1051 The availability to the industry of these clinical units calls in question the ethics of volunteer drug studies in laboratories that are sometimes a long way from the nearest hospital.
PRESCRIBING IN THE N.H.S.
SIR,-A letter from the Secretary of State for Social Services and the chairman of the B.M.A. Council (April 29, p. 946), which has been circulated to the profession exhorting them to restrict Health Service prescribing at this 30th anniversary of the N.H.S., is most logical and needed. One cannot feel, however, that it will have very much effect whilst the nation continues to be told that unlimited service is available to everyone on demand at no,cost. Most doctors endeavour to restrict their prescribing. They will find it hard to cut back further, and many will be irritated by the fact that hospital prescribers are exhorted not to order drugs which will increase their own hospital bill but to persuade general practitioners to order the drugs via local chemists at a higher price. This last point alone may cost more than can possibly be saved by the changes requested of the profession. In any case, wastage need not be sought in prescribing habits until some of the other waste and extravagances has been controlled.
Department of Clinical Pharmacology, St. Bartholomew’s Hospital Medical College,
SHIGELLOSIS AND HÆMOLYTIC URÆMIC SYNDROME
SIR,-You refer (Jan. 7,
p. 26) to a number of probable ofhaemolytic urxmic syndrome (H.u.s.), but fail to mention shigellosis as a proven cause of this condition. In Bangladesh we have seen many patients with H.u.s. accompanied by a leuksmoid reaction after dysentery, particularly that due to Shigella dysenteriae type 1, the Shiga bacillus. 1,2 Many published cases of H.u.s. have been in association with diarrhoea or have been preceded by an episode of causes
Hospital, Birmingham B4 6NH
diarrhoea. More detailed studies on patients having H.u.s. in association with shigella have shown an association between circulating endotoxin and this syndrome.3 The circulating endotoxin preceded the episode of H.u.s. rather than accompanying it. It serves as a predictor that H.u.s. may develop later in patients with dysentery. We feel that the association with shigella dysentery is important and may give significant clues towards the mechanism of this important syndrome of childhood.
GEORGE T. WATTS
VOLUNTEER STUDIES WITHIN THE PHARMACEUTICAL INDUSTRY
SiR,-Dr Butler’s paper (April 15, p. 816) on the ethics of volunteer studies conducted within the pharmaceutical industry resembled his contribution to a symposium on the subject about a year ago, at which contrary views were expressed by others. Butler states "The accuracy of the data may be greater in studies conducted by the clinical monitor in industry". With whom is he making the comparison? A monitor who does not have "to meet stringent scrutiny by his scientific colleagues" (of whom there are some examples within the pharmaceutical industry) ? Or does he mean that good laboratory practice can only be assured or assumed within the pharmaceutical industry and that those engaged in academic medical research pay less attention to detail? He acknowledges that there are "some limitations to what can be done within the pharmaceutical companies but danger arises only if the limitations are not recognised and the type of study undertaken is too ambitious". Surely it is precisely those limitations, which are recognised only in retrospect when damage may already have been done which make volunteer studies outside a clinical unit so undesirable. Human variation in response to drugs is such that unwanted effects in individuals are often unpredictable. His suggestion that "it should also be possible to do tolerance and activity studies on appropriately selected new compounds" fills me with dismay, for how can one predict the tolerability and safety of "new" compounds ? Perhaps he really means "me-too" products". Butler’s safeguards to ensure the ethical conduct of such studies-including volunteer selection, volunteer motivation, informed consent, insurance, and ethical review—omit the most important, the relationship of the volunteer to the investigator. This should be no less close than that between patient and doctor. In most, if not all, academic medical research departments involved in the investigation of drugs, volunteers receive the same consideration and have the same clinical resources for recognition and management of unexpected adverse effects as do patients. This cannot be said of the pharmaceutical industry. Even possession of a higher medical qualification by a medical adviser and the availability of modern resuscitation equipment will not ensure that volunteers within the industry receive treatment as good as that available in clinical departments.
Laboratory, Dacca-12, Bangladesh
M. M. RAHAMAN W. B. GREENOUGH, III
INHIBITION OF PLATELET AGGREGATION BY ONION EXTRACTS
SIR,-Baghurst et al." reported the effect of onions on platelet aggregation in people who had consumed a high fat meal. We have, therefore, examined the effect of onion extracts on platelet aggregation in vitro. Platelet-rich plasma was obtained from volunteers (four men, one woman) aged 22-47 years. Platelet aggregation was measured at 37°C by turbidornetrys in an Upchurch B1037 346 aggregometer connected to a Vitatron pen recorder. Aqueous or ethanolic extracts were obtained by homogenising onion at 300 g in either 100 ml normal saline or 100 ml ethanol using a Polytron homogeniser and filtering. The pH of the saline extract was 5.5. The ethanolic extract was evaporated to dryness at 45 °C and the residue dissolved in 1 ml normal saline. Aggregation of platelets from all five volunteers in response to arachidonic acid (500 .g/ml) and adenosine diphosphate (A.D.P.) (}jLmol/l) was completely inhibited by 0-1ml of both saline and’reconstituted alcoholic extracts of onion. Platelet aggregation induced with collagen from rabbit tendon was also inhibited by both extracts (two subjects only tested) but thrombin-induced aggregation was not. Activity was reduced in the saline extract by boiling for 30 min at pH 5.5and destroyed by boiling for 10 min at pH 9-5. In an attempt to separate the active constituent, 700 g onion was homogenised in 100 ml ethanol, filtered, and evaporated to dryness. The residue was redissolved in 67% ethanol and partitioned with petroleum spirit (b.p. 60-80°C). The ethano1. Rahaman, M. M., Alam, A. K., Islam, M. R. Lancet, 1974, i, 1004. 2. Rahaman, M. M., Alam, A. K. M. S., Islam, M. R., Greenough III, W.
Lindenbaum, J.Johns Hopkins med.J. 1975, 136, 65.
In the U.K. there
London EC1A 7BE
many departments of clinical pharmacollaborate with the pharmaceutical inprepared in volunteer research, however modest its scientific conto
3. Presented in part in abstract form for the American Federation for Clinical Research. Clin. Res. 1977, 25, 379A. 4. Baghurst, K, I., Raj, M. J., Truswell, A. S. Lancet, 1977, i, 101. 5. Born, G. V. R.J. Physiol. Lond. 1962, 162, 67P.
1052 lic fraction was evaporated to dryness, redissolved in water, and shaken three times with n-butanol. The pooled butanol phases were evaporated to dryness. 1 ml samples of the fifty 6 ml fractions of the extract eluted from a ’Sephadex LH20’ column with methanol: water (50:50) were evaporated to dryness and redissolved in 0 - 5 ml saline. Fractions 8 to 20 inhibited A.D.P.-induced platelet aggregation and all had the characteristic smell of onion. Fractions 21, 23, 25, and 26 all had some inhibiting activity shown by a reduction in the maximum deflection of the optical density curve compared with the controls. Fractions 5, 6, and 34-36 showed pro-aggregatory activity in the absence of any additional aggregation-inducing agent. Fractions 14 and 15 were evaporated to dryness and each dissolved in 0.5 ml methanol. The methanolic solutions were applied to silica gel thin-layer-chromatography plates and run in methanol: chloroform (3:1). Each plate (20 cm) was then divided horizontally into zones of either 2, 3, or 4 cm length. The zones were scraped off the plate and washed twice with 5 ml methanol. The methanol eluates were evaporated to dryness, and dissolved in 0.5 ml saline. Zones 11-15 cm, 15-18 cm and 18-20 cm inhibited platelet aggregation induced by A.D.P. (5XJO-6 mol/l); zones 3-4 cm, 5-8 cm and 8-11 cm showed no activity. The isolation and identification of these biologically active substances may be an important and interesting line of further investigation. We conclude that onions contain several anti-aggregatory substances which are polar but as yet uncharacterised chemically. These substances may account for the effects of dietary onions on platelet aggregation observed by Baghurst et al. in subjects after high fat meals. Department of Pharmacology, University of Edinburgh, Edinburgh EH8 9JZ
CHRISTINE PHILLIPS NORMAN L. POYSER
CONGESTIVE CARDIOMYOPATHY IN WERNER’S SYNDROME
SIR,-Werner’s syndrome is a rare autosomal recessive disorder characterised by arrest of growth at puberty, scleroderma-like involvement of the skin, and premature aging.’ Cardiovascular involvement is a prominent feature,2 and precocious generalised arteriosclerosis and coronary-artery disease manifested by congestive heart-failure, angina, and myocardial infarction has been described frequently.3 We would like to add cardiomyopathy to the list of possible manifestations of Werner’s syndrome. A 17-year-old boy (155.5cm, 45.5 kg) had a 3-week history of worsening dyspnoea on exertion, dry non-productive cough, orthopnoea, and paroxysmal nocturnal dyspnoea. His father had died aged 44 from heart-disease, but he had no history of hair graying, baldness, or cataracts. His mother was in good health and there were no siblings. The patient looked older than 17. He had tightly drawn skin over the face and a beak-shaped nose (fig. 1). The skin of the extremities was also tightly drawn and there was a loss of subcutaneous tissue. Facial and axillary hair was decreased. There was no graying of the hair, alopecia, or cataracts. His voice was high-pitched and hoarse. External genitalia were normal. The first heart sound was decreased in intensity. Prominent third and fourth heart sounds were audible at the apex. A grade 3/4 blowing systolic murmur was heard at the apex with radiation to the axilla. There was no jugular venous distension, hepatomegaly, or oedema. Routine admission laboratory data were normal. Chest X-ray demonstrated cardiomegaly, pulmonary congestion, and a small right pleural effusion. An electrocardiogram revealed 1. Riley, T. R., and others Ann.intern. Med. 1965, 63, 2. Perloff, J. K., Phelps, E. T. ibid. 1958, 48, 1205. 3. Epstein, C. J., and others Medicine, 1966, 45, 177.
intraventricular conduction delay, left-axis deviation, leftatrial abnormality, occasional unifocal premature ventricular contractions, and small Q waves in V5 and V6. X-rays of the legs revealed diffuse osteoporosis and loss of subcutaneous tissue. A biopsy of a lesion in the right ear was consistent with chondrodermatitis nodularis helicis chronicus, an entity which usually occurs in middle-aged and older persons.4 Viral and antibody studies were negative. On admission, the patient was in moderate congestive heartfailure. He was treated with bed-rest, digitalis, and diuretics, and improved a little. However, his degree of compensation remained borderline and there were intermittent episodes of overt pulmonary oedema. Cardiac catheterisation findings were consistent with a congestive cardiomyopathy: Dr H. A. McAllister, Jr., Armed Forces Institute of Pathology, Washington, D.C., reviewed the histopathology of this case and agreed with our interpretation. Left-ventriculography revealed a poorly contracting left ventricle with 2+ mitral insufficiency. Coronary arteriography was normal. Hydrogen studies excluded a left-to-right shunt. Over the ensuing months the patient had intermittent pulmonary oedema and progressive congestive heart-failure unaltered by attempts to increase diuresis and bed-rest. Prednisone resulted in transient improvement only. He died in a profound low cardiac output state 7 months after admission to hospital. Necropsy revealed extensive myocardial cell drop-out with replacement by fibrous connective tissue with a few small aggregates of lymphocytes scattered throughout the fibrosis. Many of the remaining myocardial cells had large hyperchromatic nuclei, but there was no evidence of active necrosis (fig. 2). Secondary changes resulting from the massive pulmonaryoedema with bilateral hydrothorax and hepatic congestion. The aorta and coronary arteries were virtually free of atheromatous involvement. Since Otto Werner first described this entity in 1904,5 some 175 cases have been published. Our patient had many characan
in Textbook of Dermatology (edited by A. Rook, D. S. Wilkinson, and F. J. G. Ebling); p. 1298. Philadelphia, 1968.
Fig. 1-Facial tightly drawn skin, beakshaped nose, and sparse facial hair.