Donald B. Calne

Multiple receptors for dopamine

Pharmacological and biochemical criteria can be used to separate those dopamine receptors which are linked to the enzyme adenylyl cyclase and those which are not.

Parkinson's disease in 65 pairs of twins and in a set of quadruplets

Among 43 monozygotic (MZ) and 19 dizygotic (DZ) pairs in which an index case had definite Parkinsons disease (PD), only one MZ pair was definitely concordant for PD. When pairs with questionable clinical features were included, 4 of 48 MZ and 1 of 19 DZ pairs were concordant. The frequency of PD in MZ cotwins of index cases with PD was similar to that expected in an unrelated control group matched for age and sex. Although we were unable to identify a single environmental agent, we conclude that the major factors in the etiology of PD are nongenetic.

Twin study of Parkinson disease.

zero concordance for Parkinson disease was found in the first 12 monozygotic twin pairs examined in an ongoing twin study. One co-twin (subject without Parkinson disease) had essential tremor, another had cerebral vascular disease, and a third was an alcoholic. Cigarette smoking appeared to be less frequent in the probands than in the co-twins (11.9 versus 16.1 pack-years). There was also evidence of premorbid personality differences between probands and co-twins dating back to late adolescence or early adult years. These preliminary findings suggest that genetic factors do not play a major role in the etiology of Parkinson disease and point to a prodromal onset of the disease as early as late adolescence or early adult life.

Lisuride versus bromocriptine treatment in Parkinson disease: A double‐blind study

Twenty-eight parkinsonian patients were studied in a double-blind, crossover comparison of lisuride and bromocriptine. All but two patients completed the study, with each drug adjusted to an optimal dose (mean daily intake of 4.5 mg for lisuride and 56.5 mg for bromocriptine). Treatment with each drug was given for 7 to 10 weeks; three assessments were made at biweekly intervals with optimal dose levels. Conventional antiparkinsonian medications, including lev- odopa, were not changed. Efficacy and adverse effects were assessed by objective and subjective techniques. The only significant difference was slightly better control of akinesia with bromocriptine. There was considerable variability in the optimal dose of each drug, though the clinical profile of lisuride was quite similar to that of bromocriptine.

Studies of parkinsonian movement: 1. Programming and execution of eye movements

Rapid voluntary eye movements in bradykinetic parkinsonian patients and normal subjects were recorded when the movement was executed with visual feedback (closed‐loop mode) and in darkness without visual feedback (open‐loop mode). The patients had a tendency to generate abnormal saccades consisting of multiple small steps (multiple step saccade), both in the closed‐loop and open‐loop mode. They were, however, also capable of generating large amplitude saccades. The amplitude‐velocity relation of both the small step saccades and the large saccades was normal. The presence of multiple step saccades in the open loop mode suggests that the patients used internal rather than external (visual) feedback to compare the actual eye position with the desired (programmed) eye position and the program for rapid movement is normal but its execution is defective.

Lisuride in parkinsonism

we studied the actions of lisuride, a dopaminergic ergot derivative, in 20 parkinsonian patients. When the dose was increased gradually, most patients tolerated up to 5 mg daily. Clinical assessment and objective, computer-assisted evaluation revealed improvement in akinesia, rigidity and tremor. Adverse reactions were similar to those seen with levodopa and bromocriptine, but somnolence tended to occur more often with lisuride.

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.

Studies of parkinsonian movement: 2. Initiation of fast voluntary eye movement during postural disturbance.

Delay in initiation of rapid voluntary eye movements (saccades) in brady‐kinetic parkinsonian patients and normal subjects was recorded with and without postural disturbances (rotation of the body and head).

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.