Clinical evaluation of pramipexole in advanced Parkinson's disease: results of a double-blind, placebo-controlled, parallel-group study.

We compared the efficacy, safety, an tolerability of pramipexole, an aminobenzathiazol-derived dopamine agonist with novel properties, with those of placebo in advanced PD patients with motor fluctuations under levodopa treatment. Pramipexole improved motor function of patients during "on" and "off" periods, decreased the time spent in "off" periods, reduced the severity of "off" periods, decreased disability and PD severity during "on" and "off" periods, as assessed by the Unified Parkinson Disease Rating Scale, and permitted a reduction in levodopa dosage. Adverse effects related to the central nervous system were similar to those reported with other dopamine agonists, and the gastrointestinal and cardiovascular tolerability of the compound was satisfactory.

Pramipexole in patients with early Parkinson's disease.

We evaluated the efficacy, safety, tolerability, and pharmacokinetics of pramipexole, a novel dopamine D2 receptor agonist, in early Parkinson's disease (PD). The study design was a parallel, placebo-controlled trial using an ascending dose of 4.5 mg/day pramipexole maximum. All subjects received selegiline (10 mg/day) but were not treated with levodopa. Of the 55 subjects who received at least one dose of the study medication, all but one, in the placebo group, completed the trial, which was 9 weeks in duration. The primary efficacy endpoints were changes in scores from baseline to final measurement on the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. The pramipexole group had a significantly greater improvement (p = 0.002) than the placebo group on UPDRS Part II (Activities of Daily Living). The change in score from baseline to final measurement on UPDRS Part III (Motor Examination) was not significantly different (p = 0.10) between the pramipexole and placebo groups, although the trend favoured the pramipexole group. All subjects in both the pramipexole and the placebo groups experienced one or more episodes of asymptomatic orthostatic hypotension; there was no significant difference between the pramipexole and the placebo groups in the number of subjects experiencing symptomatic orthostatic hypotension. The adverse events profile of pramipexole was similar, in general, to that of other dopamine receptor agonists. Plasma pramipexole levels increased linearly with dose. Pramipexole appears to be promising agent in the treatment of early PD.

A phase II trial of PALA + dipyridamole in patients with advanced soft-tissue sarcoma.

A total of 21 patients with advanced soft tissue sarcoma enrolled in a phase II trial of 3.5 g/m2 N-phosphonacetyl-L-aspartate (PALA) given intravenously every 3 weeks plus 50 mg/m2 dipyridamole (Persantine) given orally every 6 h. Dipyridamole administration was initiated 1 week before the first dose of PALA. Peak and trough plasma concentrations of dipyridamole were measured before and after the first dose of PALA in 14 patients. In all, 19 patients were evaluable for therapeutic response. One subject experienced partial regression of a pulmonary metastasis; no other major response was observed. Diarrhea was the most prominent toxicity; in one patient it was life-threatening and was associated with a severe rash. On the day preceding PALA administration, the median peak plasma concentration of dipyridamole was 2,208 ng/ml and the median trough value was 904 ng/ml. Similar values were obtained on the day of PALA administration. Although the levels achieved were similar to those required to modulate the activity of PALA in preclinical systems, the therapeutic results obtained in the present study were not superior to those reported for PALA alone in previously treated patients with soft-tissue sarcoma.

The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Intravenous Dipyridamole Thallium Imaging Study Group.

Clinical data on 3,911 patients were collected from 64 individual investigators to evaluate the safety of intravenous dipyridamole-thallium imaging as an alternative to exercise thallium imaging for the evaluation of coronary artery disease. There were two deaths because of myocardial infarctions, two nonfatal myocardial infarctions, and six cases of acute bronchospasm. Chest pain occurred in 770 patients (19.7%). Headache and dizziness were reported by 476 patients (12.2%) and 460 patients (11.8%), respectively. ST-T changes on the electrocardiogram were seen in 292 patients (7.5%). Use of parenteral aminophylline to treat adverse events associated with intravenous dipyridamole brought complete relief of symptoms in 439 of 454 patients (96.7%). There is a potential for increased risk for serious ischemic events in patients with a history of unstable angina who are administered intravenous dipyridamole. In patients with acutely unstable angina (i.e., continuing chest pain) or in the acute phase of myocardial infarction, use of intravenous dipyridamole in thallium scintigraphy should be avoided. There is also an increased risk for bronchospasm in patients with a history of asthma; acute bronchospasm can be relieved immediately by administration of aminophylline. These results demonstrate that intravenous dipyridamole-thallium scintigraphy is a relatively safe, noninvasive technique for the evaluation of coronary artery disease.

Biochemical assessment of the effects of acivicin and dipyridamole given as a continuous 72-hour intravenous infusion.

Since this Phase I trial was based on a strategy of biochemical modulation, namely, the inhibition of nucleoside uptake by dipyridamole, a biochemical assessment of the actions of acivicin and dipyridamole was undertaken in order to aid our interpretation of the clinical findings. The primary biochemical objectives of this trial were: (a) to determine whether plasma levels of dipyridamole sufficient to inhibit nucleoside uptake could be achieved with a 72-h continuous i.v. infusion; (b) to monitor the effects of acivicin on two key enzymatic targets, CTP synthetase and GMP synthetase; and (c) to evaluate changes in cellular ribonucleoside triphosphate pools during therapy. Since peripheral blood mononuclear cells have relevant biochemical targets and can be serially obtained during the course of therapy, the biochemical effects of acivicin and dipyridamole were determined in these cells. At the maximally tolerated dose of dipyridamole (23.1 mg/kg/72 h), the steady-state concentrations of total and free dipyridamole averaged 11.9 microM and 27.8 nM, respectively. These levels were sufficient to inhibit cytidine (1 microM) uptake by greater than 50% in the lymphocytes of five of six patients so treated. Using lymphocytes obtained from 14 normal volunteers the concentration of free dipyridamole needed to inhibit the uptake of 1 microM cytidine by 50% averaged 13.8 +/- 1.1 nM. The plasma levels of alpha 1-acid glycoprotein, which tightly binds dipyridamole, ranged from 60 to 300 mg/dl in the patients in this study. As a consequence there were wide variations in the percentage of dipyridamole present as the unbound, pharmacologically active form and in the rates of dipyridamole clearance. The decreased rate of dipyridamole clearance seen in patients with high levels of alpha 1-acid glycoprotein resulted in higher plasma concentrations of total dipyridamole and compensated for the reduced fraction of free drug. Therefore, the plasma concentration of free dipyridamole varied much less than the total drug concentration in these patients. CTP synthetase and GMP synthetase activities were measured in patients' peripheral mononuclear cells prior to and at various times during therapy. CTP synthetase activity was inhibited in a time-dependent fashion by greater than 75% in seven of 13 evaluable courses; GMP synthetase was similarly inhibited in only three of ten cases. Ribonucleoside triphosphate pools were also measured in the patient's lymphocytes. CTP pool reductions of 30 to 50% were seen in nine of 19 courses, but in only four cases was the inhibition greater than 50%.(ABSTRACT TRUNCATED AT 400 WORDS)