trimethoprim--sulfamethoxazole-drug-combination and Phenylketonurias

A child with dihydropteridine reductase (DHPR) deficiency developed signs of dopamine insufficiency after being given trimethoprim-sulfamethoxazole (TMP-SMX). She recovered function after the antibiotic was stopped, which suggests that it adversely influenced dopamine metabolism in the CNS. The authors speculate that TMP, a dihydrofolate reductase inhibitor, was the major cause of the patient's deterioration, and suggest that it and other dihydrofolate inhibitors, notably methotrexate, are contra-indicated for patients with DHPR deficiency.

Topics: Child, Preschool; Dopamine; Epinephrine; Female; Humans; NADH, NADPH Oxidoreductases; Norepinephrine; Phenylalanine; Phenylketonurias; Sinusitis; Tremor; Trimethoprim, Sulfamethoxazole Drug Combination

The administration of several compounds that can increase plasma phenylalanine levels and/or inhibit phenylalanine hydroxylase in rats was studied in order to determine their usefulness in inducing a phenylketonuria-like state. The results of this investigation revealed that 4.5 microns/10 g p-chlorophenylalanine is more effective than L-phenylalanine, alpha-methylphenylalanine, trimethoprim, Bactrim and Septra, since the former compound produced both adequate hyperphenylalaninemia and marked inhibition of hepatic phenylalanine hydroxylase activity. In addition, a 24-h study provided important insights into the changing diurnal patterns of specified biochemical parameters.

Topics: Animals; Disease Models, Animal; Drug Combinations; Female; Fenclonine; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Rats; Rats, Inbred Strains; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

We report a family (parents and two sets of twin girls) in which the propositus presented as a case of phenylketonuria with a somewhat less severe degree of phenylalanine intolerance than occurs in patients with classical phenylketonuria and whose phenylalanine tolerance was further impaired by giving cotrimoxazole. The trimethoprim component of cotrimoxazole reduces the phenylalanine tolerance of normal subjects but does not augment the degree of phenylalanine intolerance in patients with classical phenylketonuria. The results of the present study of the phenylalanine tolerance and the way in which cotrimoxazole modifies it in the members of this family are compatible with the segregation of an abnormal gene which causes a previously unrecognized type of phenylketonuria when it is present in the homozygous state. The possible relationship of this to other inherited biochemical lesions of the phenylalanine hydroxylase system is briefly discussed.

Topics: Adult; Child; Diseases in Twins; Drug Combinations; Drug Tolerance; Female; Humans; Intelligence; Male; Middle Aged; Pedigree; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Tyrosine