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Drug Metabolism and Pharmacokinetics in Malnourished Children

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Summary

Malnutrition is a complex condition in which many deficiencies occur simultaneously. Protein-energy malnutrition is a major public health and clinical problem in paediatric practice that accounts for high child mortality and morbidity. It includes many different clinical syndromes with protean manifestations.

The malnourished often have several concomitant diseases; drugs are therefore as widely used as in the well-nourished. The pathophysiological profile in malnutrition can alter pharmacokinetic processes, drug responses and toxicity. This review summarises the available knowledge on nutrient-drug interactions in malnourished children.

Although there is much evidence in the literature that diet and nutritional status are 2 important environmental variables determining the pharmacotoxicological properties of chemicals, there are few data on humans. Recently, intense effort has been initially directed at studying drug kinetics in grade III malnutrition, namely kwashiorkor and marasmus. Studies on drugs and nutrients indicate delayed or decreased absorption, reduced protein binding of several drugs, fluctuations in volume of distribution, altered hepatic oxidative drug biotransformations and conjugations, reduced elimination of conjugates and reduced elimination of renally excreted drugs. The estimated steady-state levels of a few drugs suggest accumulation. Bioavailability problems with certain drugs are due to divergent effects of pharmacokinetic processes. Clinical risk of toxicity appears to be higher in malnourished children. Rehabilitation studies suggest that a number of these pharmacological abnormalities can be reversed.

The majority of studies have concentrated on single-dose pharmacokinetics in severely malnourished children. A number of abnormalities seen in drug disposition during the’ acute phase of malnutrition need to be confirmed for other grades of malnutrition. For practical purposes, it is important to consider steady-state levels and data in mild and moderate forms of growth-retarded children; drug-induced nutritional deficiencies can occur more easily in these populations. Although some of the drugs described in this review have been in use for many years, knowledge on drug response and toxicity is still only approximate. There is at present enough evidence to support monitoring plasma drug concentrations in malnourished children, particularly for those drugs which have dose-dependent kinetics and narrow margins of safety.

The metabolism and disposition of xenobiotics seem to vary widely in children with protein-energy malnutrition. Therapeutic inadequacies and toxicities need careful evaluation in malnourished children.

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References

  • Akbani Y, Bolme P, Lindblad BS, Rahimtoola RJ. Control of streptomycin and isoniazid in malnourished children treated for tuberculosis. Acta Paediatrica Scandinavica 66: 237–240, 1977

    PubMed  CAS  Google Scholar 

  • Alleyne GAO. Cardiac function in severely malnourished Jamaican children. Clinical Science 30: 553–562, 1966

    PubMed  CAS  Google Scholar 

  • Alleyne GAO. The effect of severe protein calorie malnutrition on the renal function of Jamaican children. Paediatrics 39: 400–411, 1967

    CAS  Google Scholar 

  • Alleyne GAO, Flores H, Picors DIM, Waterlow JC. Metabolic changes in children with protein calorie malnutrition. In Winick M (Ed.) Nutrition and development, pp. 201–238, John Wiley and Sons, New York, 1972

    Google Scholar 

  • Anderson KE, Conney AH, Kappas A. Nutritional influences on chemical biotransformations in humans. Nutritional Reports International 40: 161–171, 1982

    CAS  Google Scholar 

  • Balmer S, Howells G, Wharton B. The effects of tetrachlorethylene in children with kwashiorkor and hookworm infestation. Journal of Tropical Pediatrics 16: 20–23, 1970

    PubMed  CAS  Google Scholar 

  • Bano G, Sharma DB, Raina RK. Pharmacokinetics of phenytoin in protein energy malnutrition. Indian Journal of Pharmacology 17: 77–78, 1985

    Google Scholar 

  • Bano G, Raina RK, Sharma DB. Pharmacokinetics of carbamazepine in protein energy malnutrition. Pharmacology 22: 232–236, 1986

    Google Scholar 

  • Basu TK. Nutritional status and drug therapy. In Basu TK (Ed.) Clinical implications of drug therapy, Vol. 2: pp. 61–95, CRC Press, Florida, 1980

    Google Scholar 

  • Bhramara pravathi N. The liver in protein calorie malnutrition. In Olson RE (Ed.) Protein calorie malnutrition, pp. 299–307, Academic Press, New York, 1975

    Google Scholar 

  • Bosch J, Saccaggi A, Lauer A, Ronco C, et al. Renal function reserve in humans: effect of protein intake on glomerular filtration rate. American Journal of Medicine 75: 943–949, 1983

    PubMed  CAS  Google Scholar 

  • Boston Collaborative Drug Surveillance Program. Diphenyl hydantoin side effects and serum albumin level. Clinical Pharmacology and Therapeutics 14: 529–532, 1973

    Google Scholar 

  • Bravo ME, Arancibia A, Japra S, et al. Pharmacokinetics of gentamicin in malnourished infants. European Journal of Clinical Pharmacology 21: 499–504, 1982

    PubMed  CAS  Google Scholar 

  • Bravo IG, Bravo ME, Plate G, et al. The pharmacokinetics of cotrimoxazole sulphonamide in malnourished (marasmic) infants. Pediatric Pharmacology 4: 167–176, 1984

    PubMed  CAS  Google Scholar 

  • Bridges JW, Wilson AGE. Drug serum protein interactions and their biological significance. In Bridges JW, Chasseaud LF (Eds) Progress in drug metabolism, Vol. 1, pp. 193–247, John Wiley and Sons, London, 1976

    Google Scholar 

  • Broad DA. Drug nutrient interactions. Medical Clinics of North America 63: 985–1003, 1979

    Google Scholar 

  • Buchanan N. Drug protein binding and protein energy malnutrition. South African Medical Journal 52: 733–737, 1977

    PubMed  CAS  Google Scholar 

  • Buchanan N. Effect of protein energy malnutrition on drug metabolism. World Review of Nutrition and Dietetics 43: 129–139, 1984

    PubMed  CAS  Google Scholar 

  • Buchanan N, Eyeberg C. Intramuscular tobramycin administration in kwashiorkor. South African Medical Journal 53: 273–274, 1978

    PubMed  CAS  Google Scholar 

  • Buchanan N, Hansen JDL, Vander LA, et al. Chloramphenicol metabolism in children with protein calorie malnutrition. American Journal of Clinical Nutrition 29: 327–330, 1976

    PubMed  CAS  Google Scholar 

  • Buchanan N, Eyeberg C, Davis MD. Antipyrine pharmacokinetics and D-glucaric aeid excretion in kwashiorkor. American Journal of Clinical Nutrition 32: 2439–2442, 1979a

    PubMed  CAS  Google Scholar 

  • Buchanan N, Robinson R, Jornholf HJ, Eyeberg C. Penicillin pharmacokinetics in kwashiorkor. American Journal of Clinical Nutrition 32: 2233–2236, 1979b

    PubMed  CAS  Google Scholar 

  • Buchanan N, Davis MD, Eyeberg C. Gentamicin pharmacokinetics in kwashiorkor. British Journal of Clinical Pharmacology 8: 451–453, 1979c

    PubMed  CAS  Google Scholar 

  • Buchanan N, Davis M, Danhof M, Breimer DD. Antipyrine metabolite formation in children in the acute phase of malnutrition and after recovery. British Journal of Clinical Pharmacology 10: 363–368, 1980a

    PubMed  CAS  Google Scholar 

  • Buchanan N, Davis MD, Henderson DB, Mucklow JC, Rawlins MD. Acetanilide pharmacokinetics in kwashiorkor. British Journal of Clinical Pharmacology 9: 525–526, 1980b

    PubMed  CAS  Google Scholar 

  • Buchanan N, Eyeberg C, Davis MD. Isoniazid pharmacokinetics in kwashiorkor. British Journal of Clinical Pharmacology 9: 525–526, 1980c

    PubMed  CAS  Google Scholar 

  • Buchanan N, Mithal Y, Witcomp M. Cefoxitin: intravenous pharmacokinetics and intramuscular bioavailability in kwashiorkor. British Journal of Clinical Pharmacology 9: 623–627, 1980d

    PubMed  CAS  Google Scholar 

  • Campbell TC. Nutrition and drug metabolizing enzymes. Clinical Pharmacology and Therapeutics 22: 699–706, 1977

    PubMed  CAS  Google Scholar 

  • Conney AH, Pantuck EJ, Hsiao KC, Garland WH, et al. Enhanced phenacetin metabolism in human subjects fed charcoal broiled beef. Clinical Pharmacology and Therapeutics 20: 633–642, 1976

    PubMed  CAS  Google Scholar 

  • Conney AH, Burning MK, Pantuck EJ, et al. Regulations of human drug metabolism by dietary factors. Ciba Foundation Symposium 76: 147–167, 1980

    PubMed  CAS  Google Scholar 

  • Eriksson M, Paalzow L, Bolme P, Mariam TW. Chloramphenicol pharmacokinetics in Ethiopian children of differing nutritional status. European Journal of Clinical Pharmacology 24: 819–823, 1983a

    PubMed  CAS  Google Scholar 

  • Eriksson M, Paalzow L, Bolme P, Mariam TW. Pharmacokinetics of theophylline in Ethiopian children of differing nutritional status. European Journal of Clinical Pharmacology 24: 89–92, 1983b

    PubMed  CAS  Google Scholar 

  • Feldman C, Hutchinson VE, Pipenger CE, et al. Effect of dietary protein and carbohydrate on theophylline metabolism in children. Pediatrics 66: 956–962, 1980

    PubMed  CAS  Google Scholar 

  • Golden MHN, Ramalatt D. Free radicals in the pathogenesis of kwashiorkor. In Southampton TG, Jenkin NF (Eds) Proceedings of the 13th International Congress of Nutrition, pp. 597–598, John Libbey and Company Ltd, London, 1986

  • Gopalan C. Kwsashiorkor and marasmus: evaluation and distinguishing factors. In McCance RA, Widdowson EM (Eds) Calorie deficiencies and protein deficiencies, pp. 49–58, Churchill, London, 1967

    Google Scholar 

  • Gopalan C, Narasinga Rao BS. Nutritional constraints on growth and development in current India dietaries. Indian Journal of Medical Research 59 (Suppl.): 111–122, 1971

    PubMed  CAS  Google Scholar 

  • Gopalan C, Srikantia SG. Nutrition and disease, In Recheigal Jr M (Ed.) Nutrition and world food problem. Vol. 6, pp. 134–163, Karger, Basel, 1979

    Google Scholar 

  • Gupta SP, Mehta S, Walia BNS. Small bowel function in protein calorie malnutrition. Indian Pediatrics 7: 481–488, 1970

    Google Scholar 

  • Hahn TJ, Avioli LV. Anticonvulsant drug-induced mineral disorders. In Roe DA, Campbell TC (Eds) Drugs and nutrients, Vol. 21, pp. 409–427, Marcel Dekker, New York, 1984

    Google Scholar 

  • Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Federation Proceedings of Federal American Society of Experimental Biology 44: 124–129, 1985

    CAS  Google Scholar 

  • Hathcock JN, Coon JC (Eds). Nutrition and drug interrelations, Academic Press, New York, 1978

    Google Scholar 

  • Hendrickse RG, Coulter JBS, Lamplugh SM, et al. Aflatoxins and kwashiorkor: a study in Sudanese children. British Medical Journal 285: 843–846, 1982

    PubMed  CAS  Google Scholar 

  • Higashi A, Ikeda T, Matsukura M, Matsuda I. Serum zinc and vitamin E concentration in handicapped children treated with anticonvulsants. Developmental Pharmacology and Therapeutics 5: 109–113, 1982

    PubMed  CAS  Google Scholar 

  • Homeida M, Karrar ZA, Roberts CJC. Drug metabolism in malnourished children: a study with antipyrine. Archives of Disease in Childhood 54: 299–302, 1979

    PubMed  CAS  Google Scholar 

  • Hurd RW, Van Rinsvelt HA, Wilder BJ, et al. Selenium, zinc and copper changes with valproic acid: possible relation to drug side effects. Neurology 34: 1393–1395, 1984

    PubMed  CAS  Google Scholar 

  • Jagadeesan V, Krishnaswamy K. Drug binding in undernourished: a study on the binding of propranolol to α 1 acid glycoproteins. European Journal of Clinical Pharmacology 27: 657–659, 1985

    PubMed  CAS  Google Scholar 

  • Jaya Rao KS. Evaluation of kwashiorkor and marasmus. Lancet 1: 709–711, 1974

    Google Scholar 

  • Jaya Rao KS. Endocrines in protein energy malnutrition. World Review of Nutrition and Dietetics 39: 53–84, 1982

    PubMed  CAS  Google Scholar 

  • Kato R. Drug metabolism under pathological and abnormal physiological status in animals and man. Xenobiotica 7: 25–92, 1977

    PubMed  CAS  Google Scholar 

  • Kauffman RE, Miceli JN, Stebel L, et al. Pharmacokinetics of chloramphenicol and chloramphenicol succinate in infants and children. Journal of Pediatrics 98: 315–320, 1981

    PubMed  CAS  Google Scholar 

  • Kinnear AA, Pretorius PJ. Liver function in kwashiorkor. British Medical Journal 1: 1528–1530, 1956

    PubMed  CAS  Google Scholar 

  • Krishnaswamy K. Drug metabolism and pharmacokinetics in malnutrition. Clinical Pharmacokinetics 3: 216–240, 1978

    PubMed  CAS  Google Scholar 

  • Krishnaswamy K. Drug metabolism and pharmacokinetics in malnutrition. Trends in Pharmacological Sciences 4: 295–299, 1983

    CAS  Google Scholar 

  • Krishnaswamy K. The effect of nutritional status on drug action. Pharmacy International 6: 41–44, 1985

    CAS  Google Scholar 

  • Krishnaswamy K. Drug xenobiotic metabolism in undernutrition. Proceedings of the Nutrition Society of India 32: 35–42, 1986

    Google Scholar 

  • Krishnaswamy K. Effects of malnutrition on drug metabolism and toxicity in humans. In Hathcock JN (Ed.) Nutritional toxicology, pp. 105–123, Academic Press Inc., New York, 1987

    Google Scholar 

  • Krishnaswamy K, Naidu AN. Microsomal enzymes in malnutrition as determined by plasma half life of antipyrine. British Medical Journal 1: 538–540, 1977

    PubMed  CAS  Google Scholar 

  • Krishnaswamy K, Kalamegham R, Naidu AN. Dietary influences on the kinetics of antipyrine and aminopyrine in human subjects. British Journal of Clinical Pharmacology 17: 139–146, 1984

    PubMed  CAS  Google Scholar 

  • Kumar RV, Gokhale SV, Ambaye RY, Shetty PA. Pharmacokinetics of methotrexate in Indian children and its relationship to nutritional status. Chemotherapy 33: 234–239, 1987

    PubMed  CAS  Google Scholar 

  • Malmon KL, Nierenberg DW. Drug interactions and the prepared observer. New England Journal of Medicine 304: 723–724, 1981

    Google Scholar 

  • Massa E, McLean Jr WC, Lopez de Romana G, et al. Oral iron absorption in infantile protein energy malnutrition. Journal of Pediatrics 93: 1045–1049, 1978

    PubMed  CAS  Google Scholar 

  • McDanell RE, McLean AEM. Role of nutritional status in drug metabolism and toxicity. In Sidransky H (Ed.) Nutritional pathology, pp. 321–356, Washington DC, 1987

    Google Scholar 

  • McLean AEM, Witts DJ, Tame D. The influence of nutrition and inducers on mechanisms of toxicity in humans and animals. Ciba Foundation Symposium 76: 275–288, 1980

    PubMed  CAS  Google Scholar 

  • Mehta S, Kalsi HK, Jayaraman S, Mathur VS. Chloramphenicol metabolism in children with protein calorie malnutrition. American Journal of Clinical Nutrition 28: 977–981, 1975

    PubMed  CAS  Google Scholar 

  • Mehta S, Nain CK, Sharma B, Mathur VS. Metabolism of sulfadiazine in children with protein calorie malnutrition. Pharmacology 21: 369–374, 1980

    PubMed  CAS  Google Scholar 

  • Mehta S, Nain CK, Kalsi HK, Mathur VS. Bioavailability and pharmacokinetics of chloramphenicol palmitate in mainourished children. Indian Journal of Medical Research 74: 244–250, 1981a

    CAS  Google Scholar 

  • Mehta S, Nain CK, Sharma B, Mathur VS. Steady state of chloramphenicol in malnourished children. Indian Journal of Medical Research 73: 538–542, 1981b

    PubMed  CAS  Google Scholar 

  • Mehta S, Nain CK, Yadav D, Sharma B, Mathur VS. Disposition of acetaminophen in children with protein calorie malnutrition. International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 311–315, 1985

    CAS  Google Scholar 

  • Melander A. Influence of food in the bioavailability of drugs. Clinical Pharmacokinetics 3: 337–351, 1978

    PubMed  CAS  Google Scholar 

  • Melander A, McLean A. Influence of food intake on presystemic clearance of drugs. Clinical Pharmacokinetics 8: 286–296, 1983

    PubMed  CAS  Google Scholar 

  • Monckberg F, Bravo M, Gonzalez O. Drug metabolism and infantile undernutrition. In Hathcock JN, Coon JC (Eds) Nutrition and drug interrelations, pp. 399–408, Academic Press, New York, 1978

    Google Scholar 

  • Narang RK, Mehta S, Mathur VS. Pharmacokinetics study of antipyrine in malnourished children. American Journal of Clinical Nutrition 30: 1979–1982, 1979

    Google Scholar 

  • Obama M, Cangir A, Van Eys J. Nutritional status and anthracycline cardiotoxicity in children. Southern Medical Journal 76: 577–578, 1983

    PubMed  CAS  Google Scholar 

  • Olness KN. Nutritional consequences of drugs used in pediatrics. Clinical Pediatrics 24: 417–420, 1985

    PubMed  CAS  Google Scholar 

  • Ovesen L. Drugs and vitamin deficiency. Drugs 18: 278–298, 1979

    PubMed  CAS  Google Scholar 

  • Parke DV, Ioannides C. The role of nutrition in toxicology. Annual Review of Nutrition 1: 207–234, 1981

    PubMed  CAS  Google Scholar 

  • Polasa K, Murthy KJR, Krishnaswamy K. Rifampicin kinetics in undernutrition. British Journal of Clinical Pharmacology 17(4): 481–484, 1984

    PubMed  CAS  Google Scholar 

  • Raghuram TC, Krishnaswamy K. Tetracycline absorption in malnutrition. Drug Nutrient Interactions 1: 23–29, 1981a

    PubMed  CAS  Google Scholar 

  • Raghuram TC, Krishnaswamy K. Tetracycline kinetics in undernourished subjects. International Journal of Clinical Pharmacology, Therapy and Toxicology 19: 409–413, 1981b

    CAS  Google Scholar 

  • Raghuram TC, Krishnaswamy K. Pharmacokinetics of tetracycline in nutritional oedema. Chemotherapy 28: 428–433, 1982

    PubMed  CAS  Google Scholar 

  • Raghuramulu N, Reddy V. Studies on vitamin D metabolism in malnourished children. British Journal of Nutrition 47: 231–234, 1982

    PubMed  CAS  Google Scholar 

  • Reddy V, Srikantia SG. Serum vitamin A in kwashiorkor. American Journal of Clinical Nutrition 18: 105–109, 1966

    PubMed  CAS  Google Scholar 

  • Reynolds EH. Iatrogenic nutritional effects of anticonvulsants. Proceedings of the Nutrition Society of India 33: 225–229, 1974

    CAS  Google Scholar 

  • Roe DA. Risk factors in drug-induced nutritional deficiency. In Roe DA, Campbell TC (Eds) Drugs and nutrients, pp. 505–523, Marcel Dekker, New York, 1984

    Google Scholar 

  • Rugmini PS, Mehta S. Hepatotoxicity of isoniazid and rifampicin in children. Indian Paediatrics 21: 119–126, 1984

    CAS  Google Scholar 

  • Samotra K, Gupta S, Raina RK. Pharmacokinetics of gentamicin in protein energy malnutrition. European Journal of Clinical Pharmacology 29: 255–256, 1985

    PubMed  CAS  Google Scholar 

  • Santosa B, Rawlins MD. Isoniazid pharmacokinetics in tuberculosis patients. 2nd World Conference on Clinical Pharmacology and Therapeutics. Abstract no. 18. p. 3, 1983

  • Shastri RA. Undernourished adults and acetylation phenotype. International Journal of Clinical Pharmacology, Therapy and Toxicology 20: 194–196, 1982

    Google Scholar 

  • Singh LM, Mehta S, Wohra RM, Nain CK. Monitoring of phenobarbitone in epileptic children. International Journal of Clinical Pharmacology, Therapy and Toxicology 25: 18–22, 1987

    CAS  Google Scholar 

  • Sjoqvist F, Von Bahr C. Interindividual differences in drug oxidation: clinical importance. Drug Metabolism and Disposition 1: 469–482, 1973

    PubMed  CAS  Google Scholar 

  • Slattery JT, Wilson JM, Kalhorn JF, Nelson SD. Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in man. Clinical Pharmacology and Therapeutics 41: 413–418, 1987

    PubMed  CAS  Google Scholar 

  • Suskind RM. Gastrointestinal changes in the malnourished children. Pediatric Clinics of North America 22: 873–883, 1975

    PubMed  CAS  Google Scholar 

  • Syed GB, Sharma DB, Raina RK. Pharmacokinetics of phenobarbitone in protein energy malnutrition. Developmental Pharmacology and Therapeutics, in press

  • Tandon BN, Ramanujan RA, Tandon HD, et al. Liver injury in protein-calorie malnutrition: an electron microscopic study. American Journal of Clinical Nutrition 27: 550–558, 1974

    PubMed  CAS  Google Scholar 

  • Toothaker RD, Welling PG. The effect of food on drug bioavailability. Annual Review of Pharmacology and Toxicology 20: 173–199, 1980

    PubMed  CAS  Google Scholar 

  • Varma DR. Protein deficiency and drug interactions: a review. Drug Developmental Research 1: 183–198, 1981

    CAS  Google Scholar 

  • Walker O, Dawodu AH, Salako LA, et al. Single dose disposition of chloroquine in kwashiorkor and normal children — evidence for decreased absorption in kwashiorkor. British Journal of Clinical Pharmacology 23: 467–472, 1987

    PubMed  CAS  Google Scholar 

  • Walker WA. Cellular and immune changes in the gastrointestinal tract in malnutrition. In Winick M (Ed.) Nutrition and gastroenterology, pp. 197–218, John Wiley and Sons, New York, 1980

    Google Scholar 

  • Wateriow JC. Adaptation to low protein intakes. In Olson (Ed.) Protein calorie malnutrition, pp. 23–24, Academic Press, New York, 1975

    Google Scholar 

  • Wateriow JC. Adaptation and regulation — general concepts. In Taylor JJ, Jenkins MR (Eds) Proceedings of 13th International Congress of Nutrition, pp. 391–393, John Libbey, London, 1986

    Google Scholar 

  • Wateriow JC, Alleyne GAO. Protein malnutrition in children: advances in knowledge in the last ten years. Advances in Protein Chemistry 25: 117–241, 1971

    Google Scholar 

  • West J, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut 16: 93–98, 1975

    PubMed  CAS  Google Scholar 

  • Williams RT. Nutrients and detoxication reactions. In Hathcock JN, Coon JC (Eds) Nutrition in drug interrelations, pp. 303–318, Academic Press, New York, 1978

    Google Scholar 

  • Wilkinson GR. Plasma binding, distribution and elimination. In Roe DA, Campbell TC (Eds) Drugs and nutrients, Marcel Dekker, New York, 1984

    Google Scholar 

  • Winick M. Protein calorie deprivation in children. In Nutrition in health and disease, pp. 47–59, John Wiley and Sons, New York, 1980

    Google Scholar 

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  1. Food & Drug Toxicology Research Centre, National Institute of Nutrition, Jamai-osmania, Hyderabad-500 007, A.P., India

    Kamala Krishnaswamy

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Krishnaswamy, K. Drug Metabolism and Pharmacokinetics in Malnourished Children. Clin-Pharmacokinet 17 (Suppl 1), 68–88 (1989). https://doi.org/10.2165/00003088-198900171-00006

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