802

succeeding few weeks. Acute renal tu~ular necrosisis a serious hazard of interference with pregnancy-notably of septic abortion. SMITH and his co!le~­

gueslZshowed a striking stepwise crescendo of IOCI­dence at 9, 13, and 17 weeks as suspicion turnedfirst to certainty then to despair. For reasons bothmedical and social, this complication has becomerare in Britain-fortunately since a third of thepatients of SMITH et al. died, mostly of sepsis.The mean delay before diuresis in those who re­covered was 14 days, with a range of 4-38 days.Acute tubular necrosis may also be caused by apost-partum hsemorrhage, but acute renal. failurelate in pregnancy is more likely to herald Irrever­sible renal cortical necrosis associated with ante­partum hremorrhage or, more rarely, with eclamp­sia. Acute post-partum renal failure-" is one of th.estrangest complications of an apparently uncompli­cated pregnancy and delivery. With an onset fromone day to several weeks after parturition, t?e ~rig­

ger to this catastrophe is obscure. T?ere IS IIttl.edoubt, however, that intrarenal arter~olar deposi­tion of fibrin is an essential element III the renalfailure; a microangiopathic hsemolytic anamiausually coexists. Renal failure is usually irr~ver­

sible although FINKELSTEIN et a1. IS saw 2 patientsmak~ an excellent recovery. Heparin apparentlyimproved renal function in some cases but no~ inothers. IS Occasionally the same syndrome strikesduring pregnancy.!" Urinary-tract infections are acommon nuisance in pregnancy. KAss17 was thefirst to show that they are often preceded by symp­tomless bacteriuria and can largely be prevented ifbacteriuria is eradicated early in pregnancy. It isstill not settled whether pre-eclamptic toxemia,prematurity, and fetal loss are more common inbacteriuric women, or whether antibiotic treatmentreduces these possible associations. 18 19

What advice should be given to a woman withchronic renal disease who is contemplating preg­nancy? For most women the risks are sm~ll.

Serious uncertainty surrounds only those withmoderate or severe renal failure, and in particularthose already hypenensive. The woman should betold that there is a considerable risk to her infantand a small risk to herself, but dogmatic prohibi­tions do not seem justified today. Instead, obstetri­cian and physician must batten down the hatchesand prepare to ride out the storm together withthose determined to set sail.

13. Smith, E. K, M., McClure Brown, J. C., Shackman, 'R.~ Wrong, O. M.Lances, 1965, ii, 351.

14. Robson, j. S., Martin, A. M., Ruckley, V. A., MacDonald, M, K, Q.]I Med.1968,37,423.

15. Finkelstein, F. 0., Kashgarian, M., Hayslett, J. P. Am.]. Med. 1974,57,649.

16. Vandewalle, A., Kanfer, A., Kourilsky, O. BT. med.]: 1975, I"~ 479.17. Kass, E. H. in Biology of Pyelonephritis (edited by E. L. Quinn and E. H.

Kass); p. 399. Boston, 1960. .18. Condie, A. P.) Brumfitt, W., Reeves, D. S., Williams, J. D. in Urinary Tract

Infection (edited by W. Brumfitt and A. Asscher); p. 108. London,1973.

19. Williams, J.D., Reeves, D. S" Brumfitt, W., Condie, A. P. ibid. p. 103.

THE LANCET, OCTOBER 25,1975

Burimamide, Metiamide, Cimetidine ...SINCE last year's editorial I on this new class of

antihistamines, much experience has accumulated.Unlike the older antihistamines, histamine Hz-recep­tor antagonists are potent inhibitors of gastri~-acidsecretion.Z Burimamide, the first Hz antagornst tobe used in man is effective intravenously but less, . .so orally. 3 Metiamide, the second Hz antagornst, ISactive by mouth4

.: it profoun.dly decr~as~s, n.octur­nal" and meal-stimulated acid secretion III pa­tients with duodenal ulcer; it virtually abolishesgastric secretory activity in patie~ts with gastr~c

ulcers: and it counteracts every stimulant of acid, .secretion tried in man-histamine, pentagastrin,food and insulin hypoglycemia." 6-13 It decreases, .pepsin secretion! 10 12 and it inhibits acid secretionmore completely than the highest tolerated doses ofan anticholinergic. 7

• •

The clinical relevance of these excitmg pharma­cological observations ~as n~w b~en tes~ed by t~o

double-blind therapeutic trials III patients Withduodenal ulcer. In the first, patients treated withmetiamide Ig daily had significantly less noctur~al

pain and consumed less antacid than those receiv­ing placebo.P The second, a multicentre trial inwhich the healing of duodenal ulcers was assessedby fibreoptic endoscopy, is reported at the front ofthis issue: a significantly higher percen~age ofulcers healed on metiamide 1·0g or 1·3g dally thanon placebo, though it is a little discoura-'Png thatrelief of symptoms did not correlate well With endo­scopic ulcer healing-a discrepancy reported alsoin an earlier trial. IS In addition to the likely thera­peutic use of H2 blockade in this commo.n.disease,several workers have already reported striking ben­efit from control of acid hypersecretion in the Zoll­inger-Ellison syndrome. 16- zo However, the relati~e

importance of Hz-receptor blockade and surgery in

I. Lancet, 1974, i,666.2. Black, J. W., Duncan, W. A. M., Durant, C. 1-, Ganellin, C. R., Parsons,

E. M. Nature, 1972,236,385.3. Wyllie, j. H., HesseIbo, T., Black, j. W. Lancet, 1972, ii, III 7.4. Black, J.W., Duncan, W. A. M., Emmett, J. c., GaneIlin, C. R., Hesselbo,

T., Parsons, M. E., Wyllie, j. H. Agents and ActIOns, 1973,3.,133.5. Milton-Thompson, G. j., Williams, J. G., Jenkins, D. J. A., MISIeWICZ, J. J.

Lancet. 1974, i, 693. .6. Mainardi, M" Maxwell, V., Sturdevant, R. A. L., Isenberg, ]. I. Neul Engl.

]. Med. 1974,291, 373. .7. Richardson, C. T., Bailey, B. A., Walsh, J. H' J Fordrran, J. S.J. elm. lnrest.

1975,55,536. ..8. Thjodleifsson, B., Wormsley, K. G. BT. med.}. 1974, II, 304.9. Wyllie, J. H., Ealding, W. D. P., Hesselbo, T., Black, J. W. GUl, 1973.14,

424.10. Konturek, S. j., Biernat, J., Oleksy, j. Am.]. dig. Dis. 1974,19,609.11. Barbezat, G. 0., Bank, S., Clain, ]., Nevis, B., Marks, I. N. S. Afr. med.

]. 1974,48, 2018.12. Thjodleifsson, B., Wormsley, K. G. Gut, 1975,16,501..13. Carter, D. C., Forrest, J. A. H., Werner, M., Heading, R. C., Park, j.,

Shearman, D. J. C. BT. med.]. 1974, iii, 554.14. Pounder, R. E., Williams, J. G., Milton-Thompson, G .I., Misiewicz, J

j. ibid. 1975, ii, 307. . . ...15. Brown, P., Salmon, P. R., Thien-Htm, Read, A. E. lbl~. 1972, tu, 661.16, Bonfils, S., Mignon, N., Accary, J. P. Nouv. Presse. med. 1974,3,1883.17. Thompson, M. H., Venables, C. W., Miller, C. W., Read, J. D., Sanders, D.

J., Grund, E. R.) Blair, E. L. Lancet, 1975, i, 35.18. Halloran, L. G., Swank, M., Haynes, B. W. ibid. p. 281. .19. Mainardi, M., Maxwell, V,) Sturdevant, R. A. L., Isenberg, J. I. Am. J. dig.

Dis. 1975,20,280.20. Richardson, C. T., Fordtran, J. S. Gastroenterology, 1975,68,973.

THE LANCET, OCTOBER 25, 1975

the long-term management of this rare, but serious,condition remains to be determined.

These promising early results have unfortu­nately been marred by reversible bone-marrowdepression in 3 of the 450 patients who receivedmetiamide-t-s-an adverse reaction thought to bedue to the thiourea residue present in the metia­mide molecule, rather than to H2-receptor blockadein itself. In cimetidine, the latest H2 antagonist, thethiourea has been replaced by cyanoguanidine, andin animals the new compound seems to be non­toxic and slightly more potent than metiamide.P Inman it is rapidly absorbed after oral administra­tion and inhibits the same wide spectrum of secre­tory stimulants as metiamide.Pr"? A single 200mgdose of cimetidine will diminish meal-stimulatedacid output by about two-thirds." Oral cimetidinecan also decrease, by 55-72%, the mean 24-hourintragastric acidity of healthy controls, or of pa­tients with duodenal ulcer, on a normal diet.:" Thisorder of decrease was achieved by 0·8g or 1·6gdaily in four divided doses-a regimen which keptthe blood concentration of the drug above the I.c.solevel23 of 2p.mol/l most of the time.

Clinical assessment of cimetidine has alreadystarted. Will it prove not only to relieve the symp­toms of duodenal ulcer but also to heal the ulcer?Will it have any effect on gastric ulceration? Usedprophylactically, will it prevent stress ulceration?The omens are that cimetidine will be therapeuti­cally active. If it proves to be a safe compound, themanagement of peptic ulcer may well be revolu­tionised.

Radiation and the Genetic LoadEVOLUTION has provided man with a set of genes

which in an infinite variety of combinations pro­duces an organism with morphology and functionthat harmonise efficiently with the environment.But, in common with other naturally outbredpopulations, man carries a large store of variantgenes which are detrimental or even lethal. Someof these are genes with dominant effects, but mostlythey are recessive genes concealed in the heterozy­gous state. By the continuing process of selection,new mutations are ultimately eliminated from thepopulation, but since they are being replaced con­tinuously by fresh mutations the frequency remains

21. Forrest, J. A. H., Shearman, D. J. C., Spence, R., Celestin, L. R. Lancet,1975, i, 392. Burland, W. L., unpublished.

22. Brimblecombe, R. W., Duncan, W. A. M., Durant, G. ]., Emmett, ]. C.,Ganellin, C. R., Parsons, M. E. J. inc. med. Res. 1975,3,86.

23. Burland, W. L., Duncan, W. A. M., HesseIbo, T., Mills, J. G., Sharpe, P.c., Heggie, S. J., Wyllie, j. H. 1975 e-.J. clin, Pharm. (in the press).

24. Pounder, R. E., Williams, j, G., Russell, R. C. G., Milton-Thompson, G. j.,Misiewicz, j. j. Gut, 1975,16,397.

25. Richardson, C. T., Fordtran, J. S. Gastroenterology, 1975,68,972.26. Herm, R. M., Isenberg, J. I., Maxwell, V., Sturdevant, R. A. L. N(!u' En!!,'.

J. Med. 1975,293,371.27. Carter, D. C., Forrest, J. A. H., Logan, R., Ansell, I., Lidgard, G., Heading,

R. C., Shearman, D. J. C./.R.C.S. 1975,3,377.28. Pounder, R. E., Williams, 1. G., Misiewicz, J. j., Milton-Thompson, G. J.

Gut, 1975,16,831.

803

fairly constant in successive generations. Exposureof animals to ionising radiation has been shown tolead to an increment in the magnitude of this gene­tic load. There is general awareness that nuclearexplosions, accidents at thermonuclear reactors,and nuclear waste may present long-term genetichazards to all species, including man. Less well­known is that the genetic effect of very small dosesof radiation to a large section of a population iscumulative and more harmful to later generationsthan a massive exposure of a much smaller numberof people. For this reason the chief source of an in­crease in genetically significant radiation to man isfrom medical radiology.

The genetically significant dose (G.S.D.) is theradiation delivered to the gonads during the repro­ductive years. It is estimated that from thenaturally occurring background radiation ofcosmic rays and radioactive elements in the earth'scrust this averages 100 mrad per person per year.In a World Health Organisation publication deal­ing with radiation protection in medical practice, 1

Dr W. SEELENTAG forecasts that by 1980 the G.S.D.from X-ray examinations will, in some industria­lised countries, amount to a further 100 mrad. Ifit was assumed that the spontaneous-mutation ratewas due to background radiation alone-s-anassumption with a generous safety margin-thendoubling the G.S.D. would substantially increase thefrequency of disorders due to mutant genes."Dominant conditions could be expected to rise infrequency by 80% in the first generation, reaching100% in two to three generations if the higher levelof radiation persisted. X-linked recessive disorderswould increase by 29% in immediate descendantsand by 90% by the sixth generation. The effect ofdoubling the mutation-rate for recessive geneswould be to increase the incidence of autosomalrecessive disorders by 1% per generation, so that a50% increase would occur only after fifty gene­rations. Dr SEELENTAG1 draws attention to aBavarian investigation showing that "the G.S.D.could be reduced to one-third without reducing thefrequency [of X-ray examinations] provided allradiologists adopted the techniques used .in insti­tutes that made a constant effort to minimise gonaddoses". It was also found that, by applyingtechniques employed in "inadequate institutionswhich did not agree to participate. in the pro­gramme", the gonadal doses exceeded that deliveredusing "careful techniques (which did not detractin the slightest from the diagnostic value of theapplication)" by factors of up to 22 000. In thisexample, "a single examination performed on oneperson using a bad technique has the same genetic

1. Seelentag, W. in Manual on Radiation Protection in Hospitals and GeneralPractice (edited by B. E. Keane and K. B. Tikhonov); vol. III (X-ray Diag­nosis), p. 85. World Health Organisation, Geneva, 1975.

2. Medical Research Council. The Hazards to Man of Nuclear and AlliedRadiations. H.M. Stationery Office, 1956.