Jan Koch-Weser

Increased gamma-aminobutyric acid (GABA), homocarnosine and β-alanine in cerebrospinal fluid of patients treated with γ-vinyl GABA (4-amino-hex-5-enoic acid)

Abstract γ-Vinyl GABA, an enzyme-activated irreversible inhibitor of GABA transaminase (GABA-T), was administered orally to 15 patients with various neurological conditions at daily doses of 0.5, 1, 2 or 6 g/day for 3 days. CSF samples were obtained by lumbar puncture before treatment and within 24 hours after the last dose and the CSF concentrations of free GABA, total GABA, homocarnosine, β-alanine and γ-vinyl GABA determined by ion-exchange chromatography with fluorometric detection. γ-Vinyl GABA treatment produced dose-dependent increases in free GABA, conjugated GABA (defined as total minus free GABA), homocarnosine and β-alanine. The concentrations of CSF γ-vinyl GABA also depended on the dose administered. These results indicate that γ-vinyl GABA enters the CNS after oral administration and alters GABA metabolism by inhibition of GABA-T and suggest that such treatment may achieve therapeutic benefit in conditions where such neurochemical alterations are desirable.

Inhibition of monoamine synthesis by irreversible blockade of aromatic aminoacid decarboxylase with α-monofluoromethyldopa

Abstract DL-α-monofluoromethyldopa is a potent enzyme-activated irreversible inhibitor of purified aromatic aminoacid decarboxylase. Single doses from 0.25 to 25 mg/kg cause partial to total inhibition of this enzyme in kidney and heart. Inhibition of brain enzyme becomes significant at doses above 2.5 mg/kg and is complete at 100 mg/kg. Enzyme activity begins to return after 24 hr, so that repetition of a dose at 12 hr intervals markedly increases the inhibition. Single doses of 100–250 mg/kg almost completely deplete kidney, heart and brain of endogenous catecholamines by blocking dopa decarboxylation. Serotonin is also decreased, presumbaly by the same mechanism.

FURTHER STUDIES ON THE INHIBITION OF MONOAMINE SYNTHESIS BY MONOFLUOROMETHYLDOPA

1 α‐Monofluoromethyldopa (MFMD, RMI 71963), a potent and selective enzyme‐activated irreversible inhibitor of aromatic l‐amino acid decarboxylase produces a substantial and long‐lasting decrease in the catecholamine content of mouse brain, heart and kidney. 2 Single doses of MFMD reduce the 5‐hydroxytryptamine concentration of mouse brain without altering the tryptophan concentration. 3 In animals treated with MFMD, peripheral but not brain noradrenaline is restored within 1 h to control levels by an intraperitoneal injection of dopamine.

Cerebrospinal fluid homocarnosine in Huntington's disease

Abstract The concentration of homocarnosine (γ-aminobutyryl-L-histidine) in the cerebrospinal fluid (CSF) of ten patients with Huntingtons disease (HD) and 24 control subjects was determined by high-performance cation exchange chromatography. The mean CSF homocarnosine level was significantly lower in HD patients (0.86 ± 0.16 nmo1/m1) than in controls (1.69 ± 0.18 nmo1/m1).

Schmiedeberg in Strassburg 1872–1918: The making of modern pharmacology

Abstract One century ago pharmacology was an antiquated, denigrated and waning discipline content with transmitting impressionistic and largely erroneous dictums. In one generation one man in one city redefined its tasks, demonstrated its experimental methods and trained its work force. Virchow, Pasteur and Koch profoundly influenced their fields, but Schmiedeberg brought scientific pharmacology into being. Their names have become household words, his is rarely found even in medical dictionaries. Fortunately, he cared not about fame but about knowledge.