Double-blind, crossover placebo controlled trial of selegiline in Parkinson's disease--an interim analysis.

The response to selegiline was assessed in ten (2 females, 8 males) idiopathic parkinsonian patients with the wearing off response. Selegiline was compared to placebo in each patient in a double blind crossover study carried out over ten months. After 16 weeks of therapy selegiline significantly prolonged response to levodopa, extending response to 3 hours (p less than 0.05) in most patients and to 4 hours (p less than 0.001) in some patients. Baseline scores (zero time: 12 hours after their previous dose of medication) were also significantly better after selegiline therapy (p less than 0.05). Selegiline did not improve peak response (1 hour after medication) to levodopa indicating that these patients were on optimum therapy prior to receiving selegiline. Adverse effects (nausea (2), dyskinesia (2), fear reaction (1) and postural dizziness (1] occurred in 5 patients during the trial.

Bromocriptine: long-term low-dose therapy in Parkinson's disease.

Low-dose bromocriptine therapy (average dose 14.5 mg/day at 2 years) produced significant improvement in 25 of 39 parkinsonian patients. Bradykinesia was less in de novo subjects; tremor and rigidity improved most in the levodopa subjects. Five of six patients improved after a low-dose bromocriptine drug "holiday." After the addition of bromocriptine any reductions in levodopa dosage were small, with repeated cuts made gradually over months preventing the deterioration commonly seen with larger sudden reductions in levodopa dosage. Five patients withdrew because of intolerable adverse effects, two because of worsening response. Adverse effects were mild and generally dose dependent, and in some patients they disappeared without reduction in continuing bromocriptine therapy. Eighty percent of those who tolerated bromocriptine maintained response over 2 years. Bromocriptine did not induce dyskinesia, the wearing-off response, or the on-off phenomenon in de novo subjects and was used as a first choice drug in these parkinsonian patients. Best results were obtained from a combination of bromocriptine and levodopa.

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.

Cross tolerance between two dopaminergic ergot derivatives--bromocriptine and lergotrile.

1. When initially given to patients with idiopathic parkinsonism, lergotrile induced marked supine arterial hypotension. Tolerance to this hypotensive effect developed and larger doses of lergotrile were administered without this adverse effect. 2. Cross tolerance occurred between lergotrile and a structurally related ergot derivative, bromocriptine. A high dose of lergotrile given to patients who had been on long term bromocriptine therapy did not induce any significant hypotension when compared to placebo whereas hypotension still occurred when lergotrile was given after previous treatment with levodopa.

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.

Hepatocellular injury with distinctive mitochondrial changes induced by lergotrile mesylate: a dopaminergic 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.

Bromocriptine inhibits norepinephrine release.

Bromocriptine is a dopamine agonist that induces postural hypotension and can be used as an antihypertensive. The drug inhibits release of norepinephrine (NE) from an isolated artery by stimulating presynaptic receptors. In normotensive subjects it lowers both plasma and cerebrospinal fluid (CSF) levels of NE by 50% and lowers blood pressure moderately in standing subjects and slightly in recumbent subjects. Through central and peripheral mechanisms, bromocriptine inhibits sympathetic nervous discharge of NE.

Ergot derivatives for Parkinsonism.

The response of Parkinsonism to three ergot derivatives which modify dopaminergic transmission was studied. CF 25-397 behaved more as an antagonist than an agonist. Lergotrile was an agonist with therapeutic properties marred by prominent hepatotoxicity. Bromocriptine is an effective anti-Parkinsonian agent, particularly useful in patients with prominent dyskinesia or "on-off" reactions to levodopa; in most patients optimal results have been obtained by combining from 40 to 90 mg of bromocriptine daily with approximately 60% of the previous maximal dose of levodopa. Unfortunately, only some 50% of patients tolerate long-term bromocriptine therapy, but all adverse reactions have been dose dependent and reversible.

Comparison between lergotrile and bromocriptine in parkinsonism.

The therapeutic and adverse effects of two ergot derivatives, bromocriptine and lergotrile, were compared in idiopathic parkinsonism. At both low (50 mg daily) and high (150 mg daily) dosage there was a similar but not identical profile of response. Initially, lergotrile tended to induce more severe but always transient hypotension. At higher doses, bromocriptine caused more dyskinesia. Neurological deficits improved with increasing doses up to an average daily level of 80 to 150 mg of ergot derivatives combined with levodopa, 450 to 1,150 mg, and carbidopa, 45 to 115 mg. However, efficacy often declined at the highest doses of antiparkinsonian agents. Adverse effects caused by ergot derivatives are more common with dosages greater than 100 mg per day. In general, the best overall therapeutic results with bromocriptine and lergotrile were obtained in the dose range of 50 to 100 mg daily for each. It is concluded that bromocriptine and lergotrile are similar in their therapeutic properties and that both are comparable in efficacy to levodopa plus carbidopa (though optimal results are commonly obtained by combining submaximal doses of levodopa with ergot derivatives). The role for each drug in the treatment of parkinsonism is likely to be determined by factors such as cost (bromocriptine) and hepatotoxicity (lergotrile).

Long-term treatment of parkinsonism with bromocriptine.

92 patients with parkinsonism have been treated with bromocriptine for up to 30 months. 48 continue to receive bromocriptine with benefit; of these, 35 take bromocriptine (mean dose 53 mg daily) in combination with levodopa and 13 take bromocriptine (mean dose 45 mg daily) without levodopa. In those who were originally on levodopa, addition of bromocriptine allowed a mean 41% reduction in the dose of levodopa; the largest group of patients to benefit from bromocriptine entered the study because of excessive dyskinesia or "on-off" phenomena induced by levodopa. In 40 patients bromocriptine was stopped because of adverse reactions, absence of therapeutic response, or non-compliance with the protocol. The main problems were psychiatric disturbance (8 patients) and erythromelalgia (7 patients); these effects tended to occur late (mean 6 months and 10 months, respectively) and with high dosage (mean 66 mg and 115 mg daily). Other frequent adverse effects were dizziness and nausea; these began considerably earlier (at 2 months and 1 month) and with much lower dosage (31 mg and 12 mg daily). 4 patients died, for reasons apparently unrelated to therapy.

A model of fulminant hepatic failure in the rabbit.

A highly reproducible model of fulminant hepatic failure was developed by administering intravenously the selective hepatotoxin galactosamine hydrochloride (4.25 mmoles per kg) to genetically uniform rabbits. The great majority of rabbits died between 21 and 44 hr after injection following a period of coma which lasted 2.6 hr on average. Serum biochemical tests and liver histology reflected massive hepatic injury. Changes in plasma ammonia and amino acid concentrations, in coagulation parameters, and in the electroencephalogram were similar to those found in human fulminant hepatic failure. This model appears promising for future studies of the pathogenesis and treatment of fulminant hepatic failure.

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.

Nomifensine in parkinsonism.

1. The effect of nomifensine was compared with that of placebo in a double-blind crossover study in patients with parkinsonism. 2. Of the 29 patients who entered the study, three were previously untreated and 26 continued their L-DOPA or other antiparkinsonian therapy, or both, during the trial. 3. Clinical assessments were made at fortnightly intervals throughout the study. 4. The most noticeable improvement during active treatment--namely, tremor, facial expression and finger flexion were moderate in extent. 5. When placebo was substituted for active drug a significant deterioration of physical signs and functional disability occurred (P less than 0.001). 6. Elderly patients fared less well than younger patients, and the most common adverse effect was involuntary movements.

Nomifensine in parkinsonism.

Nomifensine, a tetrahydroisoquinolone antidepressant which facilitates dopaminergic and noradrenergic transmission, was studied in 28 Parkinsonism patients most of whom were also receiving conventional medications. Double-blind evaluations revealed a moderate therapeutic action at a mean dose level of 150 mg daily. Adverse reactions were encountered, similar to those identical by levodopa.

Penicillin transport from cerebrospinal fluid.

The passage of penicillin G from cerebrospinal fluid (CSF) was studied by continuous ventriculocisternal perfusion in conscious rabbits. The concentration of penicillin G in the perfusate, collected from the cisterna magna, was 76.5 percent +/- 1.0 (SEM) of that entering the ventricles (having adjusted for normal secretion of CSF). The mean concentration of penicillin G rose 15 percent (p less than 0.005) in the cisternal CSF after probenecid (2 mg per milliliter) was added to the perfusion fluid. We conclude that an active transport system removes penicillin G from the CSF; this mechanism can be inhibited by intraventricular probenecid. Our results are in accord with observations deriving from studies on anesthetized animals given probenecid intravenously or intraperitoneally.

The encephalopathic action of five-carbon-atom fatty acids in the rabbit.

1. Five-carbon-atom organic acids (C-5 acids) have been administered intravenously to rabbits with ventriculocisternal perfusion and continuous electroencephalographic recording (EEG). The concentration of the acids in the cerebrospinal fluid (CSF) perfusate have been compared with changes in integrated low-frequency activity in the EEG. 2. The C-5 acids investigated were those accumulating in inborn errors of metabolism, i.e. isovaleric acid, beta-methylcrotonic acid, tiglic acid and alpha-keto- and alpha-hydroxy-isovaleric acid. There activity was compared with that of valeric acid. 3. Valeric acid and isovaleric acid produced coma and pronounced increase in slow-wave electrical activity and these changes paralleled the increase in concentration of the acids in the CSF perfusate. 4. The concentration of beta-methylcrotonic acid and tiglic acid in the CSF perfusate reached values comparable with valeric acid and isovaleric acid but showed less encephalopathic activity. An interaction between beta-methylcrotonic acid and isovaleric acid was observed. 5. Although the concentrations of alpha-ketoisovaleric acid and alpha-hydroxyisovaleric acid rose to the lesser extent in the CSF perfusate, changes in rousability of the animal and in the EEG recording were demonstrated. 6. It is concluded that all the C-5 acids tested have encephalopathic activity although this is lessened by the presence of either a double bond or an oxygenated functional group.