cream

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364 Although the idea is attractive, anti-inflammatory activity cannot always be satisfactorily explained by antagonism of these chemical mediators. Evidence is mounting that the prostaglandins may also be involved in inflammation and that their effects may be influenced by the acidic non-steroid anti-inflammatory drugs. Prostaglandins have been detected in exudates from experimentally induced inflammation, and abnormally high concentrations of prostaglandins El, E2, Fia, and F201: were observed in skin perfusion studies in allergic volunteers with contact dermatitis challenged with skin-patch tests. 1 It is not known yet, however, whether prostaglandins are direct mediators of the inflammatory process, or whether they are released in response to the tissue reaction. Fenamic acids, phenylbutazone, and aspirin block the bronchoconstrictor activity of prostaglandin F 201:’ and aspirin or salicylate antagonise some of the effects of arachidonic acid, a prostaglandin precursor. 2 Vane and his colleagues 3-5 have now provided important evidence relating the actions of aspirin, sodium salicylate, and indomethacin to the prosta- glandins. They showed that these drugs inhibit the synthesis by guineapig lung homogenates of prosta- glandins E2 and F2« from arachidonic acid. The concentrations of aspirin and indomethacin causing 50 % reduction in prostaglandin F201: activity were 6-3 and 0-27 g. per ml. respectively-well within the ranges in plasma after therapeutic doses, even allowing for plasma-protein binding. Sodium salicyl- ate was less effective, and there was no inhibition with hydrocortisone, morphine, or mepyramine. Aspirin and indomethacin also inhibited the release of prosta- glandin E2 from the perfused dog spleen both under basal conditions and in response to injection of adrenaline. In some experiments as little as 370 ng. per ml. of indomethacin and 40 g. per ml. of aspirin abolished the release of prostaglandin induced by adrenaline. Furthermore, Smith and Willis have shown that aspirin and indomethacin strongly inhibit thrombin-induced release of prostaglandin E2 from human platelets. This effect was interpreted as inhibition of synthesis and appeared to be selective, since there was no inhibition of release of 5-hydroxy- tryptamine, p-N-acetyl glucosamidase, or phos- pholipase A. Again, the concentration of aspirin required for 50% inhibition was very low (0-3 jjt.g. per ml.; indomethacin was about ten times as potent as aspirin, and sodium salicylate was roughly ten times less effective. Furthermore, when platelets obtained from 3 volunteers one hour after ingestion of 600 mg. of aspirin were incubated with thrombin, prostaglandin Ez activity was only 5-20% of that observed in control studies. The same effect was observed in volunteers taking 50-100 mg. of indo- methacin. These observations have attracted much interest, and inhibition of prostaglandin synthesis may prove to be a common mechanism of action of the acidic 1. Greaves, M. W., Søndergaard, J., McDonald-Gibson, W. Br. med. J. 1971, ii, 258. 2. Collier, H. O. J. Nature, 1971, 232, 17. 3. Vane, J. R. Nature New Biol. 1971, 231, 232. 4. Ferreira, S. H., Moncada, S., Vane, J. R. ibid. p. 237. 5. Smith, J. B., Willis, A. L. ibid. p. 235. non-steroid anti-inflammatory drugs. The prosta- glandins are a group of widely distributed acidic lipids, which have striking pharmacological actions on many tissues and seem to act as local regulators of hormonal activity. Could other actions of aspirin and related drugs also be explained by inhibition of prostaglandin synthesis ? Vane suggests that anti- pyretic activity could be explained on this basis. Several prostaglandins (including E2 and F 2OC) produce fever on intracerebral injection, and prostaglandin E1 is the most potent pyrogen known. Paracetamol (which has no anti-inflammatory activity) does not antagonise fever induced by prostaglandin El, although it is apparently active against prostaglandins Pm, F2oc, and A1.1 Aspirin has well-documented effects on platelet adhesiveness and aggregation, but it is not known whether these effects are related to prosta- glandin release. Vane speculates that the gastro- intestinal toxicity of the anti-inflammatory drugs could be related to inhibition of prostaglandin syn- thesis, and he also raises the interesting possibility that these drugs might reduce the efficacy of intra- uterine contraceptive devices. Clearly, these findings open up many new areas for investigation and should stimulate further studies of the role of prostaglandins in different types of inflamma- tion. Anti-inflammatory agents might even prove useful in the treatment of other conditions involving prostaglandins (for example, threatened abortion)," 3 and studies of the physiological role of the prosta- glandins will be facilitated by the ability to selectively inhibit their synthesis. It is odd, however, to find that such a widely used drug as aspirin inhibits such apparently active compounds as prostaglandins Ea and F21X with so little obvious effect. CREAM THE consumption of fresh cream in Great Britain increases year by year, but there has been no corre- sponding increase in infectious disease from this source. Whatever its metabolic consequences, cream is, in fact, a more or less blameless foodstuff. It is true that there have been incidents of food-poisoning attributable to cream-name a food which has never been found guilty-but they are few. Nevertheless, a survey 6 of the cream trade by the Public Health Laboratory Service is welcome. Members of the committee observed the practices of 31 dairies engaged in the cream trade and examined just over 5000 sam- ples. Of these, 4385 were heat-treated, 517 untreated, and 282 were clotted cream. All were tested by a methylene-blue reduction test and by counts of total bacterial content, of coliforms, and of Escherichia coli type I. There were some anomalies in the results, but the general picture is fairly clear. By all tests, raw cream gave results less satisfactory than heat-treated cream. Clotted cream also gave good results, but it is a product which presents problems of its own. The process of clotting involves holding the cream for a considerable time at a near-bactericidal temperature but with a large surface exposed to the air. Subsequent 6. Report by a working-party to the Director of the Public Health Laboratory Service. J. Hyg., Camb. 1971, 69, 155.

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364

Although the idea is attractive, anti-inflammatoryactivity cannot always be satisfactorily explained byantagonism of these chemical mediators. Evidenceis mounting that the prostaglandins may also beinvolved in inflammation and that their effects may beinfluenced by the acidic non-steroid anti-inflammatorydrugs. Prostaglandins have been detected in exudatesfrom experimentally induced inflammation, and

abnormally high concentrations of prostaglandins El,E2, Fia, and F201: were observed in skin perfusionstudies in allergic volunteers with contact dermatitischallenged with skin-patch tests. 1 It is not known

yet, however, whether prostaglandins are directmediators of the inflammatory process, or whetherthey are released in response to the tissue reaction.Fenamic acids, phenylbutazone, and aspirin blockthe bronchoconstrictor activity of prostaglandin F 201:’and aspirin or salicylate antagonise some of the effectsof arachidonic acid, a prostaglandin precursor. 2Vane and his colleagues 3-5 have now provided

important evidence relating the actions of aspirin,sodium salicylate, and indomethacin to the prosta-glandins. They showed that these drugs inhibit thesynthesis by guineapig lung homogenates of prosta-glandins E2 and F2« from arachidonic acid. Theconcentrations of aspirin and indomethacin causing50 % reduction in prostaglandin F201: activity were6-3 and 0-27 g. per ml. respectively-well withinthe ranges in plasma after therapeutic doses, evenallowing for plasma-protein binding. Sodium salicyl-ate was less effective, and there was no inhibition withhydrocortisone, morphine, or mepyramine. Aspirinand indomethacin also inhibited the release of prosta-glandin E2 from the perfused dog spleen both underbasal conditions and in response to injection ofadrenaline. In some experiments as little as 370 ng.per ml. of indomethacin and 40 g. per ml. of aspirinabolished the release of prostaglandin induced byadrenaline. Furthermore, Smith and Willis haveshown that aspirin and indomethacin strongly inhibitthrombin-induced release of prostaglandin E2 fromhuman platelets. This effect was interpreted as

inhibition of synthesis and appeared to be selective,since there was no inhibition of release of 5-hydroxy-tryptamine, p-N-acetyl glucosamidase, or phos-pholipase A. Again, the concentration of aspirinrequired for 50% inhibition was very low (0-3 jjt.g.per ml.; indomethacin was about ten times as potentas aspirin, and sodium salicylate was roughly tentimes less effective. Furthermore, when plateletsobtained from 3 volunteers one hour after ingestionof 600 mg. of aspirin were incubated with thrombin,prostaglandin Ez activity was only 5-20% of thatobserved in control studies. The same effect wasobserved in volunteers taking 50-100 mg. of indo-methacin.These observations have attracted much interest,

and inhibition of prostaglandin synthesis may proveto be a common mechanism of action of the acidic

1. Greaves, M. W., Søndergaard, J., McDonald-Gibson, W. Br. med.J. 1971, ii, 258.

2. Collier, H. O. J. Nature, 1971, 232, 17.3. Vane, J. R. Nature New Biol. 1971, 231, 232.4. Ferreira, S. H., Moncada, S., Vane, J. R. ibid. p. 237.5. Smith, J. B., Willis, A. L. ibid. p. 235.

non-steroid anti-inflammatory drugs. The prosta-glandins are a group of widely distributed acidic

lipids, which have striking pharmacological actionson many tissues and seem to act as local regulators ofhormonal activity. Could other actions of aspirinand related drugs also be explained by inhibition ofprostaglandin synthesis ? Vane suggests that anti-

pyretic activity could be explained on this basis.Several prostaglandins (including E2 and F 2OC) producefever on intracerebral injection, and prostaglandinE1 is the most potent pyrogen known. Paracetamol(which has no anti-inflammatory activity) does notantagonise fever induced by prostaglandin El, althoughit is apparently active against prostaglandins Pm,F2oc, and A1.1 Aspirin has well-documented effectson platelet adhesiveness and aggregation, but it is notknown whether these effects are related to prosta-glandin release. Vane speculates that the gastro-intestinal toxicity of the anti-inflammatory drugscould be related to inhibition of prostaglandin syn-thesis, and he also raises the interesting possibilitythat these drugs might reduce the efficacy of intra-uterine contraceptive devices.

Clearly, these findings open up many new areas forinvestigation and should stimulate further studies of therole of prostaglandins in different types of inflamma-tion. Anti-inflammatory agents might even proveuseful in the treatment of other conditions involvingprostaglandins (for example, threatened abortion)," 3and studies of the physiological role of the prosta-glandins will be facilitated by the ability to selectivelyinhibit their synthesis. It is odd, however, to findthat such a widely used drug as aspirin inhibits suchapparently active compounds as prostaglandins Eaand F21X with so little obvious effect.

CREAM

THE consumption of fresh cream in Great Britainincreases year by year, but there has been no corre-sponding increase in infectious disease from thissource. Whatever its metabolic consequences, creamis, in fact, a more or less blameless foodstuff. It istrue that there have been incidents of food-poisoningattributable to cream-name a food which has neverbeen found guilty-but they are few. Nevertheless,a survey 6 of the cream trade by the Public HealthLaboratory Service is welcome. Members of thecommittee observed the practices of 31 dairies engagedin the cream trade and examined just over 5000 sam-ples. Of these, 4385 were heat-treated, 517 untreated,and 282 were clotted cream. All were tested by amethylene-blue reduction test and by counts of totalbacterial content, of coliforms, and of Escherichia colitype I. There were some anomalies in the results, butthe general picture is fairly clear. By all tests, rawcream gave results less satisfactory than heat-treatedcream. Clotted cream also gave good results, but it isa product which presents problems of its own. The

process of clotting involves holding the cream for aconsiderable time at a near-bactericidal temperaturebut with a large surface exposed to the air. Subsequent

6. Report by a working-party to the Director of the Public HealthLaboratory Service. J. Hyg., Camb. 1971, 69, 155.

365

contamination can arise both as a result of the physicaldifficulties in handling the product and the ways inwhich it is displayed for retail sale. Post-productioncontamination seems to occur with liquid cream rathertoo often, and the committee suggests that this is anarea where the producers could take more care. As

might be expected, the larger makers of cream withbetter premises and equipment tend to get betterresults than their humbler competitors.The samples were also examined for specific patho-

genic bacteria. About 2% of the samples containedStaphylococcus aureus, mostly of bovine origin, andsingle examples of Brucella abortus, Salmonella typhi-murium, and Esch. coli 0126 were detected. The mere

presence of pathogenic bacteria cannot be taken asmore than a warning of danger. The real threat liesin their numbers.

The argument commonly used for the establishmentof a quality standard for cream is the analogy of milk.(In an article on p. 347 this week, Miss Jones recordsan improvement over the past thirty years in thecontamination of raw milk by Esch. coli type i.)If, by statute, whole milk should reach a certain stan-dard of cleanliness, the fatty portion of it should dothe same. It is sometimes forgotten that the statutorytests for milk fall into two distinct parts establishingquite different qualities. Milk sold as pasteurised mustbe so treated. This and all other milk must also

satisfy arbitrary tests for keeping quality. The house-wife wants milk which, even without a refrigerator, willkeep for at least 24 hours. That milk satisfies this testhas little or no relation to its danger as a source ofhuman illness. The argument that milk which turnssour is dirty milk and is therefore more likely to pro-duce disease than milk which has been producedhygienically is a thesis very hard to prove. Besides, itis almost certainly true that the acidity of souring milkprevents the multiplication of bacteria pathogenic toman. So, with cream, it might well be argued that thetime taken to reduce methylene-blue is not likely toreveal cream which will cause human infection. Cookscan make good use of sour cream, but they prefer tobuy it fresh, and it is for this reason that some standardfor fresh cream is probably justified.

THE CASE FOR A HEALTH COMMISSIONER

THE Government’s Consultative Document on the

reorganisation of the National Health Service madeno mention of proposals for a health commissioner,but a statement may be expected later in the year.Meanwhile the report of the Select Committee on the

Parliamentary Commissioner endorses the decisionmade by their predecessors in 1968 that there was nojustification, on the evidence submitted by the prin-cipal officers of the then Ministry of Health, for ex-cluding the hospital service from the jurisdiction of theParliamentary Commissioner. In view of the proposedreorganisation of the N.H.S., the committee agreedin 1968 to reconsider the matter when further progress

1. Second Report from the Select Committee on the ParliamentaryCommissioner for Administration. Session 1970-71. H.M. Station-ery Office. 80p.

in this direction had been made. There were four main

objections made in 1968 by the principal officers fromthe Ministry: that it would be difficult to single outcomplaints with regard to the hospital service, becauseit was intimately connected with local-authority healthservices and the general-practitioner service; that

many complaints would be excluded from investiga-tion by the Parliamentary Commissioner because theycould be brought before a court of law; that a doctor’sclinical judgment could be brought in question; andthat a new internal complaints procedure had beenintroduced which was working satisfactorily.

Sir Alan Marre, the present Parliamentary Com-missioner, gave evidence to the committee on his

experience in dealing with complaints in hospitalsrun directly by the State (such as Broadmoor, MossSide, and Carstairs). He said that he had encounteredno particular difficulties. Questions of clinical judg-ment could not be settled by the Parliamentary Com-missioner, but he would establish, on advice, " that thedoctor or other professional person had put himselfinto a position to make a reasonable judgment andhad acted reasonably on it". Discretion had beenexercised in some cases where complaints might havebeen taken to courts of law. It was pointed out thatmany complaints did not involve clinical judgment ofany kind, and a considerable number could be dealtwith at a domestic level. A committee under the

chairmanship of Mr. Michael Davies, Q.c., was at

present examining the hospital complaints procedure.The permanent under-secretary of State in the Depart-ment of Health and Social Security told the committeethat he was satisfied on the two points concerningclinical judgment and cases that might go to law.There would, however, inevitably remain a difficultywith regard to complaints on the treatment of a patientinvolving services in addition to those given by thehospital, but the proposed integration of the threebranches of the National Health Service might removethis difficulty. The real problem now, he said, was thereaction of some parts of the professions concerned.The second green-paper on the future structure of

the National Health Service, published in February,1970, contained proposals for a health commissioner;details were circulated to 40 bodies and their reactionswere sought. The health commissioner envisaged was atotally separate officer from the Parliamentary Com-missioner, but would work on broadly the same lines,having responsibility for investigating the actions ofthe Health Service authorities where it was alleged thatmaladministration had caused injustice. Generalised

complaints about deficiencies in the service would notbe dealt with. The proposal has met with mixedreactions, as recorded in the committee’s report.Broadly speaking, the consumer bodies, the administra-tors and the management bodies, the Royal Colleges ofNursing and of Midwives, and the staff side of theWhitley Council were agreeable to the proposal, whilethe medical organisations were opposed to it. TheBritish Medical Association and the Joint ConsultantsCommittee both said that no case for a health com-missioner had been made out. Where such a strongconflict of interests exists, the case for an independenthealth commissioner seems clear enough.