trimethoprim--sulfamethoxazole-drug-combination and sapropterin

In 1988, Mello and Abbott incidentally found an effectiveness of sulfamethoxazole-trimethoprim (S-T), an antimicrobial combination which was prescribed for the treatment of dysuria, on neurologic dysfunction in a patient with MJD. However, the mechanism by which S-T exerts its pharmacological actions on the central nervous system was not delineated. The purposes of the present studies are to investigate whether or not S-T is effective in alleviating the neurological symptoms and signs in MJD, and then to clarify the mechanism how S-T exerts its pharmacological actions on the neurological deficits, and finally to test the effectiveness of tetrahydrobiopterin (BH4) as a treatment. (1) Sulfamethoxazole-trimethoprim double-blind, placebo-controlled, crossover trial. The clinical results were as follows; mild improvements of hyperreflexia of knee jerks and of rigospasticity of the legs during S-T treatment period. In addition, S-T significantly reduced the times of 8 motor activities on the timed tests. The biochemical results showed that basal levels of all biopterins and homovanillic acid in the cerebrospinal fluid(CSF) were reduced to less than half the levels of controls with other neurological diseases. After S-T treatment, total and oxidized form of biopterins in the CSF increased significantly. Therefore, S-T may be effective to neurologic deficits through its mechanism of increasing the level of brain biopterins in MJD. The present study prompted us to investigate whether or not tetrahydrobiopterin (BH4) is useful as a therapeutic strategy. (2) Tetrahydrobiopterin double-blind, placebo-controlled, crossover trial. The results were as follows: 1. Questionnaire. Choking was mildly improved on the first tetrahydrobiopterin (BH4) treatment day, though not significant (p < 0.10). 2. Neurologic examinations. Hyperreflexia of the knee jerks was mildly improved on the 10th day of BH4 treatment, but it was not significant (p < 0.10). 3. Timed tests. Significant improvements were seen on several timed tests. These results, though preliminary, implied that BH4 showed mild improvements of neurologic deficits.

Topics: Anti-Infective Agents; Biopterins; Double-Blind Method; Humans; Machado-Joseph Disease; Trimethoprim, Sulfamethoxazole Drug Combination

The introduction of sulfa drugs for the chemotherapy of bacterial infections in 1935 revolutionized medicine. Although their mechanism of action is understood, the molecular bases for most of their side effects remain obscure. Here, we report that sulfamethoxazole and other sulfa drugs interfere with tetrahydrobiopterin biosynthesis through inhibition of sepiapterin reductase. Crystal structures of sepiapterin reductase with bound sulfa drugs reveal how structurally diverse sulfa drugs achieve specific inhibition of the enzyme. The effect of sulfa drugs on tetrahydrobiopterin-dependent neurotransmitter biosynthesis in cell-based assays provides a rationale for some of their central nervous system-related side effects, particularly in high-dose sulfamethoxazole therapy of Pneumocystis pneumonia. Our findings reveal an unexpected aspect of the pharmacology of sulfa drugs and might translate into their improved medical use.

Topics: 5-Hydroxytryptophan; Adult; Alcohol Oxidoreductases; Anti-Infective Agents; Biopterins; Cell Line; Central Nervous System; Crystallography, X-Ray; Fibroblasts; Humans; Levodopa; NADP; Nausea; Pneumonia, Pneumocystis; Protein Conformation; Structure-Activity Relationship; Sulfamethoxazole; Trimethoprim, Sulfamethoxazole Drug Combination; Vomiting

Topics: Antioxidants; Biopterins; Humans; Machado-Joseph Disease; Neurologic Examination; Trimethoprim, Sulfamethoxazole Drug Combination