectrum bactericidal activity


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including Streptococcus, Staphylococcus, Proteus spp, and Pseudomonas aeruginosa. Effective topically and subconjunctivally for external ocular infections. It is available as solution and ointment because of its chemical characteristics does not readily cross lipid membranes,but readily enters the stroma when the corneal epithelium is damaged. Renal toxicity with concurrent oral therapy, may be toxic to surface epithelium. c. Tobramycin.: Two to four times more effective against Pseudomonas spp. and betalactamase producing staphylococci than gentamicin and effective against gentamicin-resistant microbes.

Polypeptides:a.Bacitracin: Bactericidal, active against gram positive microorganisms. Used in combination with other antibiotics. Poor corneal penetration. b. Polymyxin B: Poor penetration. Bactericidal. Effective mainly against gram-negative bacilli and Pseudomonas spp. Should not be given subconjunctivally.

Cephalosporins: a.Cefazolin: Broad spectrum, first generation cephalosporin.Topical use for gram + cocci resistant to other antimicrobials. Can be administered subconjunctivally-does penetrate intact cornea. Usually diluted to 50 - 100 mg/ml concentration. Mix with artificial tears to a concentration of 33 mg/ml for treatment of meibomitis

Fluoroquinolones: Eg: Ciprofloxacin ,Levofloxacin, Ofloxacin etc. Broad spectrum, active against gram positive and gram negative microorganims. Drug of choice for betalactamase producing staphylococcus and aminoglycoside resistant pseudomonas spp. Generally preferred in corneal, conjunctival, and intraocular infections. Excellent corneal penetration.not effective against streptococci spp. Because of their spectrum of activity these agents should never be used as empirical treatment.

Antiviral ocular drug therapy

The topical antiviral agents are static in action and topically irritating,so frequent dministration is necessary and client compliance and patient tolerance are issues.

Idoxuridine: Frequency of administration is 1 drop every 4hrs until corneal re-epithelialization occurs. Doesnot penetrate the cornea unless the epithelial barrier is broken. Acts by altering the viral replication by substituting for thymidine in the viral DNA chain therefore prolonged or too frequent administration may damage the corneal epithelium and prevent the ulcer healing.

Vidarabine: 3%Ointment-it is poorly lipid soluble,so corneal penetration is minimal unless ulceration is present.Penetrates the cornea better than Idoxuridine. Frequency of


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administration is to apply small amount of ointment 5 times daily until corneal re-epithelialization is complete,the every 12 hours for 7 days.

Trifluridine: 1%Solution-Current drug of choice for feline herpetic keratitis. Antiviral potency reported as over twice that of idoxuridine and 5 times greater than Vidarabine. s.penetrates the intact cornea,and ulceration and uveitis increase its intraocular penetration.; administered 4-8 times/day for 2 days, and reduced over next 2-3 weeks.

Antifungal ocular drug therapy

Topical antifungal agents are used more commonly to treat fungal keratitis in horses than in small animals. Penetration of the intact cornea is poor with all antifungals.

Polyenes : Natamycin : Used against Candida spp. and Fusarium spp. Amphotericin B: Fungistatic. Generally used systemically for fungal endophthalmitis. May be given as an intravitreal injection in mcg dosages.

Imidazoles. Miconazole 1%: the drug of choice for most veterinary fungal keratitis.Tolerated well as subconjunctival injection. 1 ml SID x 3-5 days if tolerated. Treatment frequency of a fungal keratitis may warrant 1 to 4hour treatment intervals.lotions or sprays that contain ethyl alcohol should not be applied to the eye. .Fluconazole is the synthetic triazole, fungistatic.currently drug of choice for topical use, subpalpebral lavage unit, and intracameral (100 μg) injection. Treatment for fungal keratitis may warrant 2 to 4hour treatment intervals.

Anti-inflammatory ocular drug therapy:

Corticosteroids: Subconjunctival injection of corticosteroids provide a greater local anti-inflammatory effect than can be achieved by topical or systemic administration. Posterior segment inflammation requires systemic corticosteroid therapy. In general, topical therapy should be continued two weeks beyond resolution of clinical signs. Local side effects of corticosteroid use include delayed corneal healing, increased corneal collagenase activity, and an increased incidence of bacterial and mycotic keratitis. In addition, topical corticosteroids may result in systemic changes. These include reduced baseline cortisol levels, suppression of the adrenocorticotropic hormone response curve, and altered carbohydrate metabolism. Frequency of administration-dependent on clinical signs and the type of steroid used..

Nonsteroidal anti-inflammatory ocular drugs : Some degree of GI intolerance may occur such as gastroduodenal ulceration and hemorrhage-when NSAIDs are used systemically.


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Aspirin: dog-10 to 20 mg/kg, BID; cat-10 mg/kg, q 48 hours. Carprofen :. May have fewer side effects.Do not use in Labrador retrievers - may cause liver disease. Dosages: 2.2mg/kg BID. Not approved for use in cats. Etodolac :: dog-10 - 15 mg/kg, PO SID. Should not be used in dogs < 5 kg in the horse and dog , although not currently approved for use in dogs.: dog-0.75 to 1.20 mg/kg, IV, SID, not to exceed 2 days. Commonly given 30 minutes prior to surgery to minimize postoperative swelling and inflammation .; Not to be used. In cat. Flurbiprofen: Used topically preoperatively to stabilize the blood-aqueous barrier in inflammation (in diabetes mellitus), decrease production of ocular prostaglandins and maintain pupil size. Used to treat anterior uveitis and in the presence of corneal ulceration.

Ocular topical Anesthetics : To be effective, local anesthetics must have properties similar to drugs that penetrate the cornea. They must be capable of existing in ionized (water-soluble) and nonionized (lipid soluble) forms. Local anesthesia is less effective in inflamed tissue which has more acidic pH than normal. Most topical anesthetics are effective within 30 seconds to 3 minutes to facilitate procedures such as tonometry, corneal and conjunctival scrapings, and subconjunctival injections. Microbial cultures should be taken prior to application of topical anesthetics as inhibition of microorganisms has been attributed to topical anesthetic agents. The agents used are Proparacaine - 0.5%, . Tetracaine - 0.5% to 2%.. Topical anesthetics should not be used on a regular basis with painful eyes because: Animal may scratch off corneal epithelium (feels no pain) and may inhibit mitosis (thus healing) in corneal cells.

a. Osmotic Agents (topical) : 2-5% NaCl (hypertonic saline). Indicated primarily for treatment of severe chronic corneal edema originating from superficial epithelial disruption and for severe cornea bullae formation. Side effect-localized irritation.

b.Tear Film Supplements : Many tear film supplements currently exist today. All are indicated to control keratitis sicca. May provide temporary comfort to corneal irritation resulting from distichia, entropion, or sutures, and as a vehicle for delivery of medications. Tear supplements are available in solution and ointment form and are intended to replace the aqueous or lipid layer of the tear film. Preservative-free products generally recommended.

c.Lacrimogenics: These are drugs potentially capable of stimulating tear secretion.

1. Pilocarpine: May be effective in the rare case of neurogenic KCS. Prescribed as 2 drops of 2% Pilocarpine per 4.5kg body weight added to the food twice daily.


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2. Cyclosporine A 0.2% ointment : Cyclosporine is a potent suppressor of T-cell growth factor and of the cytotoxic T-cell response to this growth factor.

3. Tacrolimus 0.02%, 0.03% ointment or solution : Effective alternative to cyclosporine. T-cell surpressor with a distinct receptor site to cyclosporine.

Anticollagenase/Mucolytic Agents :Collagenase inhibitors are indicated for the treatment of melting corneal ulcers. Acetylcysteine : Diluted from 10 to 20% with artificial tears to a 5 to 8% concentration. Administered every 1 to 4 hours until desired effect is achieved.

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ANTIMICROBIAL THERAPY OF FUNGAL SKIN INFECTIONS

SANTOSH .P SARANGAMATH

The ideal antifungal agent would be one that targets structures present in fungal pathogens that are absent in other eukaryotic cells. The fungal cell wall, a structure that is both unique and essential to fungi, would seem to be such a target. The vast majority of traditional antifungal drugs selectively target ergosterol, an essential component of the fungal cell membrane, with greater affinity than for cholesterol in the mammalian cell membrane. New antifungals have evolved especially azoles and triazoles, which selectively target fungal cell wall with least toxic effect on the body. Compounds that interfere with the synthesis of important fungal cell wall components such as glucan, chitin and mannoproteins have become a focus in the development of new antifungal agents.

Among the cutaneous diseases fungal diseases involving skin and appendages (Dermatophytosis) i.e cutaneous mycosis are commonly encountered as compared to the deep mycosis involving deeper organs of the body. Fungal infections involving the keratinized layers of the skin and its appendages like hoof, nails, and horns caused by group of mycelial keratinophilic fungi are called dermatophytes, The term dermatophytosis indicates the relationship of the disease with dermatophytes as etiological agents. Dermatophytes of dog and cats mainly belong to T. mentagrophytes, M. canis, M. gypseum.

The clinical signs of dermatophytosis are extremely variable; lesions are circular, irregular and vary from scaly patches of alopecia to inflammed to nodular erythematous patch of alopecia. Hairs partially broken/ fallen with bran like scales and crusts, signs like erythema, scales, crusts, thinning of hairs frequently in the form of broken hairs with secondary folliculitis with pruritus are usually observed.

Diagnosis is based on clinical signs, skin scraping examination, examination of hairs by wood’s lamp, and finally by fungal culture on saborauds dextrose agar or dermatophyte test medium. The gold standard for diagnosis is a fungal culture. Wood's light examinations are only screening tools, and direct hair examinations, although inexpensive, are only practical when infected hairs fluoresce on Wood's light examination. Finding these hairs allows rapidly diagnosing the infection and starting therapy. However, if the hairs are not present, this tool is time-consuming and not cost-effective in practice.

Another type of fungal or yeast disease is malassezia dermatitis; the clinical signs of which may be localized or generalized. Involving the external ear canal,


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interdigital skin, ventral neck, axillae, and inguinal region. Affected areas are erythematous, alopecic and often lichenified with or without hyperpigmentation. The lesions surface is often greasy and affected dogs have musty or malodour.

Diagnosis of malassezia dermatitis is by cytological examination or acetate tape impressions, stained with methylene blue which will be examined for the presence of round to oval monopolar budding yeasts. ANTIFUNGAL THERAPY

Dermatophytosis will spontaneously resolve in most healthy cats, but treatment is recommended as the disease is zoonotic and highly contagious. The end point of therapy will go up to the achievement of mycological cure as well as decontaminated environment but not the clinical cure on the animal itself so as to prevent re-infection. A mycological cure is defined as two or three consecutive negative fungal culture results at weekly or biweekly intervals, and treatment should continue until all these negative culture results are obtained.Treatment recommendations:

1) Clipping the coat:. Clipping the coat removes infected hairs , minimizes continued shedding of hair fragments and spores; also makes topical therapy application easier and allows for more thorough penetration of topical antifungal agent. In addition, clipping helps shorten the duration of therapy and ultimately decreases the cost of treatment. It may temporarily worsen the infection by causing microtrauma to the skin. Also, it may result in environmental contamination if appropriate efforts to capture infected hairs and spores are not taken.Dipping is required in pets that live with children and elderly or immunosuppressed people, as well as in shorthaired breeds with generalized lesions and in longhaired cats regardless of lesion severity

2) Administering topical antifungal therapy twice weekly: The most effective topical antifungal agents are lime-sulfur, enilconazole, and miconazole. Lime-sulfur is suitable for sole therapy; combined topical and systemic therapy is the treatment of choice. It is important to note that fungicidal efficacy does not imply that one application of any of these products is 100% fungicidal. These products are fungicidal with repeated application. Lime-sulfur (8 oz/gal water ) has been used as the topical therapy of choice, and in some cases as the sole therapy. Enilconazole topical solution 10% concentrated solution (100 mg/ml) is effective against M. canis. It is associated with hypersalivation, anorexia, weight loss, emesis, idiopathic muscle weakness, and slightly elevated serum alanine aminotransferase activity. Miconazole, as a sole therapeutic agent or in combination with chlorhexidine, the shampoo needing a contact time of 10 minutes for the therapeutic effect. This product can be irritating to the eyes


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and can cause skin irritation. Other dips like povidone-iodine, chlorhexidine have been consistently found to be ineffective against M. canis.

3) Administer systemic antifungal therapy - Systemic therapy is the treatment of choice for feline dermatophytosis. The efficacy of griseofulvin, itraconazole, terbinafine hydrochloride, and lufenuron alone or in combination with other therapies showed that griseofulvin, itraconazole and terbinafine are most effective agents Griseofulvin : is fungistatic that inhibits nucleic acid synthesis and cell mitosis metaphase by interfering with function of spindle microtubules.Its absorption is enhanced by administering it with fatty meal or by using formulations containing polyethylene glycol. It is teratogenic and should not be given to pregnant animals. also may interfere with spermatogenesis, so it is best avoided in breeding males. Anorexia, vomiting, and diarrhea are seen, which can be managed by dividing the dose into twice-daily administrations. Bone marrow suppression and neurologic side effects are most likely idiosyncratic reactions. Do not use griseofulvin in cats that have feline immunodeficiency virus (FIV) infections, because severe neutropenic reactions have been seen in cats with FIV.

The most commonly used dosing regimen is daily: griseofulvin microsize at a dosage of 25 to 50 mg/kg given orally once a day or divided twice a day; griseofulvin ultramicrosize at a dosage of 5 to 10 mg/kg given orally once a day or divided twice a day. Higher doses may be needed in refractory cases. Ketoconazole : is administered at the rate of 5 to 10 mg/kg b.wt. orally once daily for 21 days. Available in the form of tablets or shampoos, this will be useful for topical as well as systemic use. This drug is also tolerated in dogs, but long term therapy may involve the potential risk of causing liver as well as renal damage. Itraconazole : is a triazole derivative that alters fungal cell membrane permeability by inhibiting ergosterol synthesis; is fungistatic at low doses, fungicidal at higher doses.It is well-tolerated in cats and dogs, with vomiton, anorexia being most common adverse effects a) Daily dosing: 10 mg/kg orally once a day; b) Combined continuous/pulse therapy: 10 mg/kg given orally once day for 28 days and then on an alternate week regimen (one week off and one week on) . c) Short-term cycle therapy: 10 mg/kg given orally once a day for 15 days, followed by fungal cultures 10 -15 days later, this cycle is repeated until the cure. . It has replaced griseofulvin as the drug of choice for treating dermatophytosisTerbinafine : is the newest systemic antifungal agent to be used in treating dermatophytosis. It is an allylamine antifungal agent that suppresses the biosynthesis of ergosterol by inhibiting the fungal enzyme squalene epoxidase.31 The drug is considered to be fungicidal against dermatophytes.


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Fluconazole : Fluconazole is also hepatotoxic and nephrotoxic, but its elimination from the stratum corneum is approximately 2 to 3 times slower than the plasma. Also, due to its rapidity in accumulation the skin after oral ingestion makes the drug to be administered once a week or daily for 2 to 4 weeks will help in improvement of the condition. This is administered safely at a dosage of 5 mg/kg/day which is well tolerated in both dogs and cats. Lufenuron : is a benzoylphenylurea drug that disrupts chitin synthesis and is used for flea control. Chitin is a critical component of the outer cell wall of fungi, and it is possible that drugs that disrupt chitin synthesis might also have antifungal activity. One report suggested it is useful in treating variety of fungal diseases including dermatophytosis. But still, lufenuron has been a widely debated topic in veterinary practice. 4) Considering Fungal vaccines: Intense interest in developing a fungal vaccine to prevent and possibly treat dermatophytosis continues. Fungal vaccines as sole therapy are not effective in treating dermatophytosis, but they may be a useful adjuvant therapy when combined with appropriate topical and systemic therapy and environmental control or a practical alternative to topical therapy in situations in which topical therapy cannot be used.

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CLINICAL PHARMACOLOGY OF MISCELLANEOUS CLASS OF ANTIBACTERIALS

GANESH. B. KUMBHAR

The following is a brief description of various miscellaneous class of antibacterials

Polymyxins : Two members- .Colistin (Polymyxin E)(Available as sulphates for oral and topical use) and Polymyxin B. The spectrum is gram negative bactericidal. They are commonly used topically due to their systemic toxicity(nephrotoxic, neurotoxic, neuromuscular blocking effects) . They are synergestic t with sulfonamide and trimethoprim against variety of enterobacteriaceae.colistin is synergestic with rifampin (In vivo) against multidrug resistant P.aeruginosa and is employed in coliform mastitis.

Vancomycin-: The spectrum is gram positive aerobic cocci and bacilli bactericidal. It is used against staphylococcal bone and soft tissue.infections in in dog.Dogs-3 mg/kg PO, 2 to3 times daily & 10-20 mg/kg IV , 3 to 4 times daily. Ototoxicity and nephrotoxicity, and thrombophlebitis are the adverse effects. Its administration along with aminoglcosides should be avoided as it may potentiate the toxicity of aminoglycosides.

Spectinimycin: is an aminicyclitol antibiotic, bacteristatic against many gram nagative bacteria, mycoplasmas.. It is used in dog cat, horse pigs for the treatment of enteric & respiratory infections.. Dogs & cats- 5-10 mg/kg IM, 2 times daily.; Cattle- 8-12 mg/kg IM, 3 times daily; Calves- 20-30 mg/kg IM, once times daily.; Horses- 20 mg/kg IM, 3 times daily.; Pigs-10 mg/kg PO, 2 times daily.No significant adverse effects have been obseveved (by parenteral route). On high doses may produce neuromuscular blockade. Concurrent use along with tetracyclines or chloramphenicol may produce antagonistic effect.

Rifampicin: is a semisynthetic bactericidal for both intracellular & extracellular organisms. High activity against gram positive bacteia & mycobacteria also against some gram negative organisms like Brucella, shows activity against yeast & fungal microorganisms when combined with amphoterecin B.It is used for treating Rhodococcus equi and other bacterial infections in Foals- 5 mg/kg PO, 2 times daily (in combination with erythromycin 25 mg/kg, PO, 3 times daily.; Dogs & Cats - 5 mg/kg PO, 1- 2 times daily.; For CNS fungal infections; Dogs & Cats-10-20 mg/kg PO,


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3 times daily in combination with amphotericin B & flucytocine. Hepatotoxicity in animals with pre-exsiting liver diseases. In horse ( IV ) CNS depression, sweating, heamolysis anorexia. In few cases partial immunosuppression of lymphocytes. GIT disturbances – nausea, vomition, anorexia, abdominal cramps, diarrhea & hypersensitivity reactions are the avderse ffects. As a potent inducer of hepatic microsomal enzymes it may enhances elimination half life of several drugS viz. digitalis, coticosteroides etc.Synegestic effect with amphotericin B against some fungi.

Furazolidone is bacteriostatic , broad spectrum activity ( both gram positive & negative organisms).Also active against giardia toxoplasmas. Coccidia & histomonas. It is used for enteric infectios: Dogs – 2.2 mg/kg PO, 3 times daily for 7 days.; Cats- 4 mg/kg PO, 2 times daily for 7-10 days.; Horses- 4 mg/kg PO, 3times daily; GIT disturbances – inappetence, nausea, vomition, anorexia, abdominal cramps, diarrhea. And CNS effects- tremors, ataxia, convulsions, visual impirement. May be seen

Fusidic acid (Sodium fusidate) : is bacteriostatic effective only on gram-positive bacteria such as Staph. and Corynebacterium. It is used topically for minor local skin infections, wounds. It should not be used with quinolones, with which they are antagonistic

Methanamine (Hexamine) : a urinary antiseptic have antibacterial activity is due to release of formaldehyde in water. It is bacteriostatic agent but becomes cidal in acidic urine. Active against both gram positive & negative organisms.Methamine mandalate - Dogs – 10-20 mg/kg PO, 1-2 times daily.GI disturbances (nausea, vomiting & diarrhea), gastritis, painful & frequent micturation, albinuria, hamaturia, cystitis, CNS symptoms produced occasionally.Use of urinary alkanizing drugs e.g. Na bicarbonate, carbonic anhydrase inhibitors may antagonise its action.Sulphonamides combine chemically with hexamine in urine leads to antagonism.Concurrent use of urinary acidifires such as ascorbic acid, methionine enhances its action.

Tiamulin: Is a semi-synthetic derivative of pleuromutilin. It is typically available for oral use as the tiamulin base or the hydrogen fumarate salt. Tiamuli nHCl as injectable.. It is bacteriostatic against gram positive pathogens including Mycoplasma spp., Spirochaetes (e.g. Treponema) and obligate anaerobes. It is useed for enteric pneumonia complex-Pigs-15 mg/kg IM, once daily for 3 days & 8.8 mg/kg PO, 3-5days

In chickens and turkeys-reductions in water intake. Rarely, redness of the skin, primarily over the ham, may occur in which case it is recommended that medication is


http://en.wikipedia.org/wiki/Corynebacterium

http://en.wikipedia.org/wiki/Staphylococcus

http://en.wikipedia.org/wiki/Gram-positive

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discontinued and the affected animals moved to clean pens. In oral overdose tiamulin may cause transient salivation, vomiting and CNS depressions (calming effect), in which case the drug should be removed and affected animals should be treated symptomatically and supportively if necessary. Tiamulin should not be administered to animals having access to feeds containing polyether ionophore antibiotics (monensin, lasalocid, narasin, salinomycin, and maduramycin) as adverse reactions may occur. Concomitant use with other drugs that bind to the 50S ribosomal sub-unit (e.g. lincomycin, erythromycin, and tylosin) may lead to decreased efficacy as a result of competition at the active site.

Virginiamycin:is bactericidal against a wide range of organisms including staphylococci, streptococci and enterococci. It is commonly used as feed additive Overdose may result in gastric disturbances, dyspnea, emesis, tremor and ataxia.

Novobiocin: Spectrum mainly gram positive; Most gram negative resistant; but some Haemophilus sp., Neisseria sp., and Proteus sp. may be susceptible.Dogs: 10 mg/kg q8h PO; Cattle:For treatment of mastitis in dry cows:Infuse contents of one syringe into each quarter at the time of drying off; not later than 30 days prior to calving. For treatment of mastitis in lactating cows-using the penicillin/novobiocinproduct. Fever, GI disturbances , rashes and blood dyscrasias after systemic use. It acts similarly to probenecid by blocking the tubular transport of drugs. thus the elimination rates of drugs excreted in this manner (e.g., penicillins, cephalosporins) could be decreased and half-lives prolonged.

Mupirocin: gram positive bactericidal spectrum; is used topically for staphylococcal and streptocococcal skin infections, wounds, burns etc

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HANDLING OF VETEROLEGAL POISONING CASES

B. KALAKUMAR

Generally every veterinarian is encountered with two types of cases in poisoning of farm animals. Accidental and Malicious poisoning. The necropsy of the animals and the rapid diagnosis is helpful in the treatment of other affected animals in case of accidental poisoning. In case of malicious poisoning, which may turn up into medico legal case, the identification of poison is a must to establish the cause of death. In all poisonous cases, chemical analysis of the biological specimens is essential to know the cause of death or illness. Therefore, every veterinarian should know the salient points in collection and despatch of toxicological specimens to a laboratory.

History of the case is of great importance in the diagnosis of poisoning. This includes the number of animals in the farm, number of affected, method of feeding, regularity of feeding, recent changes in the rations or attendants, whether pastures have been sprayed with pesticides or fertilizers, if rodenticides have been used and remnants of the bait removed and disposed properly, storage of poisonous substances etc. Inspection of the surroundings for empty pesticides or paint containers that are not really empty, presence of poisonous plants in the farm environment. Also, the possibility of industrial effluents coming in contact with grazing/watering sources should be given thought of.

POST MORTEM: Necropsy by routine procedure is to be performed as soon as possible after the death of animal. Examine the animal externally and note incisions (for sui poisoning, snake bite etc.,) on the skin or mucous membranes. Examine the oral cavity for corrosive lesions (acids/alkali) or changes in colour of mucous membrane (nitrate, co, cyanide poisoning). As most of the toxins gain entry through gut, examination of gut mucosa, the contents, their smell, colour and pH (acids, alkali, urea) is a valuable guide in diagnosing toxicoses. Poisoning by salts of heavy metals results in significant post mortem lesions but poisoning by alkaloids like strychnine produces very feeble lesions.

The natural orifices, sub-cutaneous fat tissue, muscles, bones and teeth (in fluorine poisoning), body cavities, and internal organs should be examined. The stomach should be punctured rather than cut open for organoleptic examination to note the character of smell. Puncture ensures greater accuracy and a longer time smell.


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Some of the poisons which emit characteristic smell are: bitter almond -hydrogen cyanide poisoning, garlic odour - phosphorus poisoning, rotten garlic or horse radish smell - selenium, tobacco odour –nicotine, acetylene odour - zinc phosphide and ammoniacal odour- urea.

Check the pH of the stomach contents by pH paper. Any variation in the normal pH of the sps. being examined indicates abnormality. (In urea poisoning-alkaline pH is observed in rumen liquor due to release of ammonia).

The colour of stomach contents also indicates the cause of poisoning. Copper salts impart a greenish blue colour whereas picric and nitric acid impart yellow colour to the contents. The contents of the stomach vary from traces to flakes of paints or lead objects, grains or baits, seeds etc., like wise small and large intestine should be examined. Blood should be examined for its colour and clotting characters. Cyanide poisoning imparts cherry red colour, arsenic imparts rose red colour and nitrate poisoning turns blood brown in colour. In abrus and cyanide poisoning-blood remains fluid after death.Examination of other visceral organs should be done in relation to their size, colour etc. eg: - spleen size is decreased and colour is changed to dark brown or black in copper poisoning and spleen size is increased in T-2 mycotoxicoses.Lymph nodes are swollen, haemorrhagic, oedematous and dark upon exposure to radiation. Bone marrow becomes pale and gelatinous with yellowish tint.The description of morphological changes should be noted clearly and absence of changes should be notified. The most important lesions found should be underlined.

In case of small animals (poultry, small dogs, lab animals) the cadavers are sent as it is, in case of large animals the stomach contents are collected from the vicinity of patho anatomic changes in the gastric mucosa. If there are no changes a representative sample is collected, but in medium sized animals the stomach tied at oesophageal and duodenal end, intestine tied at both ends and bladder with tied ends is sent separately.

Collection of samples: A successful toxicological investigation requires appropriate specimens, history and clinical signs, necropsy lesions and circumstantial evidences. All the specimens are to be taken in separate containers (polythene jars/covers), securely tied, properly labelled with particulars of date, case No., organs collected, species, name of preservative used etc. A sample of the preservative used, brief history of the case along with treatment given particulars should be sent. It is always preferable to send the specimens through a special messenger. In medico legal cases, the specimens should be sealed in the presence of a witness. The quantity for the kind of sample to be sent is as follows.


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Wholeblood:10-20ml;Serum:10-20ml;Milk:50-100ml;Urine:50-100 ml;Water: 200 ml; Faeces : 50 g ; Feed : 0.5 - 1kg.

Mode of preservation : 1. Ice for about 72 hrs. 2. Alcohol (95% ethyl alcohol) 1 ml/g of tissue is the ideal preservative for toxicological specimens. Formaline should never be used as it hardens the tissue without giving scope for scraping and interferes in the analysis. Blood and serum should be refrigerated and never frozen. A sample of the preservative used should be sent. It is always better to have a duplicate sample stored properly in a refrigerator for future reference Sample for analysis should include a suspected source material; often gut contents, so that ingestion of suspected material can be proved. Secondly, a sample of tissue (depending on tissue affinity of the suspected poison) must be included, to prove that absorption of the poison has occurred. It is always advisable to include a sample of liver to confirm absorption of orally ingested poison. In survival cases the following materials may be sent for analysis:Stomach wash, ruminal contents, vomitus, blood, urine, saliva, dung, water and feed, suspected forage/ poisonous plant/s is the ideal samples for laboratory analysis. Most xenobiotics are ingested. Therefore, one of the unique advantages of analyzing gastrointestinal contents is that qualitative tests can be easily carried out in order to determine the animal has oral access or not. Guidelines for submitting specimen for toxicological examination is listed in Table 1.

Table 1: Toxicological specimens for laboratory examination

Sl.No. Suspected poison

Specimen required Remarks

1. HCN/Cyanide Forage / ingesta, whole blood

Liver

Rush samples frozen in air tight bottle to laboratory

GIT/ Stomach contents in 1% mercuric chloride is ideal

2. Organochlorine pesticides/

Chlorinated hydrocarbons

Cerebrum, fat, liver, kidney, ingesta

Use only glass containers,

Avoid aluminum foil for wrapping specimens

3. Organophosphates &Carbamates

Feed, ingesta, liver, urine -

4. Znic phosphide Liver, kidney, gastric contents

-

5. Nitrate/nitrite Forage, ingesta, body Ingesta in chloroform or


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fluids, Serum . Ocular fluid water samples

formalin filled air tight container

6. Oxalates Fresh forage, kidneys Fix in formalin

7. Ammonia/Urea Whole blood or serum, urine Rumen contents

Frozen / 1-2 drops of saturated solution of mercuric chloride

8. Heavy metals(Lead, Mercury)

Kidney, whole blood, liver and urine

Heparinized, do not use EDTA

9. Mycotoxins Forages, feed sample, liver, kidney, brain

Use airtight containers or plastic bags. Cloth bags for dry feeds

Note: Always send a sample of preservative if used in separate container with proper

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GENERAL LINE OF TREATMENT OF POISONINGSM. VIJAY KUMAR

In majority of cases of poisonings, treatment with an antidote is not possible, instead prompt medical intervention to improve the condition of the animal can ensure its survival. These practices focus on promoting the removal of the poison or neutralizing it, whilst maintaining the vital functions of the animal.

Decontamination of the skin: Some substance (hydrocarbons, acids, alkalis, agrochemicals, etc.) may, as a result of an accident or a spillage, contaminate the feathers or fur of animals. In general it is important that in such circumstances the following are undertaken:

Epidermal structures (wings, nails, claws, feathers, fur) should be cleaned with the greatest care, paying particular attention to areas such as the ears, between toes, etc.

Avoid licking and ingestion of the poison, and to limit cutaneous absorption.Use soapy water (preferably a soap with a low pH), rinsing repeatedly with copious tap water

Dry carefully and thoroughly (e.g. with a hair dryer)The following must never be used: organic solvents (alcohol, white spirit, etc.) or oily substances which may actually increase percutaneous absorption of the toxin.

Do not rub the area vigorously; cleaning and drying must be gentle but thorough Gastric emptying: Emetics:Use emetics if ingestion has taken place within the preceding 2-3 hours. Never induce vomiting in following circumstances: If caustics or hydrocarbons have been ingested; If the condition of the animal does not allow such treatment, specifically if the patient is presenting with convulsions (unless controlled), coma or severe respiratory difficulties; this avoids any secondary complications due to aspiration.; in pregnancy and ingestion of slow releasing drug formulations. Apomorphine: a central depressive effect and the possibility of cardio-toxicity (arrhythmias) -Dogs: 0.05-0.1 mg/kg s.c or im; contraindicated in cats or pigs; Xylazine: acts within 10-20 minutes; 0.25-0.5 ml of a 2% sol.,s.c.Ipecachuana (10% syrup) for dogs and cats: Acts in 20-30 minutes; orally, 10-20 ml for a dog, 2-5 ml for a cat administered in a phased manner. Alternatives: Sodium chloride (salt), p.o, 1-3 teaspoons in warm water; Hydrogen peroxide, by mouth, 1 ml/kg; Copper sulphate is not recommended as it is an irritant and facilitates the absorption of poisons. Preferred in pigs (4% solution, max: 60ml,p.o)Gastric lavage in dogs is indicated: if ingestion has taken place in the preceding 2-4 hours and on anaesthetized animals with endotracheal intubation. Use 10 ml/kg of an


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isotonic solution of sodium chloride (occasionally sodium bicarbonate); repeat the procedure until the washout fluids is clear. Emergency gastrotomy with manual emptying may be necessary in some cases of plant poisoning or indigestible materials (such as plastic, polyurethane foam).

Purgatives: Never use irritant purgatives and oil-based purgatives as they facilitate absorption. Sodium sulphate, magnesium sulphate are preferred; PO, as enema, using solutions of various strengths (make up to 20%):Small animals : 2-25 g, Large animals: 100-200 g (max: 300 – 400g); Liquid paraffin (mineral oil), by mouth:Dogs: 5-15ml, Cats: 2-6ml

Diuretics: Increase glomerular filtration by instituting a forced diuresis or osmotic diuresis: 5% glucose solution, by slow IV infusion: Large animals: 2-5 ml/kg per 24h, Small animals: 5-20 ml/kg per 24hr; 10% glucose solution, by slow IV infusion: Large animals: 0.5-1 ml/kg per 24 h, Small animals: 1-2 ml/kg per 24 hr; 10% mannitol solution, by IV infusion:Large animals: 1-2 ml/kg per 24 h, Small animals: 2 ml/kg per 24 hr; :Frusemide (im or iv), Large animals: 0.5-1 mg/kg, Small animals: 2.5-5 mg/kgReduce tubular reabsorption by modifying urinary pH.: Forced acid diuresis to eliminate weak bases can be done by:Ammonium chloride, PO: Large animals: 20-40 g, Small animals: 2-5 g; Arginine chloride, im, or iv-Large animals: 7-10 g, Small animals: 0.1-0.2 g/kg; Ascorbic acid, iv, all species: 40 mg/kg

Forced alkaline diuresis to eliminate weak acids: Sodium bicarbonate, 1.4%w/v, iv infusion, Large animals: 2-4 ml/kg per 24 hr; Small animals: by regular monitoring of the acid – base balance (number of ml to perfuse = base deficit (in mmol) x 0.6 x body wt in (kg)ringer’s lactate, IV: all species: 5-10 ml/kg per hr; Use a diuretic such as acetazolamide

Dialysis: In cats and dogs peritoneal dialysis with an appropriate dialysate 20-25 ml/kg is suggested. Repeat the procedure several Times as necessary. Very effective in case of renal failure/renotoxicity. Commercial preparations meant for human use can be employed

Neutralization of poisons with in the gastrointestinal tract

Adsorbents Activated vegetable charcoal (fine medicinal charcoal).-the most effective and most highly polyvalent adsorbents. They can be administered preferably as a suspension in water, several minutes to 24 hours after ingestion, if possible before any emetic. Large animals: 250-500 g, Small animals: 5-50 g; Other adsorbents:


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Magnesium oxide (magnesia), Kaolin, Universal antidote (vegetable charcoal 10g+ magnesia 5g + kaolin 5g + tannin 5g with water added up to 200 ml)

General chemical antidotes: Substances which form a complex or insoluble precipitate with poisons and neutralize them in the gastrointestinal tract. The effects are often limited and debatable. This category includes: Water-containing albumens (proteins which are capable of forming insoluble complexes with heavy metals and which neutralize acids and bases); Tannins (these precipitate heavy metals aluminum, lead, silver and some alkaloids) ; Less useful against copper, mercury and nicotine), Lugol’s iodine can partially precipitate heavy metals like Pb, Hg, Ag and Strychnine. and Ferric hydrate .

Milk is commonly believed to act as the best general antidote; in fact, milk promotes the absorption of liposoluble poisons. A cardinal rule, therefore, is “never administer milk”.

Additional treatment measures: vary according to the symptoms observed, important agents used to support vital functions (respiration and circulation) are: Doxapram: A respiratory stimulant, Dog/Cat: 2 mg/kg, iv, repeat as required ; Caffeine and theophylline: Cardiovascular and respiratory stimulants, with diuretic action. Dosage: 100-250 mg iv, im, hypodermally or as required and Nikethamide:. Dog: 22-44 mg/kg, im, iv.

Rational Use of Charcoal : Charcoal is ineffective against cyanide. It can adsorb vitamins/minerals and continued use may prove to be harmful. Make slurry of the activated charcoal using lukewarm water. 2-8 g/kg should be given in a concentration of 1g/5-10ml water by a stomach tube using either a funnel or a large syringe. Administer a cathartic (sodium sulphate or magnesium sulphate) 30 minutes after the administration of charcoal. In pet animals this technique can be modified if the charcoal is used in conjunction with an emetic or gastric lavage (Normal saline: 10 ml/kg) with endotracheal intubation.

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CLINICAL MANAGEMENT OF POISONINGS OF VETERINARY IMPORTANCE

M.VIJAY KUMAR

In veterinary field toxicities are often found as a result of ingestion of poisonous substances while grazing or through water. Suspicion of poisoning is also aroused when illness occurs in a number of previously healthy animals, all affected at a same time, sharing the same signs, necropsy findings, to the same degree of severity. Poisoning in most occasions is accidental in farm animals, but may occasionally be deliberate .

SOURCE OF POISONINGS

1. Insecticides:Insecticides are the major source of poisonings in livestock.. Most of the insecticides are basically ‘neurotoxic’, hence they may share some of the clinical signs, Insecticides can be classified in to following categories: 1. Organochlorines: Eg: Aldrin, Endosulfan, Lindane, Dicofol etc 2. Oraganophosphates. Eg: Acephate, Malathion, Parathion, Methyl parathion, Dimethoate, Phosphamidon,, Chlorpyriphos, Chlorfenvinphos, Monocrotophos etc 3. Carbamates. Eg: Carbaryl, Metacil, Dimetan, Pyramat etc. 4. Pyrethroids (Synthetic): Deltamethrin, Cypermethrin,Permethrin, Allerthrin etc. 5. Miscellaneous: Chloro-nicotinic acid (nicotine), Arsenic compounds,Captan

Organochlorines: By virtue of their high lipid solubility these agents can enter the neuronal membrane with ease and therefore interfere with normal functioning of the nerve membrane sodium channel. The clinical signs of toxicity can be broadly categorized in to:

Behavioural signs - Anxiety, aggressiveness, abnormal posturing, maniac symptoms like jumping over inanimate objects, wall climbing etc. Neurological signs – Hypersensitive to external stimuli, spasm and twitching of fre-and hind quarter muscles, fascicualtions of facial and eye lid muscles and variations in body temperature (subnormal temperature to hyperthermia, up to 116F). Autonomic effects: Marked salivation (normally thick/ sticky saliva), Mydriasis, frequent urination, defecation and lacrimation.

Organophosphates: Clinical essentially appears as a result of irreversible inhibition of AChE, causing accumulation of acetylcholine in the neuro-muscular junction leading to


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‘spastic paralyses. The cause of death is due to respiratory collapse. Muscaranic signs (miosis, watery, drooling saliva, urination, colic and /or defecation, lacrimation are the common signs followed by nicotinic effects (muscle fasciculations, tremors) and C.N.S effects( ataxia, convulsions and later depression of respiratory and circulatory centers). Hypotension, bradycardia and dyspnoea are observed in poisoned animals.

Carbamates: The inhibition of AChE enzyme by carbamates is ‘reversible’, therefore, on most occasions animals recovers on own unless ingested large quantity of pesticide.

Synthetic pyrethroids: Although these compound process low insect: mammalian toxicity ratio, treatment of poisoned animals may be a difficult task probably because of multiple mechanisms involved in toxicity and variations among pyrethroid class (type-I & type-II). Hypersalivation, lacrimation, mucoid nasal discharge, excitement, in-coordination, extension of limbs are observed in deltamethrin toxicity in buffalo calves. Few pyrethroids also cause contact dermatitis.

2. Rodenticides:.

Anticoagulant rodenticides: These include warfarin (less used now a days) and second generation anticoagulant rodenticides viz: Bromadiolone , brodifucoum. The main source of poisoning is the ingestion of residues of the rodenticides or baits intended for killing rodents.. The poor coagulation mechanism cause massive internal haemorrhages over aperiod of time. Normally after period of about 2-5 days clinical signs appears and these include anorexia, pulmonary coughing (epitaxis, dyspnoea),hypothermia, haematuria, stiffness of hind quarters and sudden death. Internal haemorrhage, blood in the GIT(gastroenteritis), haemopericardium and menigeal/cerebral bleeding and haemorrhages in joints are the pathological lesions one can observe during necropsy. The affected animals should be shifted to quiet and warm place and the line of treatment include Vitamin-K1 in physiological saline (Vitamin-K3

not recommended) and cardio-vascular support.

Zinc phosphide/ Aluminium phosphide: It is one of the cheapest and quite effective rodenticide. Monogastric species are more sensitive rather than ruminants. Clinical signs include anorexia, lethargy, abdominal pain, bloat (in ruminants), deep respiration, ataxia, prostration and dyspnoea, gasping, convulsions and death. Post-mortum lesions include pulmonary congestion, edema, sub-pleural haemorrhages, congestion of liver and kidneys. Acetylene odour may be detected in stomach. No specific treatment is possible, however symptomatic and supportive care maybe given. Gastric lavage with


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5% Sodium bicarbonate, Calcium boro-gluconate injection, anticonvulsants and measures to prevent shock can be undertaken as a life saving measure.

3. Herbicides & Fungicides:Dinitro-compounds: Dinitrophenol, DNP; dinitro-orthro cresol, DNOC); are some of the commonly used as herbicides. Accidental ingestion of foliage sprayed with these compounds may lead to toxicity in ruminants. These compounds induce methaemoglobinemia (intravascular haemolysis),hyperthermia, dark coloured blood and gastroenteritis. Rapid onset of rigor mortis, yellowish-green coloured tissues/urine may be recorded during post mortem examination.

Zeneb & Thiram: Zeneb (Zinc-ethylene dithiocarbonate) and Thiram (Tetra-methyl thiuron sulfide) are the two most commonly used fungicides in agricultural practice. Although acute poisonings is less likely to observe in field, chronic toxicities may get unnoticed. Zeneb can induce thyroid hyperplasia, hypothyroidism, degenerative changes in myocardial, skeletal tissues and depletion of testicular germ cells. Thiram exposure may cause conjunctivitis, rhinitis, bronchitis, abortion (ewes) and teratogenic effects.

4. Hydrocyanic acid (HCN) /Cyanide:The most prevalent form of HCN poisoning in livestock is caused by various cyanogeneetc plants capable of producing hydrocyanic acid. Such plants contain cyanogenetic glucocides (dhurrin in sorghum, amygdalin in bitter almond etc.) which hydrolyzed in to HCN in ruminants. Wilted, drought affected, injured (chopping, rinsing etc.) plants are more dangerous than fresh plants because of their preformed HCN. Any plants possessing 20mg HCN per 100gm (wet wt.) may serve as potential source of HCN poisoning. Other source of cyanide poisonings are: industrial grade Na/K and calcium cyanide (also fertilizer) and effluents from vicinity of electroplating/metal coating industries workshop.

Hyperoxygention of blood would lead to cherry red/ bright red colour of venous blood . Intoxicated animals shows salivation (frothy), bradypnoea, mydriasis, ataxia,tremors, epileptiform scizure, cardiac arrhythmia and clonic-tonic convulsions. Invariably loss of conscious, coma and death with several jerky and convulsive movements if poisoned animals are not attended with in a with in 1 hour after the appearance of clinical initial signs. Odour of the breath is ammonical/ bitter almond due to benzaldehyde production (often bloating, regurgitation is observed). Opening of rumen during post-mortem examination impart similar odour. Animals suspected for HCN poisoning must be differentiated from nitrite and other sr milar agents before initiating antidote therapy . In addition to antidotes, per oral administration of Cobalt chloride(10 mg/kg)and glucose is also indicated.


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5. Nitrate/Nitrite:Drought is one of the root causes of nitrite toxicity in cattle/buffaloes. Nitrates are reduced to nitrite in ruminates. Otherwise, pigs are most sensitive species for nitrate toxicity. Contamination of drinking water with sewage, several plants species (Amarantus sps,Palak etc.), plants grown in highly acidic soil, water logging and rich nitrated fields / effluents zone, deep well water or pond water originated from leaching of top soil (after -nitrate fertilizer application) are some of the common source of nitrite poisonings. Water soaked/entry of moisture may also render paddy hays/ corn in to nitrite rich within 18-22 hours. Frequent application of fields with non-toxic weed killer 2,4-D and nitratic fertilizer favour accumulation of nitrtes in plants. Any forage that contains over 1.5% nitrate (expressed as pot. nitrite) is considered relatively unsafe for livestock and should be fed with extreme caution. Nitrite ions induce meth-haemoglobenaemia as well as marked vasodilatation. Clinical signs include cyanosis, staggering gait, muscular tremors, rapid pulse, dyspnoea and dilated pupil. Opisthotonus, polyurea, chocolate brown colour of the blood and cyanotic mucous membranes are the characteristic features of nitrite toxicity. Untreated animals die with out a struggle. Reducing agents like Methylene blue or Ascorbic acid are the antidotes (see table 2 for details). Mineral oil or mucilaginous substances and diluted vinegar (4-5 lt. in cold water, per os) must be administered to counter GI irritation and further reduction of nitrates in the rumen respectively. Cardiovascular support (vasoconstrictor); and stimulants to counter prostration.

6. Poisonous plants: Toxicities/ death due to ingestion of poisonous plants are also often being the etiology of poisoning in the farm animals. Commonly with plant poisonings there are perplexing epidemiological features. For example, animal already grazing in the dangerous field are often unaffected while recently introduced may be poisoned. Drought, starved, ailing from pica, hungry, ravenous animals, curiously excited animals (often do not eat), and young animals less discriminate plants with different texture (attraction). Poisonous plants often show geographical limitations in their distribution, particularly industrial enterprises may create ‘poison hazard’ in local areas (Ipomea carnea, Amaranthus spinosus) and certain agricultural practices / soil type may also pose toxicities (eg. Nitrite, Selenium). Severe drought followed by rain/moisture/humid atmosphere favour accumulation nitrite in many plants. Similarly re-emergence of fresh leaves following harvesting also contains dangerous levels of HCN.

Essentially the source of plant poisoning can be classified into: a. naturally occurring b. Commercial crops/byproducts and c. Conventional and non-conventional fodders. Immature sorghum, maize, flax (linseed); Manihot esculenta (tapioca) newly emerging


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bamboo shoots and rubber leaves are the common source of HCN poisonings. Accidental ingestion of castor bean, rotten beat roots, adult nicotine leaves,Mimosa invisa (used to increase nitrogen fixation in soil) may become fatal.. Plants or foliage belonging to Brassicaceae sps.(Cruciferae) family i.e kale, rape,turnip, cabbage,reddish plants and mustard seeds or meal may elicit severe toxicities in animals when fed /ingested large quantity due to the presence of glucosinolates in such plants..Digestive disturbance(enteritis),goiter polioencephalomalacia (rape blindness), pulmonary emphysema are the sequelae. Bloat, photosensitization is also observed. Affected animals are to be treated symptomatically.

Feeding of urea treated straws in excess/or fed to un-acclimatized animals may lead to urea poisoning, long term feeding of subabul may lead to hypothyrodism and feeding of fungus infested straws (sorghum, paddy or leguminous fodders) may pose threat of mycotoxicosis when fed relatively for a long period. Ficus tsjhela (Karnataka-Kerala boarder, Western Ghats); Acccia leucopholea (HCN), Amaranthus spinosus (nitrite); Jatropa curcus (purging nut); Crotalaria juncia (hepatotoxic pyrrolizidine alkaloids: monocrotaline);Flax(linseed, HCN); Ipomea carnea (LSD alkaloid like effects, also source of nitrite and cause photosensitization). Strychnous nux-vomica (coastal Karnataka); Abrus precatorius (Gulaganji); marking nut, Calitropis gigantica (yakka), croton oil and Yellow oleander are also some of the plant source of accidental poisonings and/or recorded in case of malicious poisoning in animals.

Antidotes and supportive treatments for common poisonings in large animals

Poison/toxicity Antidote/ treatment Dosage and method of treatment

Hydrocyanic acid (HCN) /Cyanide

Sodium nitrite followed by Sodium thiosulfate

Administer 1% sodium nitrite @ 15-25mg/kg,i.v followed by 25% sodium thiosulphate @ 1.25gm , slow i.v Na nitrite + Na thiosulfateCattle: 3gm + 15gm in 20ml water, s.c; Sheep/goats: 2gm+5gm in 15ml water,s.c. Cobalt chloride @10.2 mg/kg, per os; Approx. 4 lt. vinegar in 10-20lt. cold water; A large dose of vitamin B12 and anticonvulsants, if necessary. Give cobalt chloride 10mg/kg per-orally. Fluid therapy with dextrose-saline is ideal

Nitrate/nitrite Methylene blue 1% Methylene blue @ 8.8mg/kg, i.v


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Or

Ascorbic acid

and repeat 30 min later and if necessary administer at 6-8hr. interval Broad spectrum antibiotics intra-ruminally; Administer 8-10L cold water and give osmotic purgatives Treat for hypotension/shock, (vasoconstrictors like 1:1000, 0.5 ml adrenaline, slow iv); Blood transfusion, if possible

Heavy metals

(Arsenic,antimony, mercury)

Arsenic/Mercurial insecticides)

Arsenic poisoning

British anti-Lewisite(BAL)

d-penicillamine

BAL: 3mg/kg as 5% mixture of 10% benzyl benzoate in mineral oil. Give deep i.m injection every 4hr. on first two days, every 6hr. on third day and then b.i.d for next 10 days. In cattle and horse sodium thiosulfate can also be used @ 8-10gram in the form of 10-20%solution (i.v) or 20-30gram per-orally in 300ml water.

Fluid therapy and other supportive treatment as required. Administer @ 30-40mg ,i..v + 60-80mg/kg; P.O, b.i.d or t.i.d for 3-4 days

Urea No antidote

Reduce the rumen pH

Administer 20-30lt. water and drench 4-6lt. 5 % acetic acid ; Anticonvulsants, if required

Strychnine

(Strychnous- nux vomica)

Phenobarbital sodium

Chloral hydrate

Phenobarbitone sodium,30mg/kg,i.v

Chloral hydrate @ 5g/45 kg, i.v

Drench tannic acid and then purgative

Rest the animal in cool, noise free & in dark room after a dose of purgative

Lead Calcium disodium EDTA Make 6.6% solution and administer @ 73 mg/kg,i.v (repeat or two treatment daily for 3 days if required). Combined thrapy with thiamine HCl @2-4mg/kg/day, s.c is more effective,


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Anticonvulsants, if required

Warfarine

Bromodiolone

Vitamin- K1 Vitamin-K1: 300-500mg, S.C,every 4-6hr.Blood transfusion transfusion @ 20ml/kg or plasma @ 9ml/kg body wt; Sedatives/tranquilizer

Pyrethroids

(Deltamethrin,

Cypermethrin etc.)

No specific antidote, but

Diazepam HCl + Atropine SO4

Diazepam: 0.5-2 mg/kg, i.vAtropine SO4 as required

Activated charcoal (1-2kg), P.O Fluid therapy

Carbamate insecticides Atropine sulphate 0.25mg-0.5mg/kg,give ¼ intravenously and remaining ¾ by intra-muscular or sub-cutaneous route

Organophosphates Atropine sulphate +

2-PAM

Or

DAM(diacetyl -monoxime)

Atropinization: 0.25mg-0.5mg/kg,give ¼ i.v,remaining ¾ by i.m or s.c for every 3-6 hours. Observe for papillary dilatation and recovery symptoms and continue treatment as required.

2-PAM: 20%solution @ 25-50mg/kg,i.v or intra-muscualrly, Activated charcoal,P.O

Fluid therapy and supportive care

Organochorines ( D.D.T;, B.H.C & endosulphan etc.,)

Pentobarbitone sodium Or Chloral hydrate

30mg/kg,i.v and supportive care

5g/45 kg ,i.v and supportive care

Dinitro-herbicides (Dinitro-orthocresol-DNOC & Dinitrophenol-DNP)

In ruminants only: Treat for Methaemoglobinemia with methylene blue

Or

Ascorbic acid

Methylene blue: 2-4%,8-10mg/kg,i.v every 8hr. Or Ascorbic acid: 5-10mg/kg,i.v; every8hr. for first 24-48hr.Note: Do not give antipyretics to control hyperthermia. Administer saline purgatives. Fluid therapy with DNS

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CARE AND MANAGEMENT OF CRITICAL PATIENTS IN CLINICS

VIVEK .R. KASARALIKAR

Critically ill patient is special challenge to the clinician because the underline problem is not evident for about 24 to 48 hours after initial presentation. Expeditious therapy in right time can be life saving, whereas delayed adequate therapy may be ineffective therapeutic failure. Most common clinical conditions in ambulatory patients are trauma with internal/ external hemorrhage, poisoning and post surgical complication. In fact, specialized care of emergent patient begins with initial phone call from the owner and instructions to be given regarding first aid and transport procedures. Level of consciousness, breathing pattern and external hemorrhage should be enquired on priority.

The important first aid measures are:

Immobility and transport on firm flat surface Mouth to nose resuscitation in critical patient which is unconscious and not

breathing (Ten to twelve times per minute) Pulsating arterial bleeding is controlled by digital pressure and pressure bandage Penetrating foreign objects should be left in place till specialized help is available Head elevated by 200 in altered mental status after head or spinal injury

Evaluation and initial treatment: Three important assessment criterion in emergency patients are A, B and C by evaluating certain parameters .

A – Airway: Airway patency should be evaluated on priority. Noisy breathing without need of stethoscope suggests Large airway problem e.g. trachea and bronchus, whereas, inspiratory dyspnoea implies extra-thoracic airway compromise. Loud expiratory sounds reflect towards pathology of intra-thoracic airway including bronchioles and lung parenchyma.

B – Breathing: Sequence of respiratory compromise is increased in respiratory rate initially, followed by change in respiratory pattern. Laboured open mouth breathing with development of cyanosis suggests significant compromised pulmonary function.


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In both the above conditions, immediate Oxygen administration is the priority. Intra-nasal catheter is the best choice for compromised breathing patients, whereas slash tracheotomy with endotracheal intubation is preferred in unconscious and apneic patients (Nasal Oxygen flow rate should be kept at 50 – 100 ml/kg/min).

C– Circulation: Hemodynamic and cellular changes that occur as a result of abnormality in circulation is referred as shock or peripheral circulatory failure.; is clinically classified in to four main categories.

Hypovolemic: occurs due to atleast 15-25 % t deficit in circulatory blood volume Cardiogenic shock: occurs due to failure of heart to pump requisite quantity of

blood in to circulation Distributive shock: due to impaired distribution of circulatory blood volume as a

result of peripheral vasodialatation Septic shock: This is endotoxin mediated shock

Therapeutic management of critically ill patient:

1. Cardio-pulmonary Resuscitation (CPR):Hallmarks of Cardio-pulmonary arrest are a) stage of apnea with cyanosis of visible mucous membranes b) absence of palpable pulse c) absence of heart sounds and d) dilatation of pupils

Guidelines for Cardio-pulmonary resuscitation

a) Positioning of animal:Lateral recumbency on small animal examination table is optimal position in small sized dogs (< 7 kgs), whereas dorsal recumbency is preferred for large sized dogs.

b) Resuscitation:Chest compression coupled with mouth to nose ventilation should be performed in patients in apneic stage.Compression rate should be 60 to 120 per minute and the compression – ventilation ratio should be 15:2. It means for every 15 compressions 2 cycles of ventilation should be performed.

2. Management of shock: Assessment of shock is governed by these parameters Pale to cyanotic mucous membranes Tachycardia with weak pulse Significant fall in Systolic blood pressure (Below 60 mm of Hg) Central Venous Pressure (CVP) less than 5 mm of H2O Elevated level of Blood lactate (> 80 mg/dl) Significant increase in Capillary Refill Time (CRT)

Therapeutic management: Emphasis should be given to


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Fluid therapy:The main aim of fluid therapy is to restore circulation and improve the tissue perfusion. Choice between crystalloid and colloidal solutions should be determined. Crystalloid supplements fluid along with electrolytes, whereas colloidal solutions expand the plasma volume.Commonly used colloidal solutions are: Dextran 70, Hexastarch,Gelatin polymers, Frozen plasma, Packed cell component. Commonly used crystalloids are: Normal Saline, Lactated Ringer’s solution, Dextrose Normal Saline, 7.5 % Normal saline and Hypertonic dextrose solution

Corticosteroids:Stabilization of cell membrane, blocking of arachidonic acid metabolism and gluconeogenesis are few important roles of corticosteroids in the treatment of shock Cyclo-oxygenase inhibitors:These decrease the prostaglandin synthesis and other vaso-active amines.Eg; Flunixin Meglumin( 0.25 mg/kg); Ketoprofen(0.5- 2.2 mg/kg) Antibiotic therapy in septic shock: Broad spectrum antibiotic therapy has additional advantage in endotoxin related shock. Anti-bacterials with synergistic action are also preferred in septic shock. III to IV generation ceophalosporin like cefoperazone, ceftrioxone and cefixim are frequently used in small animal practice. Control of hemorrhage and blood transfusion: Antifibrinolytic drugs are preferred to counteract extensive hemorrhage. PAMBA (Para amino methyl benzoic acid), EACA (Epsilon amino caproic acid) and Botropase have fast styptic activity Alpha Adrenergic agonist: These drugs help in improving cardiac output and thereby improve tissue perfusion. Dopamine used @ 5 – 10 µg/kg/min as constant infusion has positive ionotropic effect and increase the systolic pressure.

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MANAGEMENT OF MYCOTOXINS AND ZOOTOXINS OF VETERINARY IMPORTANCE

M.VIJAY KUMAR

Mycotoxins are the toxic metabolites released by moulds under certain conditions conducive for their growth. Acute or chronic toxicoses can result from exposure to feed or bedding contaminated with toxins that may be produced during growth of various saprophytic or phytopathogenic fungi or molds on cereals, hay, straw, pastures, or any other fodder. The principles that characterize mycotoxic diseases: the cause may not be immediately identified; they are not transmissible from one animal to another; treatment with drugs or antibiotics has little effect on the course of the disease; outbreaks are usually seasonal because particular climatic sequences may favor fungal growth and toxin production and study indicates specific association with a particular feed.

There are various types of mycotoxins and are classified as follows. Based on the causative organism: Aflatoxins - Aspergillus flavus, A. parasiticus.;Rubratoxins - Penicillium rubrum, P.purpurogenum.; T-2 toxins - Fusarium sp. F.gramaenareum and F. roseum.; Ergotoxins – Claviceps purpurea and C. paspali.Among these most common are aflatoxins. Aspergillus moulds grow rapidly when the moisture is <15%and the temperature is 24-25ºC.They commonly affect GNC, CSC, coconut cake, sunflower cake, wheat, sorghum, millets, soybean, peas and almonds.

Susceptibility:Ducks, rabbits, dogs, pigs, calves, chicken, cows, quail and sheep are susceptible in the order of preference. Broilers are more susceptible than layers. Calves are more susceptible than adult dairy cattle. Maximum allowable conc. in dairy cattle is 20 ppb (0.02 ppm)Depending on fluorescence aflatoxins are classified into B1, B2, and G1, G2. B1 is most toxic and need to be converted into its active metabolites.Toxicity is through ingestion of aflatoxin-contaminated feed. Aflatoxins are not accumulated to any appreciable extent by animal tissues with the exception of milk.

Signs:Acute - sudden death or anorexia, depression, dyspnoea, coughing, nasal discharge, anaemia, epistaxis, bloody faeces, possible convulsions and death. Subacute - jaundice, hypoprothrombinemia, haematomas and haemorrhagic enteritis. Chronic - decreased feed efficiency, decreased productivity and weight gain, rough hair coat, anaemia, enlarged abdomen, mild jaundice, depression and anorexia. Abortions may occur.


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Postmortem Lesions: Wide spread heamorhages,Icterus,Gastroenteritis,Hepatic necrosis,Massive centrilobular necrosis,fibrosis of bile duct,Enlarged liver,Hydrothorax, Ascites,Oedema of Gall bladder wall,Pericellular cirrhosis

Diagnosis: based on History,Clinical signs,PM findings,Detection of Aflatoxin M1 in milk & urine,liver, kidney,Serum liver enzymes SGOT,SGPT,ALP elevated,Reduced prothrombin activity,Hyperbilerubinemia,Tlc,HPLC,RIA,ELISA

Differential diagnosis: Warfarin (haemorrhages), coal tar (mottling of liver) Copper poisoning (haemoglobinuria, hemolysis); Pyrrozolidine alkaloids (present in plants), CCl4, blue-green algae, crotalaria are hepatotoxic.Treatment: 1. Avoidance of contaminated feed. 2. Hydrated sodium calcium alumino silicate (HSCAS) adsorb aflatoxins @5kg /ton 3. Stanozolol (2 mg / kg) I/M decreases hepatic necrosis 4. Oxytetracycline (10mg / kg) I/M decreases hepatic necrosis.( Never administer oxytetracycline and stanzolol combination, they are mutually antagonistic) 5. Activated charcoal 6.7 mg / Kg I/R as 30% W/V slurry in M/15, PH7 PBS(Along with charcoal,stanzolol/oxytetracycline(any one) ) 6. GSH Precursors Cysteine,methionine @2.2mg/kgi/p 7. Multi vitamins Like E,K & Selenium 8. Feeding easily digestible and low fat diet containing adequate protein

Sample collection : Samples can be taken at various stages:growing crops or during transport or storage. Whenever possible, samples should be taken after particulate size has been reduced (Ex: by shelling or grinding) and soon after blending has occurred (as in harvesting, loading, or grinding).Most effective if small samples are taken at periodic, predetermined intervals from a moving stream of grain or feed. These individual stream samples should be combined and mixed thoroughly, after which a subsample of 10 lb (4.5 kg) should be taken.. A suggested method of probe sampling is to sample at 5 locations, each 1 ft (30 cm) from the periphery of a bin, plus once in the center. This should be done for each 6 ft (2 m) of bin depth. Thus, taller bins would require more samples, and the total weight should be >10kg.

Dry samples are preferable for transport and storage. Samples should be dried at 176-194°F (80-90°C) for > 3 hr to reduce moisture to 12-13%. If mold studies are to be done, drying at 140°F (60°C) for 6-12 hr should preserve fungal activity.Containers should be appropriate for the nature of the sample. For dried samples, paper or cloth bags are recommended. Plastic bags should be avoided unless grain is dried thoroughly. Plastic bags are useful for high-moisture samples only if refrigeration, freezing, or chemicals are used to retard mold growth during transport and storage. Once a sample has been cooled or frozen, warming may induce condensation and allow mold growth.


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Zootoxins :Out of 236 species of snakes in India, only 50 are venomous, However, the common poisonous snakes of India that man and animal come into contact, are : Cobra, Krait, Russel’s viper and Sea scaled viper, Apart from these, the other venomous snakes found in India includes Sea snakes, Pit viper and King cobra.. In animals, many a time incidence of snakes bite is near leg region and nostrils.

Sensitivity: Horse>Man>Sheep>Cattle>Goat>Dog>Pig>Cat

Venom composition: The venom compositions vary significantly among various class of poisonous snakes. Therefore, the course of toxicity as well as well as cause of death will be different, and obviously therapeutic approach will also vary. On most occasions, the identification of snake is not available or doubtful. The nature of toxicity of poisonous snakes are: Elapidae: Cobra , King Cobra, Krait- Neurotioxic; Viparidae: Russel viper- Haemotoxic; Crotalidae: Pit Viper- Neutrotoxic Haemotoxic. All the bites from venomous snakes do not lead to death due to “dry bites” which means that no venom was injected. But, some snake venoms (krait) do not have immediate effect even in a bad bite, it is wise to give veterinary/medical care.

Cobra:. identified by their “defence display” by spreading their long bones to their famous hood. ; are most active at dust, having along the wedges of agricultural fields in search of rats/mice. For this reason they live mostly in cultivated area.. The cobra venom is rich in enzymes, cardiotoxic, neurotoxic factors. The cobra venom is rich in enzyme acetylcholinesterase. Therefore, rapid depletion of acetylcholine (ACh) at neuromuscular junction occurs following envenomation. This leads to “muscular paralysis” (flacid paralysis). In addition to it, the alpha-neurotoxin is a powerful cholinoceptor blocker (nicotinic receptors). These factors hinder the function of muscles involved in respiration and consequently death occurs due to “respiratory paralysis”. It is important to identify the “big four” dangerous snakes. At first sight cobra looks like a non-venomous rat snake, but, remember that the rat snake has a pointed head and larger eyes and it can run faster.

Krait: The common krait has bluish-bluck body with white cross bands and the head is short and blunt. Kraits venom is 10 times as powerful as that of the cobra and of all the Asian snakes its venom is the most toxic (neurotoxic). Kraits are noctoural. They are active at night and rest during the day. They are found throughout India and live mostly in sandy soil in rat burrows. Their favarite hiding places are piles of wood (on bricks which provide many pray to shelter in. They are canibalistic- eat snakes, rats, lizards and birds. Famale lays eggs (10-15) and stays with them until hatch.


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Russel viper: is a fat and bulky snake, but it can move with surprising speed when in danger. Its regular chain-like pattern and flat arrow shaped head make it easy to recognise. Its fangs are along and curved.. Venom is rich in proteolytic enzymes, hemolytic factors.

Pit vipers: are forest snakes and feed on frogs and lizards. Commonly found in coffee and tea plantations in India. Pit vipes have a small “pits” between nostrils and eyes. They are heat sensitive and can detect change in temperature when warm blooded animal comes near. Venom is not powerful and seldom results in death.

First-Aid treatment: The first aim, in case of cobra/krait bite is to retard the absorption of venom from the site of bite. ;done by applying a torniquet, provided site of bite is suitable for that. Do not disturb/ or/excite the animal with little care incise the area (1/4) and bleed. It is always better to avoid KMnO4 solution for wound wash and instead use 5% soap wash in 30 min. after bite. It is not advisible to apply torniquet in case of vipers bite as this venom is rich in spreading factors (local tissue necrosis).

Hospital treatment: The nature of hospital treatment practically depends on identity of the poisonous snake. Polyvalent antivenin is the drug of choce in the absence of identity. It is better to avoid administration of antihistaminic as they are found to increase toxic potential of certain vipers venom. Popularly, hospital treatment can be remembered as “AAA”: A = Antivenin.; A = Antibiotic (broad spectrum) andA = Antitetanus / Gas gnagrene antitoxins.

The antivenin (monovalent/polyvalent) should be administered IV at the rate of 100 ml. (small animals) or 10-50ml. (large animals). Administer antivenom with 1:00 epinephrine (0.5-1 ml. s/c) to avoid shock. Apply 1-2ml. of antivenin over the wound (site of bite in case of viper bite. Monitor the cardio vascular activity constantly. Narcotic analeptic is recommended in case of cobra bite to counteract intense pain. Epinephrine and corticosteroid to overcome hypotension and shock. Employ plasma volume expander (6% dextran-40) and calcium gluconate to reduce hemolysis. In case of viper bite, even if the patient survive, amputation may be performed to avoid spread of local tissued necrosis or gangrene formation.

Note: - Anitivenom should be stored at 40C. Do not administer if they are discoloured or after the date of expiry.

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CLINICAL CONSIDERATIONS IN ADVERSE EFFECTS OF DRUGS

U. SUNILCHANDRA

Adverse drug effects includes all adverse /side effects associated with a drug; including that observed in overdose/poisoning with drugs or effects that may occur during therapy. The mportant adverse effects of the drugs, in general are discussed in this article.

Drug allergy/ hypersensitivity : Most common drug allergens implicated in producing anaphylactic reactions in domestic animals include penicillins, cephalosporins, sulfonamides, streptomycin, tranquliisers, vancomycin, vitamins, insulin, tetracyclines, quinolones, salicylates, phenothiazines, chloramphenicol, heoparin, lidocaine, erythromycin, angiotensin converting enzyme inhibitors, methyl dopa, vitamin K, iron injections, exogenously administered repeated injections of

hormones(LH,hCG,PMSG),thiopentone, suxamethonium,non-depolarising muscle relaxants, ester local anaesthetics and plasma expanders (dextrans, starches and gelatins). Other agents that can cause anaphylactoid reactions include vaccines, food and insect stings.

Clinical signs are manifested by the involving various organ systems.Cardiovascular system:hypotension and cardiovascular collapse. tachycardia, arrhythmias, cardiac arrest.; Respiratory System :oedema of the glottis, tongue and airway structures may cause stridor and airway obstruction. Bronchospasm - may be severe.; Gastrointestinal: abdominal pain, diarrhoea or vomiting.; Haematological.: coagulopathy. ; Cutaneous : flushing, erythema, urticaria. signs may be seen. Adrenaline (1:1000 epinephrine) is the most useful drug for treating anaphylaxis as it is effective in bronchospasm and cardiovascular collapse. The dose of 0.01ml/kg.IV or 0.2 – 0.5ml/kg, IM is repeated in 10-15minutes if clinical signs are not resolving. Ensure adequate breathing. Intubation and ventilation may be required.Venous return may be aided by lifting the patient's legs


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or tilting the patient head down Antihistamine agents: H1 blockers and corticosteroids are also administered

Hepatotoxicity : Drug-induced liver damge is manifested by highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure. The type of drug induced hepatotoxicity is often accompanied by fatigue, fever, and rash, usually developing after few weeks of therapy. The clinically important potential hepatotoxic drugs: acetaminophen,amoxicillin,chlorpromazine,ciprofloxacin,diclofenac,erythromycin,fluconazole, isoniazid,methyldopa,rifampin, tetracycline,phenobarbitone, phenytoin, primidone,diazepam (in cats), mebendazole, carprofen, diethylcarbamazine, oxibendazole, sulfonamides, anabolic steroids, vincristine etc. Treatment is to discontinue the suspected drug. Specific therapy against is limited to the use of N -acetylcysteine (acetaminophen toxicity) and L-carnitine( valproate toxicity).

Nephrotoxicity:

The most common drugs with nephrotoxic potentiality are aminoglycosides, NSAIDs, sulfonamides, tetracyclines, amphotericin B, antiviral agents, methotrexate, the older

cephalosporins, cimetidine, ciprofloxacin, furosemide, penicillins, phenytoin, rifampin, thiazide diuretics, polymixin etc. Crystalluria, hematuria and obstruction of renal tubules occurring with sulfonamides are prevented by adequate water intake during the therapy and alkalinisation of the urine with urinary alkaliser (eg: sodium bicarbonate) supplementation. The prevention or minimizing the drug induced nephrotoxicity is by administering single daily dose; reducing the treatment course ; avoiding concurrent administration of other nephrotoxic drugs or reducing the doses in conditions of renal insufficicency/impairment.

Drug interactions:. may lead to diminished or an enhanced effect of a drug or may lead to toxicity. Some pharmacodynamic drug interactions include : GC and NSAIDs (increased gastrointestinal toxicity), furosemide and ACE inhibitors (increased diuretic effect), sucralfate and gastric acid secretion inhiobitors( decerased efficacy of sucralfate), NSAIDs and anticoagulants(increased bleeding), opioids and general anaesthetics(enhanced respiratory depression by opioids) etc.

Some pharmacokinetic drug interactions that may affect negatively the absorption of the administered former drug include: fluoroquinolones with cations Na+ and Cl-. Al and Mg,, Orally active penicillins with antacids, tetracyclines with milk, antacid, laxatives, digitalis with phenolphthalein (laxative), erythromycin with anti-cholinergic drugs,


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linocomycin with kaolin, and orally administered antibiotics with large dose of atropine. The examples of pharmacokinetic drug interactions during metabolism: phenobarbital with griseofulvin(decreasedefficacy),chloramphenicol(decreasedefficacy),primidone/phenytoin(increasedhepatotoxcity),corticosteroids(decreased efficacy);fluoroquinolones with theophylline (theophylline toxicity-CNS stimulation) etc.

Teratogenicity: Typical manifestations include congenital malformations( birth defects), intrauterine growth restriction, carcinogenesis and fetal demise. Interference in the formation process of major body structures(first 12 weeks of conception) cause teratogenic effect.Classes of teratogens include radiation, maternal infections,chemicals,and drugs Cytotoxic drugs (antineoplastic drugs),anticoagulants(warfarin),vitamin A analogues (etretinate, isotretinoin), anticonvulsants(carbamazepine,phenytoin,sodiumvalproate),Cardiovasculardrugs(Angiotensin-convertingenzymeinhibitors,AngiotensinIIinhibitors,losartan,spironolactone), Endocrinological drugs (carbimazole,propylthiouracil,chlopropamide, sulphonylureas), Antifungaldrugs(griseofulvin,ketoconazole,triazolesfluconazole,itraconazole,terbinafine),cardiovasculardrugs(betablockers,minoxidil),Antiinflammatorydrugs(NSAIDs;3rdtrimester),antibiotics(tetracycline,ciprofloxacin, chloramphenicol, nitrofurantion, vancomycin, aminoglycosides), antihelminthics (mebendazole,albendazole, oxfendazole) and others ( misoprostol ,statins). Before using a drug, consideration must be given to any potentially harmful effects on the fetus or mother. To minimize the fetal risks, the lowest possible effective dose should be used. Antineoplastic drugs, radio isotopes and oestrogens are the potential carcinogens and mutagens.

CNS disturbances:. Antibiotics to avoid, or use with care in patients with seizures include enrofloxacin, cephalosporins and penicillins (in renal disease), and imipenum. Metronidazole in higher doses; more common in cats. Ivermectin (related drugs -milbemycin, moxidectin), loperamide and vincristine are expelled from the CNS by p-glycoprotein. Collies, Shetland sheepdogs, English sheepdogs, and Australian shepherds are susceptible to these drugs when administered at normally therapeutic concentrations. The other common drugs with potentiality of CNS disturbances: levamisole,tetramisole,loperamide,tinidazole,metoclopramide,promethazine, prochlorperazine, terbutaline,chlorpromazine, methylxanthines, piperazine, respiratory stimulants (doxapram,nikethamide)and antihistaminics (sedation,also possible), all of which may result in transcient CNS stimulation depending on the dose and condition.

Photosensitization: Photosensitivity reactions or photosensitization is a clinical condition in which skin (areas exposed to light and lacking significant protective hair, wool, or pigmentation) is hyperreactive to sunlight due to the presence of photodynamic agents.


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Tissue injury is thought to result from the production of reactive oxygen intermediates or from alterations in cell membrane permeability. It is most commonly seen in cattle,sheep,goats,and horses.Tetracyclines,fluoroquinolones,sulophonamides,antihistaminics,diuretics(thiazides,loop),tricyclicantidepressants,phenothiazines and corticosteroids are examples of drugs with phototoxic potentiality. Photosensitive animals on prolonged exposure to sunlight- scratch or rub lightly pigmented, exposed areas of skin (ears, eyelids, muzzle), inducing typical skin lesions : erythema, edema, serum exudation, scab formation, and skin necrosis . In cattle, and especially in deer, exposure of the tongue while licking may result in glossitis, ulceration and deep necrosis. Treatment involves palliative measures (steroids, topical antibiotic)

Gastrointestinal disturbances: manifested by nausea, vomition, diarrhoea, abdominal pain are most commonly observed after the oral administration of macrolides, tetracyclines, piperazine, cephalosporins, oxyclozanide, fluoroquinolones, penicillins, nitrofurans, rafoxanide, NSAIDs, sulphonamides, antineoplastic drugs. Unless severe as in case of anticancerous drugs, most of them are transcient and are self limiting.

Local pain, tissue injury and irritation :. Bleeding from the injection site and hematoma formation can occur if blood vessels are injured during particularly intramuscular injections.. Skin necrosis, neurological damage, and loss of limb can follow. The sciatic nerve is commonly injured by gluteal IM injections and the radial nerve injury at the shoulder, commonly manifested by paresis, necrosis etc. Numerous drugs like quinpyramine salts, suramin, diminazine, b complex injectables, multivitamin injectables,cephalosporins, tetracyclines, NSAIDS, oil based injectables, the long-acting injectable medications may result in complications at IM injection sites. The extravasation of anticancerous drugs outside the vein may result in thrombophlebitiis and tissue necrosis.

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DIAGNOSTIC TESTS FOR DETECTION OF COMMON TOXICANTS IN SAMPLES

M.VIJAY KUMAR

Detection of Heavy metals: Place 10g of tissue (finely minced) in a beaker or test tube.Add 10 ml of 10% HCl.Introduce a copper wire into the test tube Boil for 10-15 min. (Do not inhale fumes) Remove the copper wire and place it on a filter paper Observe the colour of the copper wire. Inference: Black coloration - Arsenic or Bismuth; Shining silver deposit – Mercury; Dull white deposit – Silver; Dark colour with purple to blue; violet green - Antimony.

Depending on the colour of copper wire the confirmatory test is conducted.If the deposit is black it can be confirmed whether it is due to arsenic or bismuth by placing the copper strip in 1-2 ml. of 10 % potassium cyanide. If the deposit is due to arsenic, it will dissolve, but if it is due to bismuth or antimony, it will persist.In mercury, colour of the deposit ranges grayish (50 mg) to shiny silver (100 mg).

Detection of lead : Mince the liver/kidney piece or collect a small amount of scraping from stomach wall.Add a few drops of conc. nitric acid and heat gently till dry, (never over heat the sample as it turns black making reading difficult). Add a few drops of water and two drops of 10% pot. iodide solution.Development of yellow colour indicates presence of lead.

Detection of Cyanide: a) in biological material: Take 50 g of finely ground tissue or stomach contents in a 100 ml flask and acidify thecontents with tartaric acid. Take a filter paper previously moistened with 10 % of guaiacol in alcohol and 0.1% of aqueous copper sulfate solution.Plug the mouth of flask and warm gently. Allow it to stand for 30 minutes. Observe the colour of paper. If cyanide is present, a blue colour develops.

b) in the plant sample: Preparation of sodium picrate paper-Dissolve sodium bicarbonate 5 g and picric acid 0.5 g in 100 ml of distilled water. Cut filter paper into strips of 2. x 6. size. Dip the strips in the reagent and dry in cool place.

Take the given sample in a test tube and add a few drops of water and chlorofom. Plug the test tube with cotton, hanging the dried picrate paper inside the test tube. The paper should not touch the fluid in the tube. Heat the tube gently till fumes evolve. Observe the colour of paper.If the colour of paper changes from yellow to brown it indicates that


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the plant sampleis positive for cyanide.(The leaves and stomach contents are to be frozen immediately after collection inpolythene bag as CN is likely to evaporate).

Detection of fluorides: To a small quantity (1-3 ml) of urine or stomach contents add 3 ml of sodium hydroxide solution in a glass or porcelain dish. Add a little quantity of powdered glass and mix thoroughly. Apply moderate heat till dry. Add 10 ml of concentrated sulfuric acid and cover the dish with a small plate from the under surface of which is suspended a drop of 5% sodium chloride solution. Place a small piece of ice on top of the plate to prevent evaporation of the drop. Heat gently for 3-5 min., carefully remove the drop and examine under low power of microscope. If the given specimen contains fluorides, silicon fluoride is formed which appears as small light pink hexagonal crystals along the rim of the drop, whereas the crystals of sodium chloride are large and square.

Detection of Nitrite: a) Draw blood (10 ml) without anticoagulant from an affected animal and also from a known normal animal in 20 ml capacity test tubes.Place them in boiling water bath for 45 minutes. Cool them.Observe the colour of the blood and the surface.Blood sample containing nitrite is Salmon pink in colour, does not pull away fromthe side and the surface is level or concave. Normal blood sample is chocolate brown,pulls away from the side of tube and the surface is convex.

b)In a plant sample: Dissolve 0.5 g of diphenylamine in 20 ml of distilled water and make up the volume to 100 ml with sulfuric acid. Store it in amber colored bottle. This is a full strength solution and can be made into half strength by diluting with equal parts of 80% sulfuric acid. To test a plant, place a drop of the reagent on the cut surface of plant. Observe the colour.A green to blue colour indicates the presence of nitrate.(A green to blue colour with a half strength solution indicates positive (++) for nitrate, which could be toxic to animal).

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chemotherapy and diagnostic toxicology

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