An open multicenter long-term treatment evaluation of Sinemet CR. Sinemet CR Multicenter Study Group.

The safety and efficacy of Sinemet CR were studied in an open-label, 52-week trial. The study was completed by 156 mildly to moderately ill Parkinson's patients (primarily Hoehn and Yahr stage II to III) at 10 sites. Patients had their treatment optimized on standard Sinemet prior to beginning Sinemet CR treatment. Following titration, there was a median reduction in dosing frequency of 25% (from 4.1 to 3.2 doses/day) relative to the standard Sinemet baseline. Total daily levodopa dosage increased from 623 to 808 mg/day (+33%), a factor consistent with the lower bioavailability of the controlled-release formulation. Mean efficacy scores on the New York University Parkinson's Disease Scale decreased from 7.4 at the end of baseline to 5.8 at 12 weeks, a decline of 20%. The scores remained at this level throughout 52 weeks of treatment. At the end of 1 year of treatment, 60% of patients rated themselves as improved, while physicians rated 64% of the patients as improved. Adverse experiences were similar to those reported by patients taking standard levodopa preparations. Two thirds of the reported adverse experiences occurred within the 1st 3 months of Sinemet CR therapy, indicating that increased length of exposure to Sinemet CR was not associated with an increasing incidence of adverse experiences.

Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies.

The pharmacokinetics of Sinemet CR, a controlled-release formulation containing carbidopa and levodopa, were investigated in healthy young and elderly volunteers and in patients with Parkinson's disease. Sinemet CR produced more sustained plasma levels of levodopa, carbidopa, and 3-O methyldopa than did conventional Sinemet. In elderly subjects, the corresponding steady-state plasma levels fluctuated in narrower ranges with Sinemet CR than those following the administration of Sinemet. Results indicate a levodopa bioavailability of 71% for Sinemet CR, in contrast to a bioavailability of 99% for Sinemet for these subjects. The carbidopa bioavailability of Sinemet CR was 58% relative to that of Sinemet. Systemic decarboxylase inhibition was comparable between the 2 regimens as indicated by the renal clearance of levodopa. The absorption of levodopa was slower and more protracted with Sinemet CR than with Sinemet. Food increased the levodopa bioavailability of Sinemet CR. This increase was attributed to an increased gastric retention time. No dose-dumping occurred with Sinemet CR in either the nonfasting or the fasting state. Levodopa bioavailability was lower in young volunteers than in elderly volunteers. This was attributed to an age-related decrease in gastric emptying and in 1st-pass metabolic decarboxylation in the gastrointestinal (GI) tract. In parkinsonian patients, as in healthy subjects, the Sinemet CR formulation produced more sustained levodopa plasma levels. These patients required a higher total daily dosage of Sinemet CR than of Sinemet for control of parkinsonian symptoms, but less frequent dosing was required during chronic therapy. Peak plasma levodopa levels increased proportionately with increasing Sinemet CR dosage. These observations were consistent with the pharmacokinetic characteristics of the formulation.

Multicenter controlled study of Sinemet CR vs Sinemet (25/100) in advanced Parkinson's disease.

Controlled-release carbidopa/levodopa 50/200 (Sinemet CR) and standard carbidopa/levodopa (Sinemet 25/100) were compared in a multicenter double-blind trial involving 202 patients with advanced Parkinson's disease and motor response fluctuations. Treatment with Sinemet CR significantly reduced daily "off" time. According to both physician and patient global ratings, patients showed significant improvements with Sinemet CR compared to treatment with standard Sinemet. Patients preferred Sinemet CR treatment by a ratio of approximately 2 to 1. Daily dosing frequency was 33% less with Sinemet CR, while daily intake of levodopa required was increased by 25%. The safety profiles of the 2 formulations were similar. We conclude that Sinemet CR is superior to standard Sinemet for many patients with advanced Parkinson's disease, although it does not solve the problem of fluctuating motor performance.

Myalgia and elevation in muscle creatine phosphokinase during zimelidine treatment.

The authors report a case involving a 65-year-old woman with DSM-III criteria for major unipolar depression in whom the administration of zimelidine, a potent and selective 5-hydroxytryptamine reuptake inhibitor, led to the development of a hypersensitivity reaction characterized by a severe headache, low grade fever, abnormal liver enzymes, and generalized myalgia 10 days after initiation of treatment. The most novel aspect of this hypersensitivity reaction to zimelidine was the development of abnormalities in muscle creatine phosphokinase in conjunction with the myalgia.

A double-blind evaluation of zimelidine in comparison to placebo and amitriptyline in patients with major depressive disorder.

This paper presents the results from a large multicenter study, performed at three clinical research units in the USA. Prior to a three to seven days of placebo washout period, patients were randomly assigned to zimelidine, a potent and selective 5-HT reuptake blocker, amitriptyline or placebo. The scheduled treatment period was four weeks. Dosage range was 75-300 mg/day for active medications. The rating instruments were the Hamilton Depression Scale and the Clinical Global Impression scale. The side effects were recorded by using a side effect inventory (TESS). Vital signs, laboratory work including clinical chemistry, ECG, and plasma levels of drugs, were performed. In the main efficacy evaluation there were 229 depressed outpatients included, all having completed at least two weeks of treatment after the washout period. The patients treated with zimelidine as well as those treated with amitriptyline showed a significant improvement relative to the placebo treated patients. For the safety evaluation 263 patients were included. Side effects, in particular anticholinergic effects but also drowsiness and cardiovascular effects, were much less pronounced in the zimelidine group as compared to the amitriptyline group. Only marginal differences regarding side effects were reported for zimelidine compared to those reported for placebo.

Moral reasoning in alcoholics and addicts: structure vs content.

19 alcoholics and 20 addicts were selected from the detoxified inpatient population of a VA hospital. 17 socioeconomically matched controls were drawn from the nonprofessional staff. Kohlberg's Moral Maturity scores were not significantly different for the three groups. However, the content variables involved in choosing between the value of life and law differentiated these groups. The value of reporting both structure and content was examined.

The solution of achromatic and chromatic Embedded Figures revisited.

Two samples of 20 males and 20 females each were drawn from two Eastern universities. Each of these two samples was presented with the 12-item Form B of Witkin's Embedded Figures Test, with half of each sex receiving the achromatic and half the chromatic format. As in the previous experiment (Bush & Coward, 1974), neither replication yielded a significant difference in mean solution time attributable to the effects of color. However, unlike the previous investigation, no sex differences were observed.

Double-blind comparison of lidocaine and etidocaine during continuous epidural anesthesia for vaginal delivery.

Etidocaine 0.5% plain, etidocaine 0.5% with epinephrine 1:200,000 and lidocaine 1% with epinephrine 1:200,000 were compared in a series of patients receiving epidural anesthesia for vaginal delivery. Results, based on data from 48 patients, showed a significant increase in the duration of action (P is less than .01%), the degree of sensory analgesia (P is less than .02%) and the degree of motor blockade (P is less than .01%) in the group that received etidocaine with epinephrine compared to the remaining groups. There were no significant differences in the duration of labor or the number of complications. It was concluded that etidocaine and lidocaine in the concentrations used were unsatisfactory for labor and delivery.

Clinical evaluation of local anaesthetic agents.

The precise evaluation of local anaesthetic drugs in clinical practice has many difficulties. The factors which may modify the clinical profile of these drugs are: (1) procedural in nature; (2) patient related; (3) drug related; and (4) investigator related. All these factors are discussed in relation to the proper design of clinical trials.