Pemetrexed and cisplatin with concurrent radiotherapy for locally advanced non-small cell and limited disease small cell lung cancer: results from 2 phase I studies.

BACKGROUND: The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival. PATIENTS AND METHODS: Treatment naïve patients received 1 cycle of cisplatin 80 mg/m(2) in study I (stage III NSCLC), 75 mg/m(2) in study II (LD-SCLC) and pemetrexed 500 mg/m(2) before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60-80 mg/m(2)), pemetrexed doses (400-500 mg/m(2)) and concurrent escalating radiotherapy doses (66 Gy in 33-27 fractions). In study II, patients were treated with cisplatin 75 mg/m(2) and escalating pemetrexed doses (400-500 mg/m(2)) with concurrent escalating radiotherapy doses (50-62 Gy). RESULTS: The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed. CONCLUSIONS: Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66 Gy (33 x 2 Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy.

Effect of cilazapril on glucose tolerance and lipid profile in hypertensive patients with non-insulin-dependent diabetes mellitus.

Hypertension frequently complicates diabetes mellitus and is associated with an increased incidence of cardiovascular and microvascular complications. Angiotensin-I converting enzyme (ACE) inhibitors are effective antihypertensive agents and it has been suggested that they may improve glucose tolerance. We performed a double-blind, randomized study comparing treatment for 8 weeks with cilazapril, a new ACE inhibitor, or placebo on metabolic variables in 22 hypertensive non-insulin-dependent diabetes mellitus (NIDDM) patients. At week 8 no significant changes in fasting plasma glucose, fasting plasma insulin, haemoglobin A1 and plasma lipids had occurred. The areas under the glucose [placebo (mean +/- SD): 10.7 +/- 3.27 and 10.6 +/- 2.53; cilazapril: 11.9 +/- 3.23 and 12.1 +/- 2.9 mmol/l per 180 min at 0 and 8 weeks, respectively] and insulin curve [placebo (median and range): 47.4 (31.4-165.1) and 65.3 (16.8-190.8); cilazapril: 51.1 (23.8-132.0) and 57.6 (29.0-150.1) mU/l per 180 min at 0 and 8 weeks, respectively] after a standardized oral liquid test meal were unaltered. A significant decrease in mean arterial blood pressure was observed after cilazapril (122 +/- 8.6 and 106 +/- 8.3 mmHg at 0 and 8 weeks, respectively), in contrast to placebo (122 +/- 6.7 and 120 +/- 6.9 mmHg at 0 and 8 weeks, respectively). In conclusion, cilazapril does not affect metabolic control in hypertensive NIDDM patients, whereas it effectively reduces blood pressure.

Lack of negative inotropic effects of the new calcium antagonist Ro 40-5967 in patients with stable angina pectoris.

We screened the antiischemic, hemodynamic, and inotropic effects of different dosages of the new calcium channel blocker Ro 40-5967 in 65 patients with stable effort-induced angina pectoris. In a double-blind way, patients were randomized to recieve a single oral dose of 50, 100, or 200 mg Ro 40-5967 or placebo, given as a drinking solution. Left ventricular ejection fraction (LVEF), blood pressure (BP), and heart rate (HR) were measured at rest and during a supine bicycle exercise test on day 0 (baseline) and 2 h after drug intake on day 1. Twenty-four hours later, the bicycle exercise test was repeated. Ro 40-5967 improved exercise duration and resting LVEF. After 200 mg, exercise time increased significantly from 8.4 +/- 0.8 min (mean +/- SEM) to 9.6 +/- 0.7 min (p = 0.018), and LVEF at rest increased from 54.5 +/- 2.2 to 58.1 +/- 2.6% (p = 0.045). Time to 0.1 mV ST-segment depression increased significantly from 4.3 +/- 0.8 to 5.5 +/- 0.9 min in the 100-mg group (p = 0.013) and from 4.3 +/- 1.3 to 5.4 +/- 1.5 min in the 200-mg group (p = 0.027). Maximum ST-segment depression decreased significantly at all dose levels (p = 0.01), with the maximum decrease noted in the 200-mg group (from 0.21 +/- 0.03 to 0.15 +/- 0.02 mV, p = 0.004). BP, HR, and rate-pressure product did not change significantly at rest or at maximum exercise. A single dose of Ro 40-5967 has antiischemic properties in patients with stable angina pectoris, with maximum effects obtained after 200 mg. No signs of negative inotropy were noted, and the drug was well tolerated.