CLOFIBRATE

423 CLOFIBRATE

carefully controlled the inoculum size with each strain by using well established bacteriological techniques, including measurement of turbidity and verification of numbers by viable counting. The technique we reported was precisely that with which, before 1974, we invariably found that the MIC of ampicillin for all strains of H. influenz6e fell within a narrow range not exceeding 0-3 mg/1. Therefore we find unacceptable Wheldon and Slack’s attempts to explain our findings on the basis of the variability of inoculum size resulting from the use of a technique irrelevant to our study. we

more,

Division of Microbiology, Prince of Wales Hospital, Randwick, New South Wales, Australia

S. M. BELL D. E. PLOWMAN

SIR,-Elsewhere in this issue (p. 379) appears the report of controlled trial of clofibrate for primary prevention of myocardial infarction. This report was made available to the Committee on Safety of Medicines before publication, by the courtesy of the authors. It indicates an increased mortality from many causes in patients treated with clofibrate. The committee is taking steps to inform practitioners of the potential hazards of widespread use of clofibrate. a

Committee on Safety of Medicines, Market Towers, 1 Nine Elms Lane, London SW8 5NQ

A.

GOLDBERG,

Chairman

W. I. Adverse Reactions Sub-Committee

ENDOTOXINS AND FUNCTIONAL RENAL FAILURE

SIR,-Wilkinson and Williams! support

your editorial’s I am not sure that their hepatorenal syndrome.2 interpretation of differences in Limulus assay positivity between the plasma and ascitic fluid has an unqualified applicability to the subject under discussion, for two reasons: (1) the usual indication for ascites reinfusion or peritoneojugular shunt is a massive ascites, and not uncommonly the volume of ascitic fluid compensates for the lower protein concentration compared to plasma; (2) after a major paracentesis or peritoneojugular shunt changed dynamics of ascites formation should facilitate the passage of solutes (including bacterial metabolites) from splanchnic tissues into the peritoneal

thesis

on

the

cavity.3 One of the

showing

no

two papers quoted by Wilkinson and Williams as improvement in renal function with ascites-con-

centrate reinfusion reports "a marked improvement in renal function" in 30% of patients with functional renal failure.4 This may be considered a uniquely high success rate for a condition notoriously resistant to treatment. It would seem that different conclusions can be derived from the same study, and also that the differences in results may possibly be due to differences in concepts. As long as a unified concept of functional renal failure is not universally accepted it remains difficult to compare results and experiences. Witte et al. have based the hepatorenal syndrome exclusively on "effective plasma volume" without even mentioning the "endotoxin theory"5 (Bias in another direction?) Others vigorously question whether endotoxin is present in plasma and ascites of subjects with cirrhosis (or at least the reliability of previous studies using L imulus assay).66 One-factor explanations do not appear to be very successful in functional renal failure which proabably represents the final stage in a chain of pathophysiological events in liver cirrhosis. When the links are identified and their mutual relationships investigated we may become better equipped to determine which factor has a major or minor pathogenetic role.

Department of Medicine, Albany Medical College, Albany, New York 12208,

U.S.A.

IVO BUHAC

1. Williamson

SP, Williams R. Endotoxins and renal failure in cirrhosis. Lancet 1980; i: 1414. 2. Editorial. Hepatorenal syndrome and hepatic nephropathy. Lancet 1980; i: 801. 3. Buhac 1. Ascites, the LeVeen shunt, and endotoxin. Ann Intern Med 1980; 92:573. 4. Levy VG, Opolon P, Pauleau N, Caroli J. Treatment of ascites by reinfusion of concentrated peritoneal fluid-review of 318 proceedings in 210 patients. PostgradMed_7 1975; 51: 564-66. 5. Wttte CL, Witte MH, Dumont AE. Lymph imbalance m the genesis and perpetuation of the ascites syndrome in hepatic cirrhosis. Gastroenterology 6.

1980;78: 1059-68. Fulenwider JT, Sibley C, Stein SF, Evatt B, Nordlinger BM, Ivey GL. Endotoxsmia of cirrhosis an observation not substantiated. Gastroenterology 1980;778:1001-04.

CRANSTON,

Chairman

ALLOPURINOL FOR MUSCULAR DYSTROPHY

SIR,-There has lately been controversy over the efficacy of allopurinol in muscular dystrophy.I Many of the abnormalities of dystrophic muscle have been to lowered concentrations of ATP.2 Thomson and Smithhave reported that allopurinol, a xanthine oxidase inhibitor, raises the concentration of ATP in dystrophic muscle

attributed

by increasing the availability of hypoxanthine to the purine salvage pathway. After a 12 month course of treatment they observed increased ATP levels and clinical improvement. Reports of other trials of allopurinol in muscular dystrophy have been conflicting.3,4 Since allopurinol has a clinical effect within 4-6 h,5 it should be possible to demonstrate increased levels of ATP in dystrophic muscle over a shorter period of time, than that used by Thomson and Smith. We treated C57 dystrophic and normal mice with allopurinol at 50 mg/kg/day intraperitoneally for 21 days, and measured muscle nucleotides by the method of Lush et al. The only significant change induced by allopurinol was a fall in the concentration of ATP in dystrophic muscle (see table). MUSCLE ADENINE NUCLEOTIDE CONCENTRATIONS NON-COLLAGEN

*

PROTEIN)

(nmol/mg

±SEM

p
We suggest two possible reasons why allopurinol is unlikely be effective in muscular dystrophy. The first is that its postulated enhancement of ATP synthesis would involve an increase in the concentrations of muscle AMP, caused by the increased availability of hypoxanthine. However, our table and to

1. Cherfas J. Drug for muscular dystrophy raises a storm. New Sci June 12 1980: 229-30. 2. Thomson WHS, Smith I. X-linked recessive (Duchenne) muscular dystrophy (DMD) and purine metabolism: Effects of oral allopurinol and adenylate. Metabolism 1978;27:151-63. 3. Bakouche P, Cheovet D, Nick J. Allopurinol not effective in muscular dys4.

5.

trophy. N Engl J Med 1979;301:785. Castro-Gago M, Jimenez JF, Pombo M, Tojo R,

Couselo JM, Pena J. Allopurinol in muscular dystrophy. Lancet 1980; i: 1358-59. Wyngaarden JB, Kelley WN. Gout. In: Stanbury JB, Wyngaarden JB, Fred-

rickson DS, eds. The metabolic basis of inherited disease, 4th ed. New York: McGraw-Hill, 1978:916-1010. 6. Lush C, Rahim ZHA, Perrett D, Griffiths JR. A microprocedure for extracting tissue nucleotides for analysis by high performance liquid chromato-

graphy. Analyt Biochem 1979, 93:227-32.