Paul F. Teychenne

IDIOPATHIC PARKINSONISM TREATED WITH BROMOCREPTINE

The efficacy and toxicity of bromocriptine, a drug which simulates dopamine, have been studied in twenty-eight patients with idiopathic parkinsonism. A double-blind, within-patient comparison between maximum tolerated doses of bromocriptine (mean 46-9 mg daily) and placebo revealed a substantial and statistically significant therapeutic response to the active drug. Adverse reactions were dose dependent, reversible, and similar to those encountered with levodopa. While taking bromocriptine fourteen patients were able to stop levodopa (with or without carbidopa); in five patients the dose of levodopa was reduced by 54% (mean). Eight patients could not tolerate bromocriptine; one patient failed to comply with prescribed adjustments of dosage.

Bromocriptine: low-dose therapy in Parkinson disease.

In a double-blind trial with a placebo phase, low-dose bromocriptine therapy (average dose, 15 mg per day) produced a significant improvement in 25 idiopathic parkinsonian patients. Tremor and bradykinesia were equally and significantly improved in both the levodopa-treated and the de novo patients. Rigidity was most improved in the levodopa-treated subjects. Age was not a factor in determining the dose of bromocriptine or the degree of improvement. Adverse effects occurred in 30% but were mild and dose-dependent. Four subjects, unable to tolerate initial doses of bromocriptine, withdrew from the trial. A low initial dose (1 mg per day) and slow escalation in dosage produced an optimal, though delayed improvement. Low-dose bromocriptine therapy is effective, does not induce significant dyskinesia nor on-off phenomenon, and is probably an alternative to levodopa as a drug of first choice in Parkinson disease.

Experiences with a new ergoline (CF 25–397) in parkinsonism

Studies on rats with unilateral nigral lesions suggest that a new ergoline, CF 25–397, is a dopaminergic agonist that might improve parkinsonism. CF 25–397 induces less stereotyped behavior than other dopaminergic agents in rats, and might therefore cause less dyskinesia than levodopa in man. We investigated the clinical actions of CF 25–397 in nine patients. During treatment, severe deterioration resulted in hypokinesia and rigidity; five patients showed marked dysphagia and dysphonia. There was statistically significant deterioration in four timed tests. Mild improvement, not statistically significant, was noted in tremor. These results indicate that clinical implication of the response to potential therapeutic agents in rodent models of parkinsonism must be interpreted with caution.

Hepatocellular Injury with Distinctive Mitochondrial Changes Induced by Lergotrile Mesylate: A Dopaminetgic Ergot Derivative

Increased serum activities of the enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 12 out of 19 patients with idiopathic parkinsonism when they were treated with the ergot derivative lergotrile at an oral dose varying from 50 to 150 mg daily. Hepatocellular injury was confirmed by microscopic examination of liver biopsies obtained from 3 of these patients when the serum activities of ALT and AST were appreciably elevated. Light microscopy revealed features of mild acute hepatocellular injury, and electron microscopy showed proliferation of the smooth endoplasmic reticulum and apparently unique mitochondrial changes in hepatocytes. This is the first report of pathological changes in the liver associated with the therapeutic use of an ergot derivative. The presence of a potentially reactive cyanide group in the lergotrile molecule could be causally related to the observed hepatocellular injury. It is suggested that serum ALT and AST activities should be monitored carefully when the therapeutic potential of any new ergot derivative is assessed.

Sodium valproate in the treatment of cerebellar disorders.

Because of the high concentrations of gamma-aminobutyric acid (GABA) in the cerebellar cortex and nuclei, an attempt was made to enhance GABAergic transmission in patients with cerebellar disease. Maximum tolerated doses of sodium valproate, a drug which inhibits the degradation of GABA, failed to influence cerebellar deficits in a double blind crossover study on six patients.

THE HEPATOTOXICITY OF ERGOT ALKALOIDS

ABSTRACT Elevated serum activities of alanine (ALT) and aspartate (AST) aminotransferases, suggestive of acute hepatocellular injury, occurred in 12 of 20 patients treated with lergotrile. Hepatic histology confirmed mild acute hepatocellular necrosis. Electron microscopy revealed hitherto undescribed ultrastructural changes in mitochondria of hepatocytes. When lergotrile was discontinued serum ALT and AST levels became normal in all patients. Elevated serum ALT and AST levels were much less frequent during bromocriptine therapy, occurring in 12 of 78 patients. Some of these abnormal values were only minimally elevated. Furthermore the elevated levels returned to normal without reducing the dose of bromocriptine. No patient in this study, receiving either lergotrile or bromocriptine, developed symptoms or clinical signs attributable to hepatic dysfunction.