Clofibrate Treatment of Neonatal Jaundice

1292

LETTERS

TO THE

EDITOR

MICHAEL TENNISON,

MD

ROBERT GREENWOOD, MD

MICHAEL MILES, PHARMD

School of Medicine Department of Neurology

The

Chapel Hill, North Carolina 27599

Clofibrate

Treatment

of Neonatal

Jaundice

To the

Editor.-We have read the article on “Clofibrate Treatment of Neonatal Jaundice” by Gabilan et al’ with great interest. Treatment of neonatal jaundice with clofibrate given by mouth as a single dose will be a new area in this field.

However, we think that several aspects of therapy with this drug should be clarified before it is applied to babies. Clofibrate has a number of side effects such as nausea, vomiting, diarrhea, skin rash, gallstones, and cholecysti-tis, but its disturbing effects on liver and muscles are of prime importance.2 Carcinogenic properties of clofibrate on various organs, mainly on liver and pancreas, have been shown in rats.3 It also has been noticed that mci-dences of alimentary and respiratory system carcinomas were high in man treated with clofibrate.4 In those reports clofibrate had been used for a long time.3’4 However, whether its administration during the early neonatal period might lead to the development of malignancies later in life is speculative but possible; it is well known that genital cancers may develop in fetuses who were exposed to diethylstilbestrol in utero as late as 31 years after exposure.’

The muscular syndrome or myopathy which is one of the most important adverse effects of clofibrate may appear within as short a time as 36 hours after the drug has been taken, and it may be irreversible.6 The risk of myopathy increases if the renal function is impaired. It is known that renal function in neonates is not as mature as in adults. The half-life of clofibrate is 15 hours in adults, but not known in neonates.’ Also, the studies by Gabilan et al7’8 showed that plasma levels of clofibrate remained high for a long time, but in both of their studies neither muscle nor liver enzymes had been determined.

This drug also possibly may predispose patients to bilirubin encephalopathy. Deesterified p-chlorophenox-yisobutyric acid which is the major fraction of clofibrate binds to plasma albumin.2 This binding may increase the level of free bilirubin and cause encephalopathy at even lower plasma levels of bilirubin.

Understanding of the metabolism and side effects of clofibrate in the neonatal period and knowledge of the long-term prognosis of these babies will clarify the ther-apeutic value of this drug.

REFERENCES

IBRAHIM ERKUL,

MD

HALUK YAVUZ,

MD

AHMET OZEL,

MD

Department of Pediatrics Sel,ik University

Konya, Turkey

1. Gabilan JC, Benattar C, Lindenbaum A. Clofibrate treat-ment of neonatal jaundice. Pediatrics. 1990;86:647-648 2. Brown MS, Goldstein JL. Clofibrate. In: Gilman AG,

Good-man LS, RaIl TW, Murat F, eds. Goodman and Gilman’s

The Pharmacological Basis of Therapeutics. New York: MacMillan Publishing; 1985:835-837

3. Reddy JK, Qureshi SA. Tumorigenicity of the hypolipi-daemic peroxisome proliferator ethyl-a-p-chlorophenoxyi-sobutyrate (clofibrate) in rats. Br J Cancer. 1979;40:476-482

4. MacGregor GA. Clofibrate and malignancy. Lancet.

1979;1(8113):445

5. Herbst AL, Holt LH. Clinical aspects of in utero DES exposure. In: Sciarra JJ, Buchsbaum HJ, eds. Sciarra Gy-necologic Oncology. Philadelphia: Harper and Row Publish-ing; 1987:1-13

6. Rush P, Baron M, Kapusta M. Clofibrate myopathy: a case report and a review ofthe literature. Semin Arthritis Rheum.

1986;15:226-229

7. Lindenbaum A, Hernandorena X, Vial M, et al. Traitement curatif de l’ict#{232}redu nouveau-ne a terme par le clofibrate. Essai th#{233}rapeutique contr#{244}l#{233}en double aveugle. Arch Fr Pediatr. 1981;38:867-873

8. Lindenbaum A, Delaporte B, Benattar C, et a!. Traitement pr#{233}ventifde l’ict#{233}r#{233}du nouveau-ne pre#{233}matur#{233}par le clofi-brate. Essai th#{233}rapeutique contr#{244}l#{233}en double aveugle. Arch

Fr Pediatr. 1985;42:759-763

In

Reply.-I. Erkul, H. Yavuz, and A. Ozel’s remarks concerning adverse and possibly pathogen effects of clofibrate in man are very important and deserve accurate answers. The potential carcinogenic effect of clofibrate in rat and

mouse is well known; its mechanism has not been

re-solved, but it occurs only after extended treatment in-volving high doses of the drug.’ In man, some authors have speculated on the possible occurrence of colonic tumors, due to the increase in fecal excretion of choles-terol, degradation of which by intestinal bacteria might produce carcinogenic substances.”6 Other authors have noted a similar chemical structure in clofibrate and some carcinogenic herbicides.7’8 Because of these theoretical reservations limiting the extended therapeutic use of clofibrate, two extensive studies have been conducted in the United States and in Europe. The American one (Coronary Drug Project), published in 1975, was a study of the course of patients suffering from ischemic heart disease after 5 year’s treatment with either clofibrate or a placebo. The result indicated that cancer mortality (or morbidity) was no higher in the treated population

(2.92%o) than in the nontreated population (2.84%). The European study (WHO Cooperative Trial) published in 1978 relates to primary prevention of ischemic heart disease. In this study, treated patients having a high cholesterol level showed a higher cancer morbidity and mortality rate (3.6%o and 2.2%o) compared with

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LETTERS

TO THE

EDITOR

1293

ac-tual fact, the statistical study turned out to be unreliable: on the one hand, cancer morbidity and death rates among nontreated patients with a high cholesterol level are particularly low (2.6%o and 1.7%o), much lower, in fact, than the usual cancer death rates encountered in the population at large (2.2%o to 2.8%o). On the other hand, they are also lower than the cancer morbidity and death rates among the reference group with a low cholesterol count (3%o and 2.5%o). An overall analysis of these studies, published in 1979, reached the conclusion that there was no evidence of a cancer hazard.” The conclu-sion was confirmed in 1980 by the final publication of the WHO Cooperative Trial which, after an average follow-up of patients for 9.6 years, no longer finds a significant difference between cancer deaths in the treated and nontreated patients.”3 Moreover, we carried out an additional in vitro study with Professor Beljansky

(Pharmacology Laboratory. Unite d’Enseignement et de

Recherche de Sciences Pharmaceutiques. Universit#{233} Paris-Sud) for testing carcinogenic drugs, using a partic-ularly carcinogen-molecule-sensitive method, ie, in vitro replication of normal and cancerous DNA. We compared a well-known reference carcinogen, acetylaminofluorene, with the action of clofibric acid on the DNA of various human cancerous tissues (breast, Ehrlich ascites cells, kidneys, neurocarcinoma) and on nonmalignant tissues of the same origin. It was found that acetylaminofluorene strongly stimulated the synthesis of cancerous DNA and only slightly of normal DNA. Clofibric acid stimulated no synthesis whatsoever, not even at levels up to 420 tg/ mL that were never reached during our therapeutic tests. Thus, we felt that we had ruled out any likely carcino-genic toxicity ofclofibrate for children undergoing a short period of treatment.

Cases of acute muscular syndrome due to clofibric acid have been described,’4’5 but always in relation to a very high level of clofibric acid in the blood (150 to 500 g/ mL) and generally due to resulting kidney failure,’6’8 and not to hypersensitivity.’7 In these cases of myotoxicity the creatine kinase (CK) rate was always very high.’9 In our study, the amount of clofibric acid was never more than 50 to 150 g/mL; CK activity in serum was deter-mined in a preliminary study on 10 babies born at term, and later during the therapeutic trial on infants of varying ages, including premature births. The level of CK re-mained normal and no clinical signs of acute muscular syndrome were observed.

We also conducted several studies on possible clofi-brate-induced liver toxicity in rats, both in vitro on isolated hepatocytes, and in vivo. We determined ami-notransferase activity, glycemia, albuminemia, and

a,-glycoproteinemia in treated infants; none of the results entitled us to hypothesize a possible hepatic toxicity or abnormality of hepatocyte function. During the in vitro studies we found a 100% increase of bilirubin-glucuron-osyltransferase activity in isolated hepatocytic cells after treatment of the animals with clofibrate.

Last, regarding the influence of clofibric acid on the binding of bilirubin on albumin, we have shown that, according to the Porter and Waters method,20the residual

binding capacities of bilirubin on albumin are unchanged by the presence of clofibric acid and, by Sephadex G-25 chromatography, that clofibric acid does not shift the bilirubin from its binding sites on albumin. Hence, there is no danger of hyperbilirubinic encephalopathy with this drug arising in conditions where the plasma total biliru-bin is relatively low.

A part of the results of these preliminary studies are given in the article on the curative treatment of neonatal jaundice published in 1981.21 The whole of these studies were reported in 1985 in the “These de Doctorat es Sciences Pharmaceutiques” by C. Benattar (Paris-Sud University, Department of Pharmaceutical Teaching and Research). The therapeutic studies were carried out with the agreement of the Institut National de la Sante et de la Recherche M#{233}dicale(INSERM): 1981 Action Th#{233}ma-tique Programm#{233}e, Biologie du D#{233}veloppement, Grant

817.

REFERENCES

J. C. GABILAN,

MD

C. BENATTAR, PHD

A.

Neonatal Intensive Care Unit Hopital Antoine B#{233}cl#{232}re 92141 Clamart (France)

1. Hartig F, Stegmeier K, Hebold G. Study of liver enzymes peroxisomes proliferation and tumor rates in rats at the end of cardinogenicity studies with Bezafibrate and Clofibrate in peroxisomes and glioxisomes. Ann N Y Aced Sci.

1982;336:464-467

2. Reddy JK, Qureshi SA. Tumorigenicity ofthe hypolipidemic peroxisome proliferator ethyl-a-p-chlorophenoxysobutyrate (Clofibrate) in rats. Br J Cancer. 1979;40:476-482

3. Reddy JK, Azarnoff DL, Hignite CE. Hypolipidemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature 1980;283:397-398

4. Svoboda DJ, Azarnoff DL. Tumors in mal rats fed ethyl chlorophenoxyisobutyrate, a hypolipidemic drug. Cancer

Res.1979;39:3419-2834

5. Fastwood M. Clofibrate. Lancet. 1972; 11:1302-1303

6. Heller F, Pourbaix S. Peroxysomes et hypolip#{233}miants.

Pa-thaI Biol. 1982;30:220-225

7. Axelson 0, Tagesson C. The clofibrate problem: a different viewpoint. Lancet. 1980;2:1081

8. Hardell L. The clofibrate problem: a different viewpoint.

Lancet. 1980;2:1081-1082

9. Coronary Drug Project Research Group. JAMA. 1975;

231:360-381

10. Committee of principal investigators. A cooperative trial in the primary prevention of ischaemic heart disease using

clofibrate.Br Heart J. 1978;40:1069-1118

11. Gennes JL de. Des risques reels ou pr#{233}tendusdes d#{233}riv#{233}sdu clofibrate aux risques assures de leur interdiction. Presse

Med. 1979;8:1223-1225

12. Commitee ofprincipal investigators. WHO Cooperative trial on primary prevention of ischaemic heart disease with do-fibrate to lower serum cholesterol: mortality follow-up.

Lan-cet. 1980;2:379-385

13. Commitee ofprincipal investigators. WHO Cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: final mortality follow-up. Lancet. 1984;2:600-604

14. Langer T, Levy R. Acute muscular syndrome associated with administration of clofibrate. N EngI J Med. 1968;

279:856

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1294 LETTERS TO THE EDITOR

15. Sekowski I, Samuel P. Clofibrate-induced acute muscular syndrome. Am J Cardiol. 1972;30:572-574

16. Pierides AM, Alvarez-Ude F, Kerr DNS, Skillen AW. Clo-fibrate induced muscle damage in patients with chronic renal failure. Lancet. 1975;2:1279-1286

17. Rimon D, Ludatscher R, Cohen L. Clofibrate induced mus-cular syndrome. Case report with ultrastructural findings and review of the literature. Isr J Med Sci. 1984;20:1082-1087

18. Rumpf RW, Albers R, Scheler F. Clofibrate induced myopa-thy syndrome. Lancet. 1976;1:249-250

19. Rush P, Baron M, Kapusta M. Clofibrate myopathy: a case report and a review ofthe literature. SeminArthritis Rheum.

1986;15:226-229

20. Porter EG, Waters WJ. A rapid micromethod for measuring the reserve albumin binding capacity in serum from newborn

infant with hyperbilirubinemia. J Lab Clin Med.

1966;67:660-668

21. Lindenbaum A, Hernandorena X, Vial M, et al. Traitement curatif de l’ict#{232}redu nouveau-ne a terme par le Clofibrate. Essai th#{233}rapeutique contr#{244}l#{233}en double aveugle. Arch Fr

Pediatr. 1981;38:867-873

Cimetidine

and Breast-Feeding

To the

Editor.-In the September 1983 report from the AAP Commit-tee on Drugs’ cimetidine (Tagamet) is classified with the “Drugs That Are Contraindicated During Breast-Feed-ing” and refers to a 1979 publication in the British

JournalofClinicalPharmacology’ by Somogyi and Gugler.

Reported signs or symptoms are “May suppress gastric acidity in infant, inhibit drug metabolism, and cause CNS stimulation.” In the November 1989 report from the AAP Committee on Drugs,3 this same drug is listed under “Maternal Medication Usually Compatible With Breast-Feeding” while referring to the same 1979 British publi-cation and adding no other reference. Even more con-spicuous is the drop of all reported signs or symptoms to “none”! What is the rationale behind changing the clas-sification of a drug from incompatible to compatible with breast-feeding without additional information? Why are some symptoms contraindicated one year and compatible another? How many more drugs have had the same fate in this last revision?

In

Reply.-When the Committee on Drugs revised the statement on the transfer of drugs and other chemicals into human milk, the decision was made to include only drugs for which there were published data on the measurement of the compound in milk, maternal serum, and/or infant urine and serum. This resulted in the reclassification of a number of drugs other than cimetidine. The publication that is cited in the 1983 and the 1989 publication for

cimetidine in human milk’ is a Letter to the Editor

describing an experience with a single mother and nurs-ing infant and the measurement of cimetidine in the milk. The infant had been nursing for 6 months while the mother was taking cimetidine. These authors describe no signs or symptoms referable to the receipt of the drug during the 6-month nursing period nor did they describe any signs or symptoms during the study period. The Committee on Drugs does not know the source of the statement “may suppress gastric acidity in infant, inhibit drug metabolism, and cause CNS stimulation.” Possibly that precaution was added because of these being known side effects of the drug in usual doses in infants and children. As the Committee mentioned in the preface to

this Statement, we urge documentation of signs and

symptoms in the infants of mothers receiving drugs to both the AAP Committee on Drugs and the US Food and Drug Administration. These reports may significantly increase our ability to respond to questions concerning the transfer of drugs in human milk and the potential or actual risk to the infant.

REFERENCES

CHESTON

M.

MD

Penn State

College of Medicine/University Hospital The Milton S. Hershey Medical Center Hershey, Pennsylvania 17033

1. Somogyi A, Gugler R. Cimetidine excretion into breast milk.

Br J Clin Pharmacol. 1979;7:627-629

Lomotil

Overdose

REFERENCES

NICOLE BERNSHAW, MSC

Breastfeeding Consultants Association of Utah

Salt Lake City, Utah 84152-6235

1. Committee on Drugs, American Academy of Pediatrics. The

transfer of drugs and other chemicals into human breast milk. Pediatrics. 1983;72:375-383

2. Somogyi A, Gugler R. Cimetidine excretion into breast milk.

Br J Clin Pharmacol. 1979;7:627-629

3. Committee on Drugs, American Academy of Pediatrics. Transfer of drugs and other chemicals into human milk.

Pediatrics. 1989;84:924-936

To the

Editor.-I read with disappointment the Lomotil overdose ar-tide by McCarron et al.’ The title states “an update” and yet 6 of the 8 new cases are from the 1970s with the most recent case from 1986. The last part of the title claims a “review of the literature,” yet two thirds of the published acute pediatric overdoses are not included. My case series of 45 exposures with 13 hospitalized acute intoxications is cited as an early reference yet excluded from “Table 2: Diphenoxylate/Atropine (DPX/ATR) Intoxication in Children: 28 Cases From the Literature.” Also missing is a case by Shearer et al,3 as well as a report on 45 children (43 acute) by Curtis and Goel from the United Kingdom.4

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1991;88;1292

Pediatrics

J. C. GABILAN, C. BENATTAR and A. LINDENBAUM

Clofibrate Treatment of Neonatal Jaundice

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Pediatrics

J. C. GABILAN, C. BENATTAR and A. LINDENBAUM

Clofibrate Treatment of Neonatal Jaundice

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