BRITISH MEDICAL JOURNAL
17 JUNE 1978
CORRESPONDENCE Diuretics in the elderly R R Bailey, MRACP; R T Rouse, MB ...... 1618 "Innovation in the Pharmaceutical Industry" B W Cromie, FRCPED .................. 1618 Cimetidine for ulcers recurring after surgery J H B Saunders, MRCP, and others ...... 1619 Maintenance treatment of duodenal ulcer with cimetidine S J Rune, M1D, and H R Wulff, MD; R H Salter, FRCP; R M Bernstein, MRCP ...... 1619 Side effects of nifedipine J Christine Rodger, MD, and A Stewart, MB 1619 SI, moles, and drugs L F Prescott, FRCPED, and others ........ 1620 Intravenous infusion of salbutamol in severe acute asthma I W B Grant, FRCPED; H R Anderson, MD; S G Spiro, MRCP, and S W Clarke, FRCP.. 1620 Electron microscopy of cell membranes Carolyn J P Jones, PHD ................ 1621 Ginseng and mastalgia 1621 M N G Dukes, MD ..................
If I had ... Fiona M Bennett, FRCSED ..... ......... 1621 Assaults on doctors W A Fraser-Moodie, FRCSED, and D I RowAley, MB .......... ................ 1621 Dopamine and dobutamine A K Yates, FRCS ...................... 1622 Stiff shoulder after stroke R E Irvine, FRCP, and T M Strouthidis, MRCP .. 1622 Non-epileptic television syncope J B P Stephenson, MRCP .............. 1622 Factors affecting length of hospital stay D Phillips-Miles, FFCM; H B J Chishick.. 1622 Intended place of delivery and perinatal outcome Jean Fedrick, MA ...................... 1623 The therapeutic Smartie Josephine M Lomax-Simpson, MRCPSYCH 1623 Klebsiella ozaenae in bronchiectasis R J Fallon, FRCPATH ...... ............ 1623 Self-poisoning with beta-blockers D A Richards, MD, and B N C Prichard, FRCP ........ 1623 ........................ Facet joints and low back pain M D Mehta, FFARCS ...... ............ 1624 .............
Correspondenits are urged to write briefly so that readers may be offered as wide a selection of letters as possible. So many are being received that the omission of somiie is inevitable. Letters must be signled personially by all their authors. Diuretics in the elderly
SIR,-I read with some concern your leading article (29 April, p 1092) on the use of diuretics in elderly patients. It could certainly be debated whether potassium supplements or the use of potassium-sparing diuretics are ever routinely necessary in the treatment of patients with oedematous states or hypertension, whatever their age. However, I am concerned with the fact that with the rapidly increasing use of potassium-sparing diuretics I am now seeing more clinical problems with hyperkalaemia resulting from their inappropriate use (either alone or in combination with thiazides) than with the hypokalaemia resulting from the use of the thiazide or "loop" diuretics. The risk of potentially fatal hyperkalaemia exists in any patient with any significant degree of renal functional impairment and not just those with severe renal failure (creatinine clearance < 10 ml/min) as mentioned in your article. It must not be forgotten that renal function progressively deteriorates with increasing age, and because of this and a declining muscle mass many elderly patients have a low creatinine clearance in the presence of a plasma creatinine concentration that may be within the normal range. I would prefer to see potassium-sparing diuretics avoided in patients with any degree of renal functional impairment, but if their use was absolutely necessary then the plasma potassium level should be monitored carefully. Ideally the plasma potassium should be measured before and again 6-12 weeks after starting the treatment with a potassium-losing diuretic so as to identify the small proportion of patients who may need a potassium supplement.
More recently it has been observed that the potassium-sparing diuretics may lead to a decline in renal function in patients who have renal insufficiency. In our department this problem was first observed with spironolactone,' 2 but this has now also been seen with triamterene and amiloride. The mechanism for this is unclear, but it does not seem to be related to diuretic-induced salt and water depletion. For these reasons the potassium-sparing diuretics, either alone or in combination, are best avoided in any patient with any degree of renal functional impairment. Ross R BAILEY Department of Renal Medicine, Christchurch Hospital, Christchurch, New Zealand
Neale, T J, et al, New Zealand Medical J7ournal, 1976, 83, 147. Bailey, R R, Druigs, 1976, 11, suppl 1, p 70.
SIR,-Today I had to reduce the insulin dose of one of my patients by almost half. Less than 48 h ago he had been discharged from hospital bearing a note which read "Diabetes stabilised." This is a common occurrence yet, since general practitioners are placid people, your correspondence columns do not reverberate with protests about the promiscuous prescription of insulin in hospitals. We all accept that the diabetic patient has different needs in hospital and at home-and even from weekday to weekend. We do not yet seem to accept that the same is true of other groups of patients. Since bed rest is an im-
Methods of endometrial assessment V Sele, MD .......... ................ Diet and asthma Marianne A Ganderton, MB; L M McEwen, BM ........................ Treating pressure sores M A Nasar, MRCP .................... Levodopa in senile dementia Kate Johnson, MA, and others ........ Annual General Meeting of the Royal Society of Medicine W F Whimster, MRCPATH .............. GMC's finances D Mary Pack, MB .................... Medical Act 1978 J S Happel, FRCGP, and J H Marks, FRCGP Shortage specialties: radiology J K Davidson, FRCR .................. New consultant contract G I B Da Costa, FRCSED . .......... Housemen's pay P J Bower, MB . .............. Joint consultative committees G Behr, FRCPATH .........
1624 1624 1625
1625 1625 1626 1626 1626
Future of British anaesthetics D C Hogg, MB, DA; P K Schutte, MB .... 1626
portant part of the treatment of heart failure it is hardly surprising that patients whose failure when ambulant is controlled by diuretics can manage without those drugs when they are admitted to a hospital bed. I can assure Dr Leonard Rosenthal (27 May, p 1417) and other correspondents who advocate the withdrawal of all drugs when a person is admitted to hospital that family doctors on the whole do not prescribe, nor do their patients willingly take, powerful drugs unnecessarily. Patients make their continuing needs clear, usually dramatically and almost always in the early hours of the morning within a short time of their discharge from hospital. May I suggest that any policy of stopping drugs on admission be accompanied by a warning to patients that therapy may have to be restarted on returning home ? ROBERT RouSE Colwyn Bay, Clwyd
"Innovation in the Pharmaceutical Industry"
SIR,-Dr J F Cavalla (3 June, p 1486) lists the reductions in pharmaceutical research in the UK, but I would like to point out that the trend is not limited to this country. I was asked to speak on "Today's research for tomorrow's medicine" at a symposium organised by the Association of Medical Advisers in the Pharmaceutical Industry and my investigations on the subject confirmed the worst fears of all those interested in continuing therapeutic Gdvances. The total time required to conduct all the tests needed for regulatory clearance of a medicine used in chronic therapy has increased almost exponentially since their beginning in 1964. I cannot recall a single test that has been abandoned over the past 14 years, despite
BRITISH MEDICAL JOURNAL
17 JUNE 1978
the increase in knowledge and doubts on the validity of many requirements. There has just been an increase and this has been reflected in the time-lag between starting a research project and making a new medicine generally available on prescription. An analysis of over 200 medicines showed that the average time between first publication and marketing has increased from six years in 1965 to 10 years today. This is probably a very conservative estimate, as the first publication takes place well after the start of a project and the calculation ignores the many early compounds in a project which never reach the market. Bearing this in mind, an extrapolation of the current trend means that new medicines will have exceeded their 20-year patent life before reaching the UK market by the early 1990s. However, it must not be assumed that regulatory requirements are the only factors influencing pharmaceutical innovation. Almost every regulation, legislation, or proposed legislation such as price controls, reduced promotional allowances, WHO essential drug lists, postmarketing surveillance, strict or no-fault liability and compensation, "good clinical practice," and information to patients adds to the disincentives for pharmaceutical research. Many of these appear to be sensible when considered in isolation, but each one affects others and the total package could have a catastrophic impact. The result of these regulatory and non-regulatory influences is not difficult to envisage. An analysis of some of the largest researchbased pharmaceutical companies in the world demonstrates that a rapidly increasing percentage of their research budgets is devoted to non-innovative work. An extrapolation of this trend suggests that innovative pharmaceutical research will cease completely by 1990. Observers of the pharmaceutical industry today look at the few new medicines coming on to the market and discount prophecies of gloom, but these people forget that the new medicines of today are the fruit of projects started 10 or more years ago, when conditions were very different. This time-lag between starting projects and having new medicines available effectively hides the state of today's innovative pharmaceutical research, but any complacency is misplaced and today's clear and observable trend points to an end of improved medicines from innovative research within 20 or so years if current conditions are allowed to continue. B W CROMIE Hoechst UK Ltd, Hounslow, Middx
Cimetidine for ulcers recurring after surgery SIR,-We have read with interest the recent reports on the use of cimetidine in the treatment of ulcers which have recurred after gastric surgery by Mr Terence Kennedy and Dr Anne Spencer (13 May, p 1242) and Dr A M Hoare and his colleagues (20 May, p 1325). We would like to record our experience of the use of cimetidine in this context. In a study designed to test the efficacy of cimetidine in preventing the recurrence of duodenal and stomal ulcers 100 patients have been treated with full doses of cimetidine (1 g/day) for up to 12 months and subsequently
followed up after stopping the treatment. Thirteen of these patients had had previous gastric surgery (eight vagotomy plus pyloroplasty; one vagotomy plus gastrojejunostomy; four Polya gastrectomy). Eight of the postoperative recurrences were therefore duodenal ulcers and five were stomal ulcers. The mean gastric acid and pepsin responses to an intravenous infusion of pentagastrin (2 t_g/kg/h) were high: acid 28 8 mmol,h (range 8 7-44 6 mmol/h) and pepsin 21OKU,h (range 95418 KU/h). All patients were assessed endoscopically initially and monthly until the ulcer had healed. The endoscopic examination was repeated at the end of the course of treatment with cimetidine or when symptoms recurred during the course of treatment. Ten of the 13 ulcers had healed after treatment for one month and two other ulcers had healed after three months' therapy (one duodenal ulcer after vagotomy plus pyloroplasty; one stomal ulcer after vagotomy plus gastrojejunostomy). These latter two patients did, however, have rapid symptomatic relief. One patient with a stomal ulcer after Polya gastrectomy healed only when the dosage of cimetidine was increased to 1-6 g/day. Three ulcers (two duodenal and one stomal) recurred during treatment with cimetidine (two asymptomatically). Three patients remained well more than seven months after stopping treatment. In this study cimetidine has been shown to heal postoperative recurrent ulcers at a rate similar to that in unoperated patients. The pattern of recurrence of the ulcers after healing, during and after long-term treatment, is proportionately similar to that observed in our unoperated patients. We therefore conclude that cimetidine in conventional dosage will satisfactorily heal postoperative recurrent ulcers and, in addition, that maintenance treatment with cimetidine may be of use in preventing further ulcer recurrence in these
Ninewells Hospital, Dundee
represents the ultimate diagnostic truth. Cimetidine trials, for instance, have shown that there is only a poor correlation between relief of symptoms and ulcer healing in duodenal ulcer patients. Cimetidine treatment is expensive, but some of the expense may be compensated for if more duodenal ulcer patients are treated in general practice. Recommendations to refer duodenal ulcer patients for duodenoscopy and outpatient treatment will only place an unnecessary extra burden on the hospital sector. S J RUNE Medical Department F, Glostrup University Hospital, Glostrup, Denmark
H R WULFF Medical Department C, Herlev University Hospital, Herlev, Denmark
Gudmand-Hoyer, E, et al, Scandinavianz Jouirnial of Gastroenterology, 1977, 12, 611.
SIR,-Drs K G Wormsley and N R Peden (20 May, p 1351) are correct in their assertion that the radiological demonstration of a deformed duodenal cap is not sufficient justification for the use of cimetidine in clinical practice if the barium meal has been performed by the conventional method. However, when the barium meal is performed using a double-contrast technique not only does this allow an accurate prediction as to whether or not the duodenum is abnormal but in particular whether the abnormality is due to scarring or active ulceration. There is no reason, in the UK, why patients with suspected duodenal ulcers cannot have the benefit of having their diagnosis confirmed by a double-contrast barium meal, which is safe, quick, easy to perform, and exceptionally well tolerated by the patient. Endoscopy can then be reserved for the small percentage of patients in whom diagnostic doubt still remains. J H B SAUNDERS R H SALTER J M CARGILL of Medicine, N R PEDEN Department Cumberland Infirmary, K G WORMSLEY Carlisle
SIR,-Cimetidine (3 June, p 1435) is to ulcer as truss to hernia. Any enterprising and otherwise healthy person would gamble on a Maintenance treatment of duodenal ulcer good surgeon rather than stuff their guts in all with cimetidine day or swallow pills, even those greased with glamour. SIR,-Drs K G Wormsley and N R Peden ROBERT BERNSTEIN (20 May, p 1351) state that radiological signs Royal Postgraduate Medical School, of duodenal ulcer disease in patients with Hammersmith Hospital, epigastric pain do not constitute a proper London W12 indication for cimetidine treatment and they recommend the routine use of duodenoscopy for confirming or disproving the diagnosis. Side effects of nifedipine We feel that it is unwise to recommend the routine use of a diagnostic method if its SIR,-The paper by Drs A G Jariwalla and interested us; benefit to the patient has not been proved, and E G Anderson (6 May, pin1181) whom a nifedipine we have patient too we are aware of no evidence to this effect in the case of routine duodenoscopy. We have (Adalat) apparently provoked ischaemic cardiac conducted both a therapeutic trial' and a pain. Our experience suggests that this side maintenance trial (29 April, p 1095) of the effect can develop during treatment and that it effect of cimetidine in patients with radio- is not only patients starting therapy who need logically diagnosed duodenal ulcer, and the to be warned of it. A man aged 46 with a three-year history of results were similar to those obtained by others in cases of duodenal ulcer diagnosed by effort angina was changed from oxprenolol 120 mg daily to nifedipine 10 mg thrice daily. Angina endoscopy. Thus radiological and endoscopic decreased frequency, and in an attempt to diagnostic criteria seem equally valid for pre- abolish it in the dose of nifedipine was increased dicting a therapeutic response. Duodenal ulcer after six weeks to 20 mg thrice daily. Within the disease has many clinical facets and we do not next week the patient had his first protracted believe that it is justified to maintain that episode of central chest pain at rest; it occurred the result of a single endoscopic examination about 15 min after a dose of nifedipine, lasted over