Food Therapy IFood Therapy IFood Therapy IFood Therapy IDr. Alex AlexanderWeek 2 - Fall 2012

Dr. Alex AlexanderWeek 2 - Fall 2012

VITAMINSVITAMINS

ThiamineThiamine

NO Primary Indic.

Biochemistry: Thiamine is necessary for the enzyme TPP, which is involved as a cofactor in energy metabolism (rate limiting step leading into Krebs cycle). See thiamine deficiency show up in heart and brain (wernicke's encephalopathy) first. Deficiency is uncommon in US outside of alcoholics. Thiamine is water soluble (like all B-vitamins).

NO Primary Indic.

Biochemistry: Thiamine is necessary for the enzyme TPP, which is involved as a cofactor in energy metabolism (rate limiting step leading into Krebs cycle). See thiamine deficiency show up in heart and brain (wernicke's encephalopathy) first. Deficiency is uncommon in US outside of alcoholics. Thiamine is water soluble (like all B-vitamins).

Indications-ThiamineIndications-Thiamine1)Alcoholism: Alcoholics can develop encephalopathy secondary to thiamine deficiency. Parenteral administration is required initially, as oral thiamine will not be well absorbed. Especially if showing signs of loss of mental acuity.

2)Neurological conditions: Thiamine plus vitamin B12, given by intramuscular injection, may be useful for sciatic neuritis, trigeminal neuralgia, and prevention of postherpetic neuralgia (anecdotal). Typical dosage regimen is 50 mg (0.5 ml) of thiamine and 1,000 mcg (1 ml) of vitamin B12, 2-3 times per week for 2 weeks, then taper according to response.

1)Alcoholism: Alcoholics can develop encephalopathy secondary to thiamine deficiency. Parenteral administration is required initially, as oral thiamine will not be well absorbed. Especially if showing signs of loss of mental acuity.

2)Neurological conditions: Thiamine plus vitamin B12, given by intramuscular injection, may be useful for sciatic neuritis, trigeminal neuralgia, and prevention of postherpetic neuralgia (anecdotal). Typical dosage regimen is 50 mg (0.5 ml) of thiamine and 1,000 mcg (1 ml) of vitamin B12, 2-3 times per week for 2 weeks, then taper according to response.

Indications-ThiamineIndications-Thiamine1)Congestive heart failure (CHF): If thiamine deficiency is present, supplementation may improve cardiac function. An uncontrolled study of patients with CHF reported a 22% increase in left ventricular ejection fraction after treatment with 200 mg/day for 6 weeks . In other trials, results have been inconsistent. Deficiency may result from diuretic treatment or from general malabsorption (CHF leads to venous congestion→edema of the small-bowel mucosa→↑hydrostatic pressure in capillaries of small bowel→↓ in absorption).* CHF pts are usually on diuretics (lasix→lose potassium and thiamine among other things) and ACE inhibitors. Recommend multivitamin w/ thiamine for CHF pts.

1)Congestive heart failure (CHF): If thiamine deficiency is present, supplementation may improve cardiac function. An uncontrolled study of patients with CHF reported a 22% increase in left ventricular ejection fraction after treatment with 200 mg/day for 6 weeks . In other trials, results have been inconsistent. Deficiency may result from diuretic treatment or from general malabsorption (CHF leads to venous congestion→edema of the small-bowel mucosa→↑hydrostatic pressure in capillaries of small bowel→↓ in absorption).* CHF pts are usually on diuretics (lasix→lose potassium and thiamine among other things) and ACE inhibitors. Recommend multivitamin w/ thiamine for CHF pts.

Dosage, Interaction, ToxicityDosage, Interaction, Toxicity

• Usual dosage between 10 and 100 mg/day. Give IM if there is suspicion of malabsorption*

Interactions: Some diuretics, including Lasix, can deplete thiamine.

Toxicity: Generally well tolerated p.o. or i.m. Anaphylactic reactions have been reported with i.v. thiamine administration.

• Usual dosage between 10 and 100 mg/day. Give IM if there is suspicion of malabsorption*

Interactions: Some diuretics, including Lasix, can deplete thiamine.

Toxicity: Generally well tolerated p.o. or i.m. Anaphylactic reactions have been reported with i.v. thiamine administration.

RiboflavinRiboflavin

(Anemia and Migraine)Biochemistry: Necessary for the cellular redox agents FMN and FAD. Both are involved in energy production, as well as free radical processing. Deficiency is uncommon. Yellow color.

(Anemia and Migraine)Biochemistry: Necessary for the cellular redox agents FMN and FAD. Both are involved in energy production, as well as free radical processing. Deficiency is uncommon. Yellow color.

Indications- RiboflavinIndications- Riboflavin

Migraine prophylaxis: In a double-blind, randomized clinical trial, supplementation with 400 mg/day with breakfast significantly reduced the recurrence rate of migraines, compared with placebo Incidence of migraines goes down by 50% w/ 400mg/day- confirmed by 2 more double-blind studies. Mg, butterbur, allergy elimination and b-6 also helpful. Migragaurd is one product that is useful. Try Tx for at least 3mo before giving up. Hypothesized mechanism is Riboflavin is bypassing/over-riding complex 2 which is disturbed in the electron transport chain in migraine pts.

Migraine prophylaxis: In a double-blind, randomized clinical trial, supplementation with 400 mg/day with breakfast significantly reduced the recurrence rate of migraines, compared with placebo Incidence of migraines goes down by 50% w/ 400mg/day- confirmed by 2 more double-blind studies. Mg, butterbur, allergy elimination and b-6 also helpful. Migragaurd is one product that is useful. Try Tx for at least 3mo before giving up. Hypothesized mechanism is Riboflavin is bypassing/over-riding complex 2 which is disturbed in the electron transport chain in migraine pts.

Dosage, Interaction, ToxicityDosage, Interaction, ToxicityDosage: Most multivitamins contain between 10 and 25 mg of riboflavin, plenty to replete a deficiency state. Larger doses required for migraine prophylaxis.

Interactions: Deficiency or impaired utilization of riboflavin may result from the administration of adriamycin (CA Tx- breast and lymphomas)), phenothiazines, phenytoin, imipramine, or amitriptyline.* There is a published case report of a patient with metabolic acidosis secondary to AZT having symptomatic relief from riboflavin supplementation

Toxicity: Tends to make urine very yellow. No toxicity symptoms reported.

Dosage: Most multivitamins contain between 10 and 25 mg of riboflavin, plenty to replete a deficiency state. Larger doses required for migraine prophylaxis.

Interactions: Deficiency or impaired utilization of riboflavin may result from the administration of adriamycin (CA Tx- breast and lymphomas)), phenothiazines, phenytoin, imipramine, or amitriptyline.* There is a published case report of a patient with metabolic acidosis secondary to AZT having symptomatic relief from riboflavin supplementation

Toxicity: Tends to make urine very yellow. No toxicity symptoms reported.

Niacin / NiacinimideNiacin / Niacinimide

(high cholesterol and OA)Biochemistry: Either niacin or niacinamide can act as a precursor to NAD(H) and NADP(H), both of which are important cellular redox agents. Niacin and niacinamide have different actions and different side effects. Niacin, but not niacinamide, acts as a precursor for glucose tolerance factor. Glucose tolerance factor is an old term. Now called ‘low molecular weight chromium compound’→ sits on the insulin receptor and changes the confirmation such that insulin has 1000 times more affinity for the receptor. Brewers yeast is natural source of GTF.

(high cholesterol and OA)Biochemistry: Either niacin or niacinamide can act as a precursor to NAD(H) and NADP(H), both of which are important cellular redox agents. Niacin and niacinamide have different actions and different side effects. Niacin, but not niacinamide, acts as a precursor for glucose tolerance factor. Glucose tolerance factor is an old term. Now called ‘low molecular weight chromium compound’→ sits on the insulin receptor and changes the confirmation such that insulin has 1000 times more affinity for the receptor. Brewers yeast is natural source of GTF.

Indications- NiacinIndications- Niacin

1)Osteoarthritis: 500 mg, 3 to 6 times per day (frequent administration of low doses is more effective than less-frequent administration of higher doses), or 1,000 mg of sustained-release niacinamide (not niacin), twice a day.* Initially published in 1947, double-blind trials have confirmed this effect . Niacinamide reduces sedimentation rate (↓inflammation→maybe also helpful for cardio prevention) in patients with arthritis. Use for small jt arthritis (fingers and toes).

1)Osteoarthritis: 500 mg, 3 to 6 times per day (frequent administration of low doses is more effective than less-frequent administration of higher doses), or 1,000 mg of sustained-release niacinamide (not niacin), twice a day.* Initially published in 1947, double-blind trials have confirmed this effect . Niacinamide reduces sedimentation rate (↓inflammation→maybe also helpful for cardio prevention) in patients with arthritis. Use for small jt arthritis (fingers and toes).

Indications-Niacin(imide)Indications-Niacin(imide)

1) Diabetes:a. Prevention: Niacinamide in varying doses (such as 25 mg/kg/day, to

a maximum of 2-3 g/day), may prevent the loss of pancreatic beta-cells during the early stages of type 1 diabetes mellitus, or may prevent the development of type 1 diabetes in high-risk children. Numerous controlled trials have been done; results have been conflicting.* hard to catch these kids early, but if you do can slow the onset by 1-2yrs.

b. Treatment: Niacin is a precursor for glucose-tolerance factor. Low doses of niacin (such as 100 mg/day) in combination with chromium (200-500 mcg/day) may improve glucose control more effectively than either nutrient alone (controlled, unblinded trial).The effect of large doses of niacin on blood-glucose levels is said to be variable; i.e., increase, decrease or no effect. Niacin has an unpredictable effect on glucose tolerance (may help, may make worse, or may have no effect). Recommend watching glucose levels closely for 1mo when starting high dose niacin Tx.

c. Niacinamide (500 mg, 3 times per day) increased insulin release and improved metabolic control in type 2 diabetics with secondary failure of sulfonylureas* Glucophage and glipizide (conventional diabetes Rx) have a window when they work well but after that they fail- niacin may prevent this failure.

1) Diabetes:a. Prevention: Niacinamide in varying doses (such as 25 mg/kg/day, to

a maximum of 2-3 g/day), may prevent the loss of pancreatic beta-cells during the early stages of type 1 diabetes mellitus, or may prevent the development of type 1 diabetes in high-risk children. Numerous controlled trials have been done; results have been conflicting.* hard to catch these kids early, but if you do can slow the onset by 1-2yrs.

b. Treatment: Niacin is a precursor for glucose-tolerance factor. Low doses of niacin (such as 100 mg/day) in combination with chromium (200-500 mcg/day) may improve glucose control more effectively than either nutrient alone (controlled, unblinded trial).The effect of large doses of niacin on blood-glucose levels is said to be variable; i.e., increase, decrease or no effect. Niacin has an unpredictable effect on glucose tolerance (may help, may make worse, or may have no effect). Recommend watching glucose levels closely for 1mo when starting high dose niacin Tx.

c. Niacinamide (500 mg, 3 times per day) increased insulin release and improved metabolic control in type 2 diabetics with secondary failure of sulfonylureas* Glucophage and glipizide (conventional diabetes Rx) have a window when they work well but after that they fail- niacin may prevent this failure.

Indications- NiacinIndications- Niacin

1)Hypercholesterolemia: Niacin (in gram doses), but not niacinamide, has been shown to reduce serum cholesterol in a number of double-blind, clinical trials. Unlike the common prescription drugs (statins), niacin raises HDL cholesterol levels. The concurrent use of high-dose antioxidants appears to blunt the effect of niacin (doesn’t lower cholesterol)→this is a problem because not only do you want to lower cholesterol you also want to prevent oxidation of existing cholesterol. Nicain raises HDL, lowers LDL and sometimes lowers trigs.

1)Hypercholesterolemia: Niacin (in gram doses), but not niacinamide, has been shown to reduce serum cholesterol in a number of double-blind, clinical trials. Unlike the common prescription drugs (statins), niacin raises HDL cholesterol levels. The concurrent use of high-dose antioxidants appears to blunt the effect of niacin (doesn’t lower cholesterol)→this is a problem because not only do you want to lower cholesterol you also want to prevent oxidation of existing cholesterol. Nicain raises HDL, lowers LDL and sometimes lowers trigs.

Dosage- NiacinDosage- Niacin

• Dosage: Usually 25-50 mg of niacin or niacinamide are sufficient to protect against deficiency. Specific dose requirements for therapies are listed above. NADH is an active form, and is usually given at 5 mg bid. Extended release forms of niacin are available (Niaspan is common prescription form→more effective and insurances cover→has a binder that slows absorption into GI and has no hepatic toxicity).

• Dosage: Usually 25-50 mg of niacin or niacinamide are sufficient to protect against deficiency. Specific dose requirements for therapies are listed above. NADH is an active form, and is usually given at 5 mg bid. Extended release forms of niacin are available (Niaspan is common prescription form→more effective and insurances cover→has a binder that slows absorption into GI and has no hepatic toxicity).

Interactions- NiacinInteractions- Niacin

Interactions: In some, but not all studies, concurrent use of HMG-CoA reductase inhibitors and niacin led to rhabdomyolysis (breakdown of mm tissue leading to mm weakness).* Statins alone can also cause this but niacin may increase the incidence. If given together should warn pt of this risk. Some people have used aspirin to block the skin flushing associated with niacin. Antioxidant supplements appear to reduce the hypolipidemic effect of niacin.

Interactions: In some, but not all studies, concurrent use of HMG-CoA reductase inhibitors and niacin led to rhabdomyolysis (breakdown of mm tissue leading to mm weakness).* Statins alone can also cause this but niacin may increase the incidence. If given together should warn pt of this risk. Some people have used aspirin to block the skin flushing associated with niacin. Antioxidant supplements appear to reduce the hypolipidemic effect of niacin.

Interactions and ToxicityInteractions and Toxicity

• Interactions: Anticonvulsants including phenytoin, carbamazepine, primidone, and phenobarbital may promote biotin deficiency, by accelerating biotin catabolism or inhibiting its transport.*

Toxicity: No issues here.

• Interactions: Anticonvulsants including phenytoin, carbamazepine, primidone, and phenobarbital may promote biotin deficiency, by accelerating biotin catabolism or inhibiting its transport.*

Toxicity: No issues here.

Toxicity- NiacinToxicity- Niacin

1. High doses of niacin, but not niacinamide, routinely cause skin flushing. This is a transient symptom, and not thought to be reflective of any pathology. Niacin, particularly extended release forms, are hepatotoxic. Patients on long term niacin therapy should have routine screening for hepatotoxicity. Niacinamide is usually well-tolerated, but may cause a mild elevation of liver enzymes. If using gram doses you should check liver enzymes every 3 months.

1. High doses of niacin, but not niacinamide, routinely cause skin flushing. This is a transient symptom, and not thought to be reflective of any pathology. Niacin, particularly extended release forms, are hepatotoxic. Patients on long term niacin therapy should have routine screening for hepatotoxicity. Niacinamide is usually well-tolerated, but may cause a mild elevation of liver enzymes. If using gram doses you should check liver enzymes every 3 months.

Inositol hexanicotinateInositol hexanicotinate• Biochemistry: Inositol hexanicotinate (IHN) is made up

of an inositol ring, surrounded by six molecules of niacin. Theoretically, this acts as a time-release form of niacin as the inositol ring releases each member (niacin molecules are cleaved off of the inositol ring by an esterase enzyme). IHN does not normally cause skin flushing and is not known to be hepatotoxic. No modern, English-language research (some german literature from 50s & 60s) has quantified the rate at which IHN releases niacin into the blood stream (even though some companies claim they have data on this). It is not known whether IHN is a valid substitute for niacin in situations where niacin therapy is indicated.

• Biochemistry: Inositol hexanicotinate (IHN) is made up of an inositol ring, surrounded by six molecules of niacin. Theoretically, this acts as a time-release form of niacin as the inositol ring releases each member (niacin molecules are cleaved off of the inositol ring by an esterase enzyme). IHN does not normally cause skin flushing and is not known to be hepatotoxic. No modern, English-language research (some german literature from 50s & 60s) has quantified the rate at which IHN releases niacin into the blood stream (even though some companies claim they have data on this). It is not known whether IHN is a valid substitute for niacin in situations where niacin therapy is indicated.

Indications - IHNIndications - IHN1)Hyperlipidemia: A few reports have demonstrated lipid-lowering effects; however, inositol hexanicotinate does not appear to be as effective as niacin.

2)Raynaud’s phenomenon: At a dose of 2-4 g/day (in 4 divided doses), inositol hexanicotinate has been reported to relieve symptoms and prevent attacks. Improvement typically occurs within 1 month

(double-blind and open trials). 3)Intermittent claudication: Treatment with 4 g/day in divided doses improved walking distance and subjective symptoms (double-blind trials). IHN is a better Tx than conventional Tx. Conventional medicine uses pentoxifylline (synthetic derivative from a constituent of green tea)

1)Hyperlipidemia: A few reports have demonstrated lipid-lowering effects; however, inositol hexanicotinate does not appear to be as effective as niacin.

2)Raynaud’s phenomenon: At a dose of 2-4 g/day (in 4 divided doses), inositol hexanicotinate has been reported to relieve symptoms and prevent attacks. Improvement typically occurs within 1 month

(double-blind and open trials). 3)Intermittent claudication: Treatment with 4 g/day in divided doses improved walking distance and subjective symptoms (double-blind trials). IHN is a better Tx than conventional Tx. Conventional medicine uses pentoxifylline (synthetic derivative from a constituent of green tea)

DosageDosage

Dosage: Most studies have used 1500 mg - 4 g in divided doses BID-TID.Dosage: Most studies have used 1500 mg - 4 g in divided doses BID-TID.

ToxicityToxicity

• Toxicity: Proponents of IHN cite the safety of this compound compared to pharmaceutical time-release niacin preparations. Most safety data are in non-English publications, and as such, beyond my reach. The English language publications, while small studies, have not shown any measurable toxicity of IHN.

• Toxicity: Proponents of IHN cite the safety of this compound compared to pharmaceutical time-release niacin preparations. Most safety data are in non-English publications, and as such, beyond my reach. The English language publications, while small studies, have not shown any measurable toxicity of IHN.

Biotin - B4 Biotin - B4

• No PRIMARY Indic

• BIOCHEMISTRY: Biotin acts as a cofactor in the breakdown and elongation of fatty acids (decarboxylation rxns). Biotin deficiency symptoms include dermatitis, depression, hair loss, anemia, and nausea. Largest food source=eggs (cooked, not raw). DRI=60micrograms/day.

• No PRIMARY Indic

• BIOCHEMISTRY: Biotin acts as a cofactor in the breakdown and elongation of fatty acids (decarboxylation rxns). Biotin deficiency symptoms include dermatitis, depression, hair loss, anemia, and nausea. Largest food source=eggs (cooked, not raw). DRI=60micrograms/day.

Indications - BiotinIndications - Biotin

1) “Cradle cap” (seborrheic dermatitis of infancy): Some authors have recommended 2-10 mg/day for 2-4 weeks, depending on the severity of the condition.* More recent controlled trials have shown no benefit to biotin.

2) Brittle nails: A dose of 2.5 mg/day was found to strengthen dry, splitting nails after 1-4 months (average, 2 months) (uncontrolled trial). Can occur during/after chemo.

3) Pregnancy: Biotin deficiency causes birth defects in animals. Biotin status is marginal in many pregnant women. Deficiency can be seen in over half of pregnant women.

1) “Cradle cap” (seborrheic dermatitis of infancy): Some authors have recommended 2-10 mg/day for 2-4 weeks, depending on the severity of the condition.* More recent controlled trials have shown no benefit to biotin.

2) Brittle nails: A dose of 2.5 mg/day was found to strengthen dry, splitting nails after 1-4 months (average, 2 months) (uncontrolled trial). Can occur during/after chemo.

3) Pregnancy: Biotin deficiency causes birth defects in animals. Biotin status is marginal in many pregnant women. Deficiency can be seen in over half of pregnant women.

Dosage - BiotinDosage - Biotin

• 30 mcg is enough to prevent a deficiency. Doses of several milligrams per day have been used safely in clinical trials.

• 30 mcg is enough to prevent a deficiency. Doses of several milligrams per day have been used safely in clinical trials.

Folic AcidFolic Acid• Folic acid is important in any methylation reaction, including genetic

replication. Folate deficiency can show up in many areas, including cardiovascular disease, birth defects, cancers, psychiatric disease, and hematopoesis.

• Folic acid is a large molecule. Found in grains, vegetables and fruits. Folate deficiency is very common. The largest sources of folate in the American diet is orange juice and fortified white flour. Women of child bearing age should consume 400micrograms to prevent neural tube defects. Recommend 600-800micrograms during PG and much more if Hx of PG w/ neural tube defects (spina bifida)

• Folic acid is involved in 1 carbon/methylation pathways. Problems w/ 1 carbon pathways show up as:

1. Large RBCs (problem w/ DNA replication)2. Neuropathy, depression (methylation rxns are active in nerves and

neurotransmitter rxns)3. Atherosclerosis

• Folic acid is important in any methylation reaction, including genetic replication. Folate deficiency can show up in many areas, including cardiovascular disease, birth defects, cancers, psychiatric disease, and hematopoesis.

• Folic acid is a large molecule. Found in grains, vegetables and fruits. Folate deficiency is very common. The largest sources of folate in the American diet is orange juice and fortified white flour. Women of child bearing age should consume 400micrograms to prevent neural tube defects. Recommend 600-800micrograms during PG and much more if Hx of PG w/ neural tube defects (spina bifida)

• Folic acid is involved in 1 carbon/methylation pathways. Problems w/ 1 carbon pathways show up as:

1. Large RBCs (problem w/ DNA replication)2. Neuropathy, depression (methylation rxns are active in nerves and

neurotransmitter rxns)3. Atherosclerosis

Indications- Folic AcidIndications- Folic Acid

1)Prevention of neural tube defects and cleft palate: Women of childbearing age should consume 0.4 mg/day of folic acid to prevent spina bifida and possibly other neural tube defects.

Folic acid from supplements appears to be better utilized than folic acid from food.

Preliminary research has linked folic acid deficiency to heart abnormalities and urinary tract issues, as well. High homocysteine correlates with increased risk of miscarriage/spontaneous abortion (based on 3 epidemiological studies)..

1)Prevention of neural tube defects and cleft palate: Women of childbearing age should consume 0.4 mg/day of folic acid to prevent spina bifida and possibly other neural tube defects.

Folic acid from supplements appears to be better utilized than folic acid from food.

Preliminary research has linked folic acid deficiency to heart abnormalities and urinary tract issues, as well. High homocysteine correlates with increased risk of miscarriage/spontaneous abortion (based on 3 epidemiological studies)..

Indications - FA, cont.Indications - FA, cont.

1) Precancerous lesions / cancer prevention: At a dose of 10 mg/day for 3 months, folic acid induced regression of cervical dysplasia and cervical intraepithelial neoplasia in women taking oral contraceptives (double-blind trials). Folic acid was not effective in a double-blind study of women who were not taking oral contraceptives. Smaller doses, such as 0.4 mg/day, may help prevent cervical dysplasia resulting from human papilloma virus infection (theoretical, based on observational study). Take home: OC use is the requirement for the folic acid Tx to be effective in inducing regression of cervical dysplasia/neoplasia.

2 mg folic acid per day reduced tissue proliferation in the colon of patients with a history of recurrent polyp formation. Higher proliferative index=↑risk for CA. Folic acid decreases the proliferative index at a dose of 2mg/day. There is a confounding variable in folic acid studies looking at colon CA→high folic acid diets are also high in fiber which may impart it’s own preventative affects.

Women who have high folic acid intake have lower risk of breast cancer, particularly if they drink on average 1 drink/day (risk of CA increases w/ ↑ETOH intake). In one study, folate supplementation reduced postmenopausal breast cancer in women with a PMHx who DID NOT drink (epidemiologic trial)→ this sentence because it is misleading. 1 drink/day also ↓overall mortality risk and ↓cardiovascular risk. If you have people who are not willing to ↓ETOH→folic acid is a reasonable recommendation.

Folic acid, together with vitamin B12, induced regression of respiratory papilloma (foic acid w/ B12 decreased squamous metaplasia in smokers).

1) Precancerous lesions / cancer prevention: At a dose of 10 mg/day for 3 months, folic acid induced regression of cervical dysplasia and cervical intraepithelial neoplasia in women taking oral contraceptives (double-blind trials). Folic acid was not effective in a double-blind study of women who were not taking oral contraceptives. Smaller doses, such as 0.4 mg/day, may help prevent cervical dysplasia resulting from human papilloma virus infection (theoretical, based on observational study). Take home: OC use is the requirement for the folic acid Tx to be effective in inducing regression of cervical dysplasia/neoplasia.

2 mg folic acid per day reduced tissue proliferation in the colon of patients with a history of recurrent polyp formation. Higher proliferative index=↑risk for CA. Folic acid decreases the proliferative index at a dose of 2mg/day. There is a confounding variable in folic acid studies looking at colon CA→high folic acid diets are also high in fiber which may impart it’s own preventative affects.

Women who have high folic acid intake have lower risk of breast cancer, particularly if they drink on average 1 drink/day (risk of CA increases w/ ↑ETOH intake). In one study, folate supplementation reduced postmenopausal breast cancer in women with a PMHx who DID NOT drink (epidemiologic trial)→ this sentence because it is misleading. 1 drink/day also ↓overall mortality risk and ↓cardiovascular risk. If you have people who are not willing to ↓ETOH→folic acid is a reasonable recommendation.

Folic acid, together with vitamin B12, induced regression of respiratory papilloma (foic acid w/ B12 decreased squamous metaplasia in smokers).

Indications - FA, cont.Indications - FA, cont.

1) Homocysteine-related conditions: Folic acid (0.4 to 5.0 mg/day) reduces elevated homocysteine levels in many patients. As such, it may help prevent both atherosclerosis and osteoporosis (theoretical for osteoporosis, intervention trials for atherosclerosis).* Folic acid treatment reduces risk of coronary events in some, but not all, clinical trials. Homocysteine as a marker for cardiovascular dz risk factor is still controversial. High risk groups= HTN, obesity, smokers, type II diabetes, kidney dz, genetic homocystinuria (die in 30-40s). Folic acid is a reliable way to bring down homocysteine.

1) Homocysteine-related conditions: Folic acid (0.4 to 5.0 mg/day) reduces elevated homocysteine levels in many patients. As such, it may help prevent both atherosclerosis and osteoporosis (theoretical for osteoporosis, intervention trials for atherosclerosis).* Folic acid treatment reduces risk of coronary events in some, but not all, clinical trials. Homocysteine as a marker for cardiovascular dz risk factor is still controversial. High risk groups= HTN, obesity, smokers, type II diabetes, kidney dz, genetic homocystinuria (die in 30-40s). Folic acid is a reliable way to bring down homocysteine.

Indications- FA, cont.Indications- FA, cont.

2) Depression: Folic acid at a dose of 500 mcg/day enhanced the antidepressant effect of fluoxetine (Prozac) in women, but not in men, with major depression (double-blind trial). Laboratory findings (e.g., serum folate and homocysteine) suggested that men may require a higher dose of folic acid than 500 mcg/day. Folic acid may improve prozacs (and possibly other SSRI’s) affect via neurotransmitter pathways.

Efficacy of placebo in Tx of depression is about 30% and efficacy of pharmaceutical SSRI’s is about 40-45% so there is not much benefit over placebo. A study compared the efficacy of Zoloft alone, exercise alone and Zoloft + exercise. Zoloft alone was effective during Tx but effect lost w/ d/c of drug. Exercise alone was effective but when the exercise was stopped the anti-depressant effect lingered. Zoloft +exercise= same as effect of Zoloft alone but when Zoloft and exercise d/c the effect was lost→ something w/ Zoloft blunted effect of exercise.

3) Schizophrenia - if deficient

2) Depression: Folic acid at a dose of 500 mcg/day enhanced the antidepressant effect of fluoxetine (Prozac) in women, but not in men, with major depression (double-blind trial). Laboratory findings (e.g., serum folate and homocysteine) suggested that men may require a higher dose of folic acid than 500 mcg/day. Folic acid may improve prozacs (and possibly other SSRI’s) affect via neurotransmitter pathways.

Efficacy of placebo in Tx of depression is about 30% and efficacy of pharmaceutical SSRI’s is about 40-45% so there is not much benefit over placebo. A study compared the efficacy of Zoloft alone, exercise alone and Zoloft + exercise. Zoloft alone was effective during Tx but effect lost w/ d/c of drug. Exercise alone was effective but when the exercise was stopped the anti-depressant effect lingered. Zoloft +exercise= same as effect of Zoloft alone but when Zoloft and exercise d/c the effect was lost→ something w/ Zoloft blunted effect of exercise.

3) Schizophrenia - if deficient

Dosage- Folic AcidDosage- Folic Acid

Dosage: Multivitamins usually contain between 200 and 800 mcg of folic acid. Doses above 800 mcg are not generally found on OTC products due to concern about masking diagnosis of pernicious anemia. If you mask a Dx of pernicious anemia by giving high dose folic acid your pt will later present w/ an irreversible neuropathy. High risk of pernicious anemia→elderly (atrophic gastritis), auto-immune dz’s. Specialty products (I have used a folic acid mouthwash- they tell you how much folic acid is in each drop) are available at higher doses. Folic acid is now fortified in white bread. If you eat the pyramid level of grains you get only 160micrograms/day→not enough to prevent neural tube defects. We may see fortified folic acid levels go up in the near future.

Dosage: Multivitamins usually contain between 200 and 800 mcg of folic acid. Doses above 800 mcg are not generally found on OTC products due to concern about masking diagnosis of pernicious anemia. If you mask a Dx of pernicious anemia by giving high dose folic acid your pt will later present w/ an irreversible neuropathy. High risk of pernicious anemia→elderly (atrophic gastritis), auto-immune dz’s. Specialty products (I have used a folic acid mouthwash- they tell you how much folic acid is in each drop) are available at higher doses. Folic acid is now fortified in white bread. If you eat the pyramid level of grains you get only 160micrograms/day→not enough to prevent neural tube defects. We may see fortified folic acid levels go up in the near future.

Drug InteractionsDrug Interactions• 1) Large doses (15 mg/day) may interfere with the

anticonvulsant effect of phenytoin (dilantin) and may also have a mild epileptogenic effect. Conversely, administration of phenytoin may promote folic acid deficiency. Smaller doses of folic acid, such as 1 mg/day, do not appear to promote seizures in patients taking phenytoin and may, in fact, improve their clinical condition*.

2) Folic acid may interfere with the anti-cancer effect of methotrexate (Tx CA and RA). However, when methotrexate is being used to treat rheumatoid arthritis, administration of 1 mg of folic acid 5 days a week (taken when methotrexate is not being ingested) has been shown to reduce methotrexate toxicity without diminishing its efficacy.* Don’t recommend using folate along w/ methotrexate in Tx for CA (vs. RA) as effects are not known.

• 1) Large doses (15 mg/day) may interfere with the anticonvulsant effect of phenytoin (dilantin) and may also have a mild epileptogenic effect. Conversely, administration of phenytoin may promote folic acid deficiency. Smaller doses of folic acid, such as 1 mg/day, do not appear to promote seizures in patients taking phenytoin and may, in fact, improve their clinical condition*.

2) Folic acid may interfere with the anti-cancer effect of methotrexate (Tx CA and RA). However, when methotrexate is being used to treat rheumatoid arthritis, administration of 1 mg of folic acid 5 days a week (taken when methotrexate is not being ingested) has been shown to reduce methotrexate toxicity without diminishing its efficacy.* Don’t recommend using folate along w/ methotrexate in Tx for CA (vs. RA) as effects are not known.

Drug InteractionsDrug Interactions• 3. Sulfasalazine (used to Tx UC→these pts have ↑risk of colon

CA already and we are ↓folic acid which helps prevent colon CA→use 2.5micrograms/day), oral contraceptives, trimethoprim, alcohol, and tobacco smoke each may promote folic acid deficiency.* Sulfasalazine is used to Tx UC→these pts have ↑risk of colon CA already and we are ↓folic acid which helps prevent colon CA→use 2.5micrograms/day of folic acid to counter this.

• 4. 5-fluorouracil is commonly given with an agent called leukovorin, which is an active form of folic acid. It is not currently known whether nutritional folic acid interferes with the action of leukovorin

• 5. High doses of folic acid may interfere with the laboratory diagnosis of pernicious anemia→ don’t use folic acid supplementation above 800micrograms.

• 3. Sulfasalazine (used to Tx UC→these pts have ↑risk of colon CA already and we are ↓folic acid which helps prevent colon CA→use 2.5micrograms/day), oral contraceptives, trimethoprim, alcohol, and tobacco smoke each may promote folic acid deficiency.* Sulfasalazine is used to Tx UC→these pts have ↑risk of colon CA already and we are ↓folic acid which helps prevent colon CA→use 2.5micrograms/day of folic acid to counter this.

• 4. 5-fluorouracil is commonly given with an agent called leukovorin, which is an active form of folic acid. It is not currently known whether nutritional folic acid interferes with the action of leukovorin

• 5. High doses of folic acid may interfere with the laboratory diagnosis of pernicious anemia→ don’t use folic acid supplementation above 800micrograms.

Toxicity - Folic AcidToxicity - Folic Acid

• High doses may provoke seizures in people with epilepsy.

• High doses may provoke seizures in people with epilepsy.

Pantothenic Acid - B5Pantothenic Acid - B5

High Cholesterol and High TrigsBiochemistry: Pantothenic acid is a precursor to coenzyme A. This cofactor is involved in many metabolic pathways, including energy metabolism. Manufacture of fats and cholesterol also depend on pantothenic acid.

Uncommon deficiency. Found in dairy, meats, and grains. RDA=1-2mg

High Cholesterol and High TrigsBiochemistry: Pantothenic acid is a precursor to coenzyme A. This cofactor is involved in many metabolic pathways, including energy metabolism. Manufacture of fats and cholesterol also depend on pantothenic acid.

Uncommon deficiency. Found in dairy, meats, and grains. RDA=1-2mg

PantethinePantethine

Biochemistry: Pantethine is a disulfide form of pantothenic acid.Biochemistry: Pantethine is a disulfide form of pantothenic acid.

Indications- PantethineIndications- Pantethine1)Hyperlipidemia (and high Triglycerides): Pantethine, usually at a dose of 300 mg, 3-4 times per day, has been shown to reduce serum cholesterol and triglyceride levels and to raise HDL (like niacin) cholesterol in patients with hyperlipidemia (double-blind trials). One of the favorite Tx’s when diet and lifestyle alone are not able to bring down cholesterol levels. It is common for supplement companies to combine different nutrients together in sub-therapeutic doses hoping that there will be a synergistic effect→perhaps this is a poor strategy. Keep this in mind when prescribing - check that the nutrients in the formulas you are prescribing are present in therapeutic levels. Mechanism is unknown. Expect a 10-20% drop in cholesterol levels w/ this Tx.

1)Hyperlipidemia (and high Triglycerides): Pantethine, usually at a dose of 300 mg, 3-4 times per day, has been shown to reduce serum cholesterol and triglyceride levels and to raise HDL (like niacin) cholesterol in patients with hyperlipidemia (double-blind trials). One of the favorite Tx’s when diet and lifestyle alone are not able to bring down cholesterol levels. It is common for supplement companies to combine different nutrients together in sub-therapeutic doses hoping that there will be a synergistic effect→perhaps this is a poor strategy. Keep this in mind when prescribing - check that the nutrients in the formulas you are prescribing are present in therapeutic levels. Mechanism is unknown. Expect a 10-20% drop in cholesterol levels w/ this Tx.

Dosage, Interaction, ToxicityDosage, Interaction, Toxicity

Dosage: Usual dose is 300 mg tid-qid

Toxicity: No toxicity symptoms reported.

Dosage: Usual dose is 300 mg tid-qid

Toxicity: No toxicity symptoms reported.

B6B6Biochemistry: Vitamin B6 is involved in transamination and decarboxylation. These reactions are both very widespread, so deficiency of vitamin B6 can show up in many different systems (not just a liver nutrient). These include the nervous system, hematopoesis, one-carbon metabolism, and drug or metabolite clearance in the liver. Every time you see B6 in a biochemical pathway it uses Mg as a co-factor. B6 used in Homocysteine/methylation pathway.

Dr Gaby wrote a good book on B6.

Fairly common deficiency (maybe 5-10%). Mg is a common deficiency.

How do you know if a pt is deficient. Based on RBC indices, diet pattern, clinical presentation. Generally don’t test directly as these tests are expensive and b-vit supplements are fairly cheap→therapeutic trial

Biochemistry: Vitamin B6 is involved in transamination and decarboxylation. These reactions are both very widespread, so deficiency of vitamin B6 can show up in many different systems (not just a liver nutrient). These include the nervous system, hematopoesis, one-carbon metabolism, and drug or metabolite clearance in the liver. Every time you see B6 in a biochemical pathway it uses Mg as a co-factor. B6 used in Homocysteine/methylation pathway.

Dr Gaby wrote a good book on B6.

Fairly common deficiency (maybe 5-10%). Mg is a common deficiency.

How do you know if a pt is deficient. Based on RBC indices, diet pattern, clinical presentation. Generally don’t test directly as these tests are expensive and b-vit supplements are fairly cheap→therapeutic trial

Indications- B6Indications- B6

Anemia, Autism, Depression, High Homocysteine Levels, PMS, Morning SicknessPremenstrual syndrome (PMS): Controlled trials, some conflicting, have shown that 50-200 mg/day relieves various symptoms of PMS. Higher doses are sometimes used during the premenstrual phase. Vitamin B6 may also alleviate premenstrual acne flare-ups (uncontrolled trial). Vitamin B6 may be more effective when used in combination with magnesium, vitamin E, and other nutrients (theoretical). (?) Tx of PMS is one of most common uses for B6.

Anemia, Autism, Depression, High Homocysteine Levels, PMS, Morning SicknessPremenstrual syndrome (PMS): Controlled trials, some conflicting, have shown that 50-200 mg/day relieves various symptoms of PMS. Higher doses are sometimes used during the premenstrual phase. Vitamin B6 may also alleviate premenstrual acne flare-ups (uncontrolled trial). Vitamin B6 may be more effective when used in combination with magnesium, vitamin E, and other nutrients (theoretical). (?) Tx of PMS is one of most common uses for B6.

Indications-B6Indications-B6

1)Depression: In a double-blind study, women with depression associated with the use of oral contraceptives responded to 20 mg twice a day.

In an uncontrolled trial, patients with diet-controlled celiac disease reported an improvement in depression after receiving 80 mg/day for 6 months.

1)Depression: In a double-blind study, women with depression associated with the use of oral contraceptives responded to 20 mg twice a day.

In an uncontrolled trial, patients with diet-controlled celiac disease reported an improvement in depression after receiving 80 mg/day for 6 months.

Indications- B6Indications- B64)Pregnancy:

a. Nausea and vomiting (prevention and treatment): 30-75 mg/day was effective in 2 double-blind trials. Ginger can also be used.

b. Preeclampsia (prevention and treatment): Small doses, such as 10-20 mg/day throughout pregnancy, may reduce the incidence of preeclampsia (data are conflicting). Large oral doses (up to several hundred mg/day for several days), along with magnesium, have been used to treat incipient preeclampsia (clinical observation – Ellis JM). Intravenous vitamin B6 (up to 500 mg) and magnesium (0.5-1 g of magnesium chloride or magnesium sulfate) may reverse edema and hypertension in acute situations (clinical observation – Wright JV). Diagnostic criteria for preeclampsia= HTN, edema, protenuria. Some mid-wives say high protein diets help Tx preeclampsia→There is weak evidence for this and it’s dangerous to ↑ protein in someone who is already having kidney issues (proteinuria→kidneys can’t handle protein levels)

c. Birth defects: Vitamin B6 may help prevent intrauterine growth retardation, cleft palate and other birth defects (homocysteine connection).

4)Pregnancy:a. Nausea and vomiting (prevention and treatment): 30-75 mg/day

was effective in 2 double-blind trials. Ginger can also be used. b. Preeclampsia (prevention and treatment): Small doses, such as

10-20 mg/day throughout pregnancy, may reduce the incidence of preeclampsia (data are conflicting). Large oral doses (up to several hundred mg/day for several days), along with magnesium, have been used to treat incipient preeclampsia (clinical observation – Ellis JM). Intravenous vitamin B6 (up to 500 mg) and magnesium (0.5-1 g of magnesium chloride or magnesium sulfate) may reverse edema and hypertension in acute situations (clinical observation – Wright JV). Diagnostic criteria for preeclampsia= HTN, edema, protenuria. Some mid-wives say high protein diets help Tx preeclampsia→There is weak evidence for this and it’s dangerous to ↑ protein in someone who is already having kidney issues (proteinuria→kidneys can’t handle protein levels)

c. Birth defects: Vitamin B6 may help prevent intrauterine growth retardation, cleft palate and other birth defects (homocysteine connection).

Indications-B6Indications-B6

1)Autism: In double-blind trials, vitamin B6 (30 mg/kg/day), combined with magnesium (10 mg/kg/day), resulted in behavioral improvements in about one-third of autistic children (increased alertness, fewer emotional outbursts, less self-mutilation). Monitor for signs of vitamin B6 toxicity with large doses. Not recommended for two reasons: 1) he has talked to parents who found this ineffective and 2) children w/ autism experience pain differently and have difficulty communicating their experience of pain. Because this therapeutic dose is so high you may cause problems w/o knowing it since these pts have different perceptions of pain may not be able to communicate these side effects to you.

1)Autism: In double-blind trials, vitamin B6 (30 mg/kg/day), combined with magnesium (10 mg/kg/day), resulted in behavioral improvements in about one-third of autistic children (increased alertness, fewer emotional outbursts, less self-mutilation). Monitor for signs of vitamin B6 toxicity with large doses. Not recommended for two reasons: 1) he has talked to parents who found this ineffective and 2) children w/ autism experience pain differently and have difficulty communicating their experience of pain. Because this therapeutic dose is so high you may cause problems w/o knowing it since these pts have different perceptions of pain may not be able to communicate these side effects to you.

Dosage- B6Dosage- B6• Dosage: The usual dosage range is 10-200

mg/day. Larger doses have been used in some situations. Almost all published research on vitamin B6 therapy has used pyridoxine. In theory, pyridoxal-5'-phosphate (PLP) would be more effective than pyridoxine if the body's ability to convert pyridoxine to PLP is impaired; however, the absorption of oral PLP has not been well studied, and is believed to be poor.* Take home: There appears to be no benefit to using the activated form clinically.

• Dosage: The usual dosage range is 10-200 mg/day. Larger doses have been used in some situations. Almost all published research on vitamin B6 therapy has used pyridoxine. In theory, pyridoxal-5'-phosphate (PLP) would be more effective than pyridoxine if the body's ability to convert pyridoxine to PLP is impaired; however, the absorption of oral PLP has not been well studied, and is believed to be poor.* Take home: There appears to be no benefit to using the activated form clinically.

Interactions- B6Interactions- B6Interactions: Phenelzine, isoniazid, theophylline, oral contraceptives, hydralazine, tartrazine (FD&C Yellow #5), tobacco smoke, and pesticides and other agricultural chemicals that are structurally similar to hydrazine may cause a deficiency.*

a. Isoniazid (Tx for TB): Peripheral neuropathy induced by isoniazid may be prevented by administration of 50 mg/day of vitamin B6. However, larger doses could theoretically interfere with the anti-tuberculous effect of isoniazid.*

b. Hydralazine (Tx for HTN): Administration of vitamin B6 could theoretically reduce the risk of drug-induced lupus from hydralazine and other hydrazine analogs.*

c. Oral Contraceptives: Vitamin B6 may prevent or improve depression resulting from use of oral contraceptives.*

2)Vitamin B6 may interfere with the therapeutic effect of L-dopa (precursor to dopamine, historically used to Tx parkinsons) when L-dopa is used alone (i.e., without carbidopa). However, vitamin B6 may enhance the effect of Sinemet (L-dopa plus carbidopa).* L-dopa (but not carbidopa) can be converted to dopamine in circulation in presence of B6→not a good thing since we want the conversion to occur in the CNS, but no one is really on L-dopa anymore so this isn’t much of an issue clinically.3)Magnesium is a cofactor in many B6-dependent enzymes, and as such there is a large degree of overlap between the clinical uses of the two nutrients.

Interactions: Phenelzine, isoniazid, theophylline, oral contraceptives, hydralazine, tartrazine (FD&C Yellow #5), tobacco smoke, and pesticides and other agricultural chemicals that are structurally similar to hydrazine may cause a deficiency.*

a. Isoniazid (Tx for TB): Peripheral neuropathy induced by isoniazid may be prevented by administration of 50 mg/day of vitamin B6. However, larger doses could theoretically interfere with the anti-tuberculous effect of isoniazid.*

b. Hydralazine (Tx for HTN): Administration of vitamin B6 could theoretically reduce the risk of drug-induced lupus from hydralazine and other hydrazine analogs.*

c. Oral Contraceptives: Vitamin B6 may prevent or improve depression resulting from use of oral contraceptives.*

2)Vitamin B6 may interfere with the therapeutic effect of L-dopa (precursor to dopamine, historically used to Tx parkinsons) when L-dopa is used alone (i.e., without carbidopa). However, vitamin B6 may enhance the effect of Sinemet (L-dopa plus carbidopa).* L-dopa (but not carbidopa) can be converted to dopamine in circulation in presence of B6→not a good thing since we want the conversion to occur in the CNS, but no one is really on L-dopa anymore so this isn’t much of an issue clinically.3)Magnesium is a cofactor in many B6-dependent enzymes, and as such there is a large degree of overlap between the clinical uses of the two nutrients.

Toxicity- B6Toxicity- B6

1.High doses of vitamin B6 can cause a neuropathy in stocking and glove distribution. It is currently controversial at what level this becomes an issue. Some sources have reported this symptom occurring at doses as low as 10 mg per day. Many nutritional experts have concluded this symptom is unlikely to occur at doses below 200 mg/day. The National Academy of Sciences has defined a safe upper limit of 100 mg/day of vitamin B6. Recommend having pts call you if they get sx’s of stocking and glove neuropathy if giving over 100mg/day.

1.High doses of vitamin B6 can cause a neuropathy in stocking and glove distribution. It is currently controversial at what level this becomes an issue. Some sources have reported this symptom occurring at doses as low as 10 mg per day. Many nutritional experts have concluded this symptom is unlikely to occur at doses below 200 mg/day. The National Academy of Sciences has defined a safe upper limit of 100 mg/day of vitamin B6. Recommend having pts call you if they get sx’s of stocking and glove neuropathy if giving over 100mg/day.

B12B12

1. Biochemistry: Vitamin B12 is involved in methyl group transfers as part of one-carbon metabolism. It is also involved in the reduction of ribose to deoxyribose in DNA synthesis. Vitamin B12 is also a factor in normal nerve function, and deficiency can be marked by nerve demyelination.

2. At pharmacologic doses but not nutritional doses (at least very well) it scavenges nitrogen radicals (next slide)→ associate w/ neurodegenerative dz’s. This is a possible mechanism of how B12 helps w/ neurodegenerative dz’s

1. Biochemistry: Vitamin B12 is involved in methyl group transfers as part of one-carbon metabolism. It is also involved in the reduction of ribose to deoxyribose in DNA synthesis. Vitamin B12 is also a factor in normal nerve function, and deficiency can be marked by nerve demyelination.

2. At pharmacologic doses but not nutritional doses (at least very well) it scavenges nitrogen radicals (next slide)→ associate w/ neurodegenerative dz’s. This is a possible mechanism of how B12 helps w/ neurodegenerative dz’s

What’s a Nitrogen Radical?What’s a Nitrogen Radical?

• Free Radicals?• Free Radicals?

DefinedDefined

• Free radicals, also known simply as radicals, are organic

molecules responsible for aging, tissue damage, and

possibly some diseases. These molecules are very unstable,

therefore they look to bond with other molecules,

destroying their health and further continuing the

damaging process. Antioxidants, present in many foods,

are molecules that prevent free radicals from harming

healthy tissue.

• Free radicals, also known simply as radicals, are organic

molecules responsible for aging, tissue damage, and

possibly some diseases. These molecules are very unstable,

therefore they look to bond with other molecules,

destroying their health and further continuing the

damaging process. Antioxidants, present in many foods,

are molecules that prevent free radicals from harming

healthy tissue.

Indications- B12Indications- B12

*High Homocysteine, Depression and Anemia, Deficiency

1)Fatigue, anxiety, depression, insomnia: (double-blind trial for fatigue; anecdotal for other symptoms) study showed B12 shots helped w/ fatigue even in those that did not have a B12 deficiency. This is not a reliable Tx over time but still use it when can’t find a physiologic or dietary issue.

*High Homocysteine, Depression and Anemia, Deficiency

1)Fatigue, anxiety, depression, insomnia: (double-blind trial for fatigue; anecdotal for other symptoms) study showed B12 shots helped w/ fatigue even in those that did not have a B12 deficiency. This is not a reliable Tx over time but still use it when can’t find a physiologic or dietary issue.

Indications - B12Indications - B12

1)Diabetic complications:a. Neuropathy: Intramuscular injections, given in varying doses and

frequencies, and for varying periods of time, have been reported to relieve symptoms (uncontrolled trials, conflicting results). In top 5 Tx’s for diabetic neuropathy. People w/ diabetes, hashimotos, and celiacs have ↑ rates of anti-parietal cell antibodies→pernicious anemia.

b. Retinopathy: Daily subcutaneous administration of 100 mcg of vitamin B12 (along with insulin) for 1 year completely reversed signs of retinopathy in 7 of 15 type 1 diabetics (uncontrolled trial).

1)Diabetic complications:a. Neuropathy: Intramuscular injections, given in varying doses and

frequencies, and for varying periods of time, have been reported to relieve symptoms (uncontrolled trials, conflicting results). In top 5 Tx’s for diabetic neuropathy. People w/ diabetes, hashimotos, and celiacs have ↑ rates of anti-parietal cell antibodies→pernicious anemia.

b. Retinopathy: Daily subcutaneous administration of 100 mcg of vitamin B12 (along with insulin) for 1 year completely reversed signs of retinopathy in 7 of 15 type 1 diabetics (uncontrolled trial).

Indications - B12Indications - B12

1)Neurological disorders: sciatica, trigeminal neuralgia, Bell's palsy, prevention of postherpetic neuralgia: 1,000 mcg intramuscularly, 2-3 times per week for 2-3 weeks, then taper according to response. Treatment is said to work better for some of these conditions when given in combination with thiamine, 50 mg per injection. Evidence is mostly anecdotal; however, there is one randomized trial in which methylcobalamin (500 mcg, 3 times per week for a maximum of 8 weeks) promoted significantly faster recovery [MSB note: 80% faster!] from Bell's palsy than did prednisolone. Conventional Tx is prednisone (oral steroids). Bells palsy usually self-resolves in about 3mo. Prednisone will cause resolution in 9 days. B12 will cause resolution in 2 days. You don’t have to do anything to Tx Bell’s palsy, but if you want to Tx this is a good way to go.

1)Neurological disorders: sciatica, trigeminal neuralgia, Bell's palsy, prevention of postherpetic neuralgia: 1,000 mcg intramuscularly, 2-3 times per week for 2-3 weeks, then taper according to response. Treatment is said to work better for some of these conditions when given in combination with thiamine, 50 mg per injection. Evidence is mostly anecdotal; however, there is one randomized trial in which methylcobalamin (500 mcg, 3 times per week for a maximum of 8 weeks) promoted significantly faster recovery [MSB note: 80% faster!] from Bell's palsy than did prednisolone. Conventional Tx is prednisone (oral steroids). Bells palsy usually self-resolves in about 3mo. Prednisone will cause resolution in 9 days. B12 will cause resolution in 2 days. You don’t have to do anything to Tx Bell’s palsy, but if you want to Tx this is a good way to go.

Indications- B12Indications- B12

1)Dementia: Intramuscular injections of vitamin B12 may be helpful for some patients with dementia (uncontrolled trials and circumstantial evidence, based on low vitamin B12 levels in cerebrospinal fluid, despite normal blood levels). Not clear which pts w/ dementia this Tx will be helpful. Keep in mind, A certain # of your pts will have undiagnosed atrophic gastritis→B12 def

1)Dementia: Intramuscular injections of vitamin B12 may be helpful for some patients with dementia (uncontrolled trials and circumstantial evidence, based on low vitamin B12 levels in cerebrospinal fluid, despite normal blood levels). Not clear which pts w/ dementia this Tx will be helpful. Keep in mind, A certain # of your pts will have undiagnosed atrophic gastritis→B12 def

Dosage- B12Dosage- B12Dosage: For prevention of a deficiency, 2-10 mcg per day p.o. should generally be sufficient. For most of the conditions listed above, megadoses are indicated, usually given intramuscularly. I.M. vitamin B12 is often administered 1000-2000 mcg from one per week to every day. For patients with pernicious anemia (and therefore malabsorption of vitamin B12 due to low production of intrinsic factor), oral vitamin B12 at doses above 1000 mcg per day is sufficient for maintenance. The efficacy of sublingual preparations of vitamin B12 has not been compared to oral or parenteral administration. For most indications, the relative efficacy of the different parenteral preparations (hydroxycobalamin, cyanocobalamin, methylcobalamin) has not been determined. Sublingual products tend to be very expensive and may not be worth the extra $$$

Dosage: For prevention of a deficiency, 2-10 mcg per day p.o. should generally be sufficient. For most of the conditions listed above, megadoses are indicated, usually given intramuscularly. I.M. vitamin B12 is often administered 1000-2000 mcg from one per week to every day. For patients with pernicious anemia (and therefore malabsorption of vitamin B12 due to low production of intrinsic factor), oral vitamin B12 at doses above 1000 mcg per day is sufficient for maintenance. The efficacy of sublingual preparations of vitamin B12 has not been compared to oral or parenteral administration. For most indications, the relative efficacy of the different parenteral preparations (hydroxycobalamin, cyanocobalamin, methylcobalamin) has not been determined. Sublingual products tend to be very expensive and may not be worth the extra $$$

Drug InteractionsDrug Interactions

1)Antacids and drugs that inhibit gastric acid secretion may impair the absorption of vitamin B12 from food. However, these drugs do not impair the absorption of vitamin B12 from supplements. Potassium citrate, potassium chloride, colchicine, and some oral hypoglycemic agents inhibit vitamin B12 absorption. In an animal study, a single dose of methylcobalamin (1 mg/kg intramuscularly) reduced the ototoxic effect of gentamicin.*

2)Large doses of vitamin B12 may increase the requirement for folic acid.*

3)Infection with H. pylori appears to reduce the ability to absorb oral vitamin B12.

1)Antacids and drugs that inhibit gastric acid secretion may impair the absorption of vitamin B12 from food. However, these drugs do not impair the absorption of vitamin B12 from supplements. Potassium citrate, potassium chloride, colchicine, and some oral hypoglycemic agents inhibit vitamin B12 absorption. In an animal study, a single dose of methylcobalamin (1 mg/kg intramuscularly) reduced the ototoxic effect of gentamicin.*

2)Large doses of vitamin B12 may increase the requirement for folic acid.*

3)Infection with H. pylori appears to reduce the ability to absorb oral vitamin B12.

Toxicity - B12Toxicity - B12

• Well Tolerated• Well Tolerated

PABAPABA

Biochemistry: Acts as a sunscreen topically (not orally). Potentates the action of steroid hormones, including cortisol. Prevents fibrosis.

Biochemistry: Acts as a sunscreen topically (not orally). Potentates the action of steroid hormones, including cortisol. Prevents fibrosis.

Indications-PABAIndications-PABA

1)Sunscreen: Applied topically, PABA is an effective sunscreen. The evidence that sun exposure is involved in melanoma is not actually very clear→differences btwn research and public health recommendation. Not clear if PABA sunscreen allergies translates to oral PABA administration.

2)Some autoimmune diseases, fibrotic conditions, or connective-tissue disorders: PABA may be helpful in the treatment of Peyronie’s disease (fibrotic condition that causes painful erections), scleroderma, and dermatomyositis (uncontrolled trials). Only controlled trial in scleroderma found no benefit to related compound aminobenzoate potassium.

3) Infertility: Administration of 100 mg of PABA, 4 times per day for 3-7 months, to 16 women with infertility of at least 5 years' duration resulted in pregnancy in 75% of cases (uncontrolled trial).* Very compelling therapy and not very expensive.

1)Sunscreen: Applied topically, PABA is an effective sunscreen. The evidence that sun exposure is involved in melanoma is not actually very clear→differences btwn research and public health recommendation. Not clear if PABA sunscreen allergies translates to oral PABA administration.

2)Some autoimmune diseases, fibrotic conditions, or connective-tissue disorders: PABA may be helpful in the treatment of Peyronie’s disease (fibrotic condition that causes painful erections), scleroderma, and dermatomyositis (uncontrolled trials). Only controlled trial in scleroderma found no benefit to related compound aminobenzoate potassium.

3) Infertility: Administration of 100 mg of PABA, 4 times per day for 3-7 months, to 16 women with infertility of at least 5 years' duration resulted in pregnancy in 75% of cases (uncontrolled trial).* Very compelling therapy and not very expensive.

No primary indications

Dosage, Interaction, ToxicityDosage, Interaction, Toxicity

Dosage: The usual dosage ranges are 100 mg, 3-4 times per day, for estrogen potentiation, and 1-3 g, 4 times per day, for autoimmune diseases, fibrotic disorders, and glucocorticoid potentiation. PABA is available as potassium para-aminobenzoate (Potaba) by prescription, or as PABA over the counter. Potaba is somewhat better tolerated than PABA, but it is more expensive.*

Interactions: PABA is contraindicated with sulfonamide antibiotics, which work by depletion of PABA→bacteria need PABA to grow so you don’t want to supplement w/ PABA at the same time you are using sulfonamide Abx.

Toxicity: May cause fever or rash at doses greater than 12 g/day. Rare cases of fatal idiosyncratic reactions have been reported. Large doses may cause hypoglycemia; treatment should therefore be interrupted during periods in which food intake is inadequate.*

Dosage: The usual dosage ranges are 100 mg, 3-4 times per day, for estrogen potentiation, and 1-3 g, 4 times per day, for autoimmune diseases, fibrotic disorders, and glucocorticoid potentiation. PABA is available as potassium para-aminobenzoate (Potaba) by prescription, or as PABA over the counter. Potaba is somewhat better tolerated than PABA, but it is more expensive.*

Interactions: PABA is contraindicated with sulfonamide antibiotics, which work by depletion of PABA→bacteria need PABA to grow so you don’t want to supplement w/ PABA at the same time you are using sulfonamide Abx.

Toxicity: May cause fever or rash at doses greater than 12 g/day. Rare cases of fatal idiosyncratic reactions have been reported. Large doses may cause hypoglycemia; treatment should therefore be interrupted during periods in which food intake is inadequate.*

CholineCholine

Biochemistry: Methyl-group donor. Involved in the synthesis of carnitine, membrane phospholipids, and acetylcholine.* Some research suggests that supplemental choline does not affect neurotransmitter levels.

Part of the neurotransmitter called Acetylcholine. There is no evidence that choline is involved in the rate limiting step in the production of Ach.

Lipotropic factor- something that can prevent fatty liver in animal models. Choline, inosital and methionine deficiencies in animal studies (rats) leads to fatty liver.

Biochemistry: Methyl-group donor. Involved in the synthesis of carnitine, membrane phospholipids, and acetylcholine.* Some research suggests that supplemental choline does not affect neurotransmitter levels.

Part of the neurotransmitter called Acetylcholine. There is no evidence that choline is involved in the rate limiting step in the production of Ach.

Lipotropic factor- something that can prevent fatty liver in animal models. Choline, inosital and methionine deficiencies in animal studies (rats) leads to fatty liver.

Indications- CholineIndications- Choline

1)Fatty liver:* Choline is one of the ‘lipotropic factors’, nutrients that prevent fatty liver in animal studies.

2)Blepharospasm: Choline in doses of approximately 2-6 g/day was helpful in 3 of 8 patients (uncontrolled trial).

1)Fatty liver:* Choline is one of the ‘lipotropic factors’, nutrients that prevent fatty liver in animal studies.

2)Blepharospasm: Choline in doses of approximately 2-6 g/day was helpful in 3 of 8 patients (uncontrolled trial).

No Primary Indications

Dosage, Interaction, ToxicityDosage, Interaction, Toxicity

Dosage: The usual dosage range is 1-4 g/day; higher doses have been used in some cases. Choline dihydrogen citrate is said to be more palatable than choline chloride. Food can be an important source of choline. Major food sources include peanuts, whole wheat, cauliflower, eggs, and lettuce.*

Toxicity: Doses above 9 grams per day have been reported to cause depression (know this for exam). High doses of choline can cause a fishy body odor.*

Dosage: The usual dosage range is 1-4 g/day; higher doses have been used in some cases. Choline dihydrogen citrate is said to be more palatable than choline chloride. Food can be an important source of choline. Major food sources include peanuts, whole wheat, cauliflower, eggs, and lettuce.*

Toxicity: Doses above 9 grams per day have been reported to cause depression (know this for exam). High doses of choline can cause a fishy body odor.*

Vitamin C Vitamin C

• A bazillion PRIMARY indications. See Healthnotes• A bazillion PRIMARY indications. See Healthnotes

Vitamin CVitamin C

Biochemistry: Involved in the manufacture of collagen. Water-soluble antioxidant. Protects LDL against oxidation (early event in the pathophysiology of atherosclerosis).

Deficiency= scurvy1.pathophysiology

a.vit c involved in the cross linking of collagen→not enough vit C→weak connective tissue

2.gum deformation•bone deformation

Biochemistry: Involved in the manufacture of collagen. Water-soluble antioxidant. Protects LDL against oxidation (early event in the pathophysiology of atherosclerosis).

Deficiency= scurvy1.pathophysiology

a.vit c involved in the cross linking of collagen→not enough vit C→weak connective tissue

2.gum deformation•bone deformation

Indications- Vit CIndications- Vit C1)Common cold and other viral infections: Oral doses of 500 mg, 3 times per

day or more, up to bowel tolerance, may accelerate recovery. Some individuals with mononucleosis have reportedly tolerated up to 200 g/day during the acute stages of the illness. As their condition improved, the amount of vitamin C tolerated decreased. Intravenous administration of vitamin C in doses up to 75 g may be effective for acute viral infections (e.g., mononucleosis or hepatitis). There are numerous double-blind trials for the common cold, with most showing a reduction in severity, but no reduction in incidence. Evidence with respect to other viral illnesses is mostly anecdotal. One of the most prominent negative trials found a 20% reduction in symptom duration, but this was not statistically significant. Slight preventive effect, too.

mechanism of action Scavenging free radicals

2 clear patterns from research Must Vit C start early in dz Shortens duration (20-30%)

1)Common cold and other viral infections: Oral doses of 500 mg, 3 times per day or more, up to bowel tolerance, may accelerate recovery. Some individuals with mononucleosis have reportedly tolerated up to 200 g/day during the acute stages of the illness. As their condition improved, the amount of vitamin C tolerated decreased. Intravenous administration of vitamin C in doses up to 75 g may be effective for acute viral infections (e.g., mononucleosis or hepatitis). There are numerous double-blind trials for the common cold, with most showing a reduction in severity, but no reduction in incidence. Evidence with respect to other viral illnesses is mostly anecdotal. One of the most prominent negative trials found a 20% reduction in symptom duration, but this was not statistically significant. Slight preventive effect, too.

mechanism of action Scavenging free radicals

2 clear patterns from research Must Vit C start early in dz Shortens duration (20-30%)

Indications-Vit CIndications-Vit C

1)Atherosclerosis: Vitamin C, at a dose of 500 mg, 3 times per day for 2-6 months, induced regression of femoral atherosclerosis in 6 of 10 patients (controlled, unblinded trial). Vitamin C has been found to inhibit platelet aggregation, increase HDL cholesterol, and prevent endothelial dysfunction in humans. In one study, vitamin C at 500 mg tid helped to prevent restenosis (restenosis=renarrowing after angioplasty→80% of pts will have restenosis after 5yrs of angioplasty procedure) after angioplasty. Similar dose has been shown to improve arterial insufficiency before advent of angioplasty.

1)Atherosclerosis: Vitamin C, at a dose of 500 mg, 3 times per day for 2-6 months, induced regression of femoral atherosclerosis in 6 of 10 patients (controlled, unblinded trial). Vitamin C has been found to inhibit platelet aggregation, increase HDL cholesterol, and prevent endothelial dysfunction in humans. In one study, vitamin C at 500 mg tid helped to prevent restenosis (restenosis=renarrowing after angioplasty→80% of pts will have restenosis after 5yrs of angioplasty procedure) after angioplasty. Similar dose has been shown to improve arterial insufficiency before advent of angioplasty.

Indications- Vit CIndications- Vit C

1)Hypertension: At a dose of 500 mg/day, vitamin C produced significant reductions in systolic blood pressure in elderly individuals (double-blind trials).* Reduction in diastolic blood pressure was seen as well, but it did not reach statistical significance. Physiology lesson: Loss of compliance in the aorta can drive up systolic BP. If your systolic BP is above 140 (maybe even 130)→independent risk factor for stroke and kidney dz. Wide pulse split (40-50) → person may have atherosclerosis. Also when systolic is up and diastolic is not up think about using Vit C. When both systolic and diastolic is up think about minerals (potassium) and diet.

1)Hypertension: At a dose of 500 mg/day, vitamin C produced significant reductions in systolic blood pressure in elderly individuals (double-blind trials).* Reduction in diastolic blood pressure was seen as well, but it did not reach statistical significance. Physiology lesson: Loss of compliance in the aorta can drive up systolic BP. If your systolic BP is above 140 (maybe even 130)→independent risk factor for stroke and kidney dz. Wide pulse split (40-50) → person may have atherosclerosis. Also when systolic is up and diastolic is not up think about using Vit C. When both systolic and diastolic is up think about minerals (potassium) and diet.

Indications- Vit CIndications- Vit C

1)Asthma: Some, but not all, double-blind studies have shown a reduction in symptoms and in airway reactivity with 500-1,000 mg/day. Epidemiological studies indicate that increased vitamin C intake is associated with lower risk of asthma. This is especially effective if symptoms are related to pollution (mexico city has most polluted air). Children w/ asthma in mexico city. Vit C helped on the worst days of air quality but little affect on the best days of air quality. Vit C also helpful in kids w/ exercise induced asthma.

1)Asthma: Some, but not all, double-blind studies have shown a reduction in symptoms and in airway reactivity with 500-1,000 mg/day. Epidemiological studies indicate that increased vitamin C intake is associated with lower risk of asthma. This is especially effective if symptoms are related to pollution (mexico city has most polluted air). Children w/ asthma in mexico city. Vit C helped on the worst days of air quality but little affect on the best days of air quality. Vit C also helpful in kids w/ exercise induced asthma.

Indications-Vit CIndications-Vit C

1)Cancer: In an uncontrolled trial, 10 g/day of vitamin C increased the survival time of terminal cancer patients by more than 5-fold. This uncontrolled trial is criticized because they were comparing pts to historical controls from the 1970s→flaw=the care was different in the past. Two double-blind trials (one by Mayo clinic) failed to confirm these results; however, these trials have been criticized because of methodological flaws (urine of placebo group had vit C present & they looked at dz progression, not survival time. Looking at tumor shrinkage/dz progression is more appropriate for assessing chemo Tx not Vit C Tx). The role of vitamin C in cancer therapy remains controversial.*

Linus Pauling came up w/ this use. Using anti-oxidants w/ chemo remains controversial. Lots of people are using high dose IV vit C→may be a pro-oxidant therapy which has been shown to cause necrosis of CA cells (pro-oxidant Tx has worked w/ kidney CA’s, but these are also the most likely CA’s to spontaneously remit). research is shaky for IV vit C and has not seen good outcomes in clinics observed this Tx used in.

1)Cancer: In an uncontrolled trial, 10 g/day of vitamin C increased the survival time of terminal cancer patients by more than 5-fold. This uncontrolled trial is criticized because they were comparing pts to historical controls from the 1970s→flaw=the care was different in the past. Two double-blind trials (one by Mayo clinic) failed to confirm these results; however, these trials have been criticized because of methodological flaws (urine of placebo group had vit C present & they looked at dz progression, not survival time. Looking at tumor shrinkage/dz progression is more appropriate for assessing chemo Tx not Vit C Tx). The role of vitamin C in cancer therapy remains controversial.*

Linus Pauling came up w/ this use. Using anti-oxidants w/ chemo remains controversial. Lots of people are using high dose IV vit C→may be a pro-oxidant therapy which has been shown to cause necrosis of CA cells (pro-oxidant Tx has worked w/ kidney CA’s, but these are also the most likely CA’s to spontaneously remit). research is shaky for IV vit C and has not seen good outcomes in clinics observed this Tx used in.

Indications - Vit CIndications - Vit C

1)Glaucoma: High doses of vitamin C (10-35 g/day in divided doses) reduced intraocular pressure in patients with glaucoma (uncontrolled trials). Lower doses (such as 500 mg, 2 times per day) were of minimal benefit. Chronic simple glaucoma responded better than did secondary glaucoma or hemorrhagic glaucoma.

2)Lead accumulation: supplementation for one week with 1000 mg of vitamin C reduced blood lead levels in smokers by over 80%. 200 mg had no effect (J Am Coll Nutr. 1999 Apr;18(2):166-70). Lead of cig smoke dissolves in saliva and is absorbed via GI (not via lungs)→ vit C may prevent this GI absorption.

3)Allergies: Vitamin C has been used empirically by many physicians to reduce symptoms of nasal allergy. Only published controlled trial showed no benefit to vitamin C. Basic science research has shown an antihistamine effect of vitamin C. Vit C and quercitin can prevent the degranulation of mast cells in test tubes but at levels that are not possible to achieve in human serum.

1)Glaucoma: High doses of vitamin C (10-35 g/day in divided doses) reduced intraocular pressure in patients with glaucoma (uncontrolled trials). Lower doses (such as 500 mg, 2 times per day) were of minimal benefit. Chronic simple glaucoma responded better than did secondary glaucoma or hemorrhagic glaucoma.

2)Lead accumulation: supplementation for one week with 1000 mg of vitamin C reduced blood lead levels in smokers by over 80%. 200 mg had no effect (J Am Coll Nutr. 1999 Apr;18(2):166-70). Lead of cig smoke dissolves in saliva and is absorbed via GI (not via lungs)→ vit C may prevent this GI absorption.

3)Allergies: Vitamin C has been used empirically by many physicians to reduce symptoms of nasal allergy. Only published controlled trial showed no benefit to vitamin C. Basic science research has shown an antihistamine effect of vitamin C. Vit C and quercitin can prevent the degranulation of mast cells in test tubes but at levels that are not possible to achieve in human serum.

Dosage- Vit CDosage- Vit C

• Dosage: The usual dosage range is 200-3,000 mg/day. Larger doses (often

up to bowel tolerance) have been used for some conditions. Bowel tolerance is

determined by ingesting vitamin C in gradually increasing doses (usually 3-6

times per day) until abdominal pain and/or diarrhea occur, and then reducing

the dose to a level at which these symptoms do not occur. High Vit C increases

water in bowel→diarrhea. Vitamin C (pH neutralized) has been used

intravenously, in doses of 25-50 g or more, to treat patients with viral

infections.*

Certain anaerobic bacteria take Vit C and make gas. There is differential

absorption of vit C depending on the individual. Studies show that 400-500g

is maximal absorption of vit C in terms of increasing serum levels. Other

studies show a vast improvement in 1g dose vs 200mg. Maybe we absorb

more when our body needs it??

• Dosage: The usual dosage range is 200-3,000 mg/day. Larger doses (often

up to bowel tolerance) have been used for some conditions. Bowel tolerance is

determined by ingesting vitamin C in gradually increasing doses (usually 3-6

times per day) until abdominal pain and/or diarrhea occur, and then reducing

the dose to a level at which these symptoms do not occur. High Vit C increases

water in bowel→diarrhea. Vitamin C (pH neutralized) has been used

intravenously, in doses of 25-50 g or more, to treat patients with viral

infections.*

Certain anaerobic bacteria take Vit C and make gas. There is differential

absorption of vit C depending on the individual. Studies show that 400-500g

is maximal absorption of vit C in terms of increasing serum levels. Other

studies show a vast improvement in 1g dose vs 200mg. Maybe we absorb

more when our body needs it??

Interactions- Vit CInteractions- Vit C

1) Aspirin and tobacco smoke may promote vitamin C deficiency. Large doses of vitamin C may interfere with some narcotics and some general anesthetics. There is conflicting research on whether vitamin C (1,000 mg/day or more) increases the bioavailability of oral contraceptives.

2) A dose of 16 g/day of vitamin C was associated with an increased requirement for warfarin in one patient; 1,000 mg/day of vitamin C did not interfere with the effect of warfarin in other patients. Animal studies on the relationship between vitamin C and warfarin have yielded conflicting results.

3) The absorption of iron is enhanced by vitamin C. Large doses of vitamin C may induce copper deficiency. Concomitant administration of vitamin C may inactivate sodium selenite, but not organic forms.

1) Aspirin and tobacco smoke may promote vitamin C deficiency. Large doses of vitamin C may interfere with some narcotics and some general anesthetics. There is conflicting research on whether vitamin C (1,000 mg/day or more) increases the bioavailability of oral contraceptives.

2) A dose of 16 g/day of vitamin C was associated with an increased requirement for warfarin in one patient; 1,000 mg/day of vitamin C did not interfere with the effect of warfarin in other patients. Animal studies on the relationship between vitamin C and warfarin have yielded conflicting results.

3) The absorption of iron is enhanced by vitamin C. Large doses of vitamin C may induce copper deficiency. Concomitant administration of vitamin C may inactivate sodium selenite, but not organic forms.

Toxicity- Vit CToxicity- Vit C

1.Abdominal pain and diarrhea: These side effects occur commonly with high doses. The "bowel tolerance" dose varies from person to person and may increase during acute illness. Gastrointestinal side effects may be eliminated by reducing the dose, taking vitamin C in divided doses, taking the vitamin with meals, or using buffered forms of vitamin C. Breast-fed infants may develop colic if their mother ingests large doses of vitamin C.

3) Kidney Stones: Vitamin C does not appear to cause kidney stones in the general population,* as this has not appeared as a side effect in clinical trials. This has long been suspected to be associated with vitamin C use, since a case report was published in the early 1970’s. Some studies have shown that use of as little as 1 gram of vitamin C per day can increase urinary oxalate levels. If giving high dose Vit C w/ Hx of oxalate kid stones consider measuring urinary oxalate levels and if they ↑ then consider a different therapeutic.5) Iron overload: Ingestion of vitamin C may increase iron absorption, which could cause problems in individuals genetically predisposed to iron overload.6) Laboratory tests: Large doses of vitamin C may interfere with some stool tests for occult blood and some urine tests for glucose.*

1.Abdominal pain and diarrhea: These side effects occur commonly with high doses. The "bowel tolerance" dose varies from person to person and may increase during acute illness. Gastrointestinal side effects may be eliminated by reducing the dose, taking vitamin C in divided doses, taking the vitamin with meals, or using buffered forms of vitamin C. Breast-fed infants may develop colic if their mother ingests large doses of vitamin C.

3) Kidney Stones: Vitamin C does not appear to cause kidney stones in the general population,* as this has not appeared as a side effect in clinical trials. This has long been suspected to be associated with vitamin C use, since a case report was published in the early 1970’s. Some studies have shown that use of as little as 1 gram of vitamin C per day can increase urinary oxalate levels. If giving high dose Vit C w/ Hx of oxalate kid stones consider measuring urinary oxalate levels and if they ↑ then consider a different therapeutic.5) Iron overload: Ingestion of vitamin C may increase iron absorption, which could cause problems in individuals genetically predisposed to iron overload.6) Laboratory tests: Large doses of vitamin C may interfere with some stool tests for occult blood and some urine tests for glucose.*

FLAVONOIDSFLAVONOIDS

• Biochemistry: There are literally hundreds of flavonoids found in various fruits and

vegetables. Many of these have been isolated and researched for therapeutic use.

Flavonoids are generally potent antioxidants. Many of them help reduce capillary

fragility. Others are antihistamine, anti-inflammatory, and anticancer. Flavonoids are

similar in structure to steroid hormones, and some flavonoids have weak hormone-like

actions. Some flavonoids are water soluble (proanthocyanodins) and some are fat

soluble (quercitin) Flavonoids tend to be safe and have an affinity for the vasculature (Ix

for venous and arterial conditions). Relationship btwn flavonoids and vit c→early

research identified flavonoids (vit P) and vit C at same time. Found that Vit c and

flavonoids work better together than either alone (synergistic relationship). Hesperidin→

comes from citrus fruits and helps w/ hot flashes.

Vit C has been shown to improve neutrophil activity, especially in athletes. Marathon

runners given Vit C after a race are less likely to get an infxn. Not clear if vit C

improves immune function in non-athletes.

• Biochemistry: There are literally hundreds of flavonoids found in various fruits and

vegetables. Many of these have been isolated and researched for therapeutic use.

Flavonoids are generally potent antioxidants. Many of them help reduce capillary

fragility. Others are antihistamine, anti-inflammatory, and anticancer. Flavonoids are

similar in structure to steroid hormones, and some flavonoids have weak hormone-like

actions. Some flavonoids are water soluble (proanthocyanodins) and some are fat

soluble (quercitin) Flavonoids tend to be safe and have an affinity for the vasculature (Ix

for venous and arterial conditions). Relationship btwn flavonoids and vit c→early

research identified flavonoids (vit P) and vit C at same time. Found that Vit c and

flavonoids work better together than either alone (synergistic relationship). Hesperidin→

comes from citrus fruits and helps w/ hot flashes.

Vit C has been shown to improve neutrophil activity, especially in athletes. Marathon

runners given Vit C after a race are less likely to get an infxn. Not clear if vit C

improves immune function in non-athletes.

Indications- FlavonoidsIndications- Flavonoids

1)Capillary fragility: Hesperidin (sometimes referred to in older research as vitamin P) has been reported to reduce capillary fragility. First reported in JAMA in 1940. Horse chestnut is also used for capillary fragility. Also proanthocyanodins (pycnogenol- patented form). Would use a combination of hesperidin, horse chestnut and dietary sources of proanthocyanodins.

1)Capillary fragility: Hesperidin (sometimes referred to in older research as vitamin P) has been reported to reduce capillary fragility. First reported in JAMA in 1940. Horse chestnut is also used for capillary fragility. Also proanthocyanodins (pycnogenol- patented form). Would use a combination of hesperidin, horse chestnut and dietary sources of proanthocyanodins.

Chronic Venous Insufficiency and Hepatitis

Indications - FlavonoidsIndications - Flavonoids

1) Venous insufficiency: Controlled trials exist for rutin,

proanthocyanidins, horse chestnut and butcher’s broom.

2) Hemorrhoids: Most, but not all, double-blind trials have shown

flavonoid extracts (particularly the semi-synthetic

hydroxyethylrutosides) to be beneficial in the treatment of

hemorrhoids.3) Allergies: Many physicians have used quercetin to treat hay fever

symptoms, although no studies have been published to support its efficacy. Quercitin inhibits test tube degranulation of mast cells but can’t reach these levels in serum. Other possible mechanisms: Quercitin inhibits inflammatory response and may affect mast cells in the gut (not needed to be systemically absorbed)

1) Venous insufficiency: Controlled trials exist for rutin,

proanthocyanidins, horse chestnut and butcher’s broom.

2) Hemorrhoids: Most, but not all, double-blind trials have shown

flavonoid extracts (particularly the semi-synthetic

hydroxyethylrutosides) to be beneficial in the treatment of

hemorrhoids.3) Allergies: Many physicians have used quercetin to treat hay fever

symptoms, although no studies have been published to support its efficacy. Quercitin inhibits test tube degranulation of mast cells but can’t reach these levels in serum. Other possible mechanisms: Quercitin inhibits inflammatory response and may affect mast cells in the gut (not needed to be systemically absorbed)

Indications- FlavonoidsIndications- Flavonoids

1)Prostatitis: 500 mg bid of quercetin reduced symptoms in a double-blind placebo controlled trial. Interstitial cystitis→sterile inflammatory condition more likely in women. Some authors have hypothesized that IC in women is same condition as prostatitis in men. Quercitin has been shown effective in both conditions. These studies show that quercitin is absorbed (about 25% of the oral dose).

2)Hot flashes: At least two double-blind studies have shown a reduction in hot flashes in women taking soy isoflavones. This treatment does not appear to be successful in women who have undergone treatment for breast cancer.

3) Interstitial cystitis: Quercetin has been reported to be beneficial in a small pilot trial.

1)Prostatitis: 500 mg bid of quercetin reduced symptoms in a double-blind placebo controlled trial. Interstitial cystitis→sterile inflammatory condition more likely in women. Some authors have hypothesized that IC in women is same condition as prostatitis in men. Quercitin has been shown effective in both conditions. These studies show that quercitin is absorbed (about 25% of the oral dose).

2)Hot flashes: At least two double-blind studies have shown a reduction in hot flashes in women taking soy isoflavones. This treatment does not appear to be successful in women who have undergone treatment for breast cancer.

3) Interstitial cystitis: Quercetin has been reported to be beneficial in a small pilot trial.

Dosage - FlavonoidsDosage - Flavonoids

• Will Vary• Will Vary

Interactions and ToxicityInteractions and Toxicity

Interactions: Certain flavonoids, particularly those in grapefruit, have been shown to alter activity of cytochrome p450 enzymes (phase I detox enzyme). Those, again like grapefruit, that alter the 3A4 isoenzyme (responsible for metabolism of about ½ of all pharmaceutical drugs) will have multiple important drug interactions. Grapefruit juice will inhibit this enzyme leading to increased drug levels. Research in this area is new, and unfortunately very incomplete. If you are seeing side affects in a pt that you don’t expect look at diet and try to identify specific flavonoids showing up in diet. U of Indiana table will show meds and how it’s cleared from diet (http://medicine.iupui.edu/flockhart/). Indol-3-carbinol and st john’s wart will increase p450 enzyme levels, thus decreasing serum levels of drugs/compounds metabolized by this enzyme.Toxicity: Quercetin has been found to be mutagenic in vitro, and carcinogenic in one (but not in the majority) animal study. The clinical significance of this finding is not clear

Interactions: Certain flavonoids, particularly those in grapefruit, have been shown to alter activity of cytochrome p450 enzymes (phase I detox enzyme). Those, again like grapefruit, that alter the 3A4 isoenzyme (responsible for metabolism of about ½ of all pharmaceutical drugs) will have multiple important drug interactions. Grapefruit juice will inhibit this enzyme leading to increased drug levels. Research in this area is new, and unfortunately very incomplete. If you are seeing side affects in a pt that you don’t expect look at diet and try to identify specific flavonoids showing up in diet. U of Indiana table will show meds and how it’s cleared from diet (http://medicine.iupui.edu/flockhart/). Indol-3-carbinol and st john’s wart will increase p450 enzyme levels, thus decreasing serum levels of drugs/compounds metabolized by this enzyme.Toxicity: Quercetin has been found to be mutagenic in vitro, and carcinogenic in one (but not in the majority) animal study. The clinical significance of this finding is not clear

Next Week Next Week

• Macronutrients

• Quiz will be set Tomorrow EVE sometime, and you have until Friday at 5pm to complete it.

• Quiz covers: Fat Sol, Water Sol, Components of Healthy Diet, Malnutrition.

• Macronutrients

• Quiz will be set Tomorrow EVE sometime, and you have until Friday at 5pm to complete it.

• Quiz covers: Fat Sol, Water Sol, Components of Healthy Diet, Malnutrition.