A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin.

We performed a pilot clinical trial with safingol (L-threo-dihydrosphingosine), a protein kinase C-specific inhibitor that potentiates the effect of doxorubicin (DOX) in tumor-bearing animals. Safingol was initially administered as a 1-h infusion at escalating doses. Fourteen days later, patients received the same dose of safingol in combination with a fixed dose of DOX. The combination was repeated at 3-week intervals. Safingol dose levels ranged from 15 to 120 mg/m2. The plasma levels achieved at the final dose level were comparable to those associated with potentiation of DOX in animals. The mean Cmax and area under the curve for safingol at the 120 mg/m2 dose level were 1040 +/- 196 ng/ml and 1251 +/- 317 mg x h/ml, respectively. The mean plasma half-life for safingol was 3.97 +/- 2.51 h, the mean estimated clearance was 3140 +/- 765 ml/min, and the mean volume of distribution was of 995 +/- 421 liters. Coadministration of a fixed dose of DOX did not significantly change the pharmacokinetics of safingol, nor did increasing doses of safingol significantly affect the pharmacokinetics of DOX. Minor responses were observed in three patients with pancreatic cancer and one patient with angiosarcoma of the scalp. This pilot Phase I study indicates that the protein kinase C inhibitor safingol can be given safely with 45 mg/m2 of DOX at a dose that is potentially pharmacologically active without dose-limiting toxicity.

Preclinical and clinical pharmacology of carvedilol.

Carvedilol is a novel multiple-action cardiovascular drug that has recently been introduced to the market for the treatment of mild to moderate hypertension. Clinical studies have demonstrated that once daily therapy with carvedilol is efficacious and has a favourable side-effect profile. Clinical studies are in progress to establish the utility of carvedilol in angina and congestive heart failure. Carvedilol is a beta-adrenoceptor antagonist and a vasodilator, with the vasodilating activity resulting primarily from alpha 1-adrenoceptor blockade and possibly also from calcium channel blockade. The reduction in BP produced by carvedilol results from the vasodilating activity of the drug because peripheral vascular resistance is significantly reduced. The reduction in BP produced by carvedilol is not associated with reflex tachycardia owing to the beta-adrenoceptor blocking activity of the compound. Throughout its antihypertensive dose range, carvedilol has been a renal-sparing antihypertensive agent in animals and also in humans, inasmuch as renal blood flow, glomerular filtration rate and sodium excretion are all maintained. In preclinical experimental models of acute myocardial infarction, carvedilol has produced marked reductions in infarct size in the pig, rat and dog. The cardioprotection observed with carvedilol is greater than that provided by beta-adrenoceptor antagonists alone, suggesting that the additional activities of carvedilol may provide benefit in the setting of myocardial ischaemia.

Safety of the coadministration of carvedilol and nifedipine sustained-release in the treatment of essential hypertension.

A single-center, randomized, double-blind study in 14 hypertensive patients was conducted to investigate the acute and short-term safety of the addition of carvedilol to pre-existent nifedipine sustained-release (SR) therapy as well as on the addition of nifedipine SR to pre-existent carvedilol therapy when treatment with the initial monotherapy did not adequately control blood pressure. Mean supine blood pressure at study entry was 171/106 mm Hg. Acute reductions in blood pressure were greater with combination treatment than with either monotherapy. Dosing with 25 mg carvedilol once daily or 20 mg nifedipine SR twice daily resulted in mean peak reductions in supine blood pressure of 21/11 and 20/16 mm Hg, respectively, after 1 week of treatment with each respective monotherapy. With combination treatment, mean peak reductions (after dosing on days 1, 3, and 10) ranged from 26 to 40 mm Hg in supine systolic blood pressure and from 14 to 23 mm Hg in supine diastolic blood pressure. Acute changes in mean standing systolic and diastolic pressures were comparable to those in the supine position. Combination treatment resulted in an additive acute antihypertensive response without synergistic potentiation. Neither monotherapy nor the coadministration of the two agents in the doses used resulted in a significant antihypertensive response at the time of trough plasma levels of study medication, perhaps due to the short-term nature of the trial which did not allow the full antihypertensive effect of either agent to be realized. Before dosing with study medication, heart rates were minimally changed from study entry levels with either monotherapy or combination treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of carvedilol and nifedipine in patients with essential hypertension and non-insulin-dependent diabetes mellitus.

The safety and tolerability of carvedilol, a new antihypertensive agent with the combined pharmacological activities of beta-blockade and vasodilation, and of nifedipine were investigated in patients with essential hypertension and non-insulin-dependent (type II) diabetes mellitus. Twenty patients were openly randomized to receive 25 mg carvedilol once daily (five men and five women; mean age, 63 years) or 10 mg nifedipine t.i.d. (three men and seven women; mean age, 64 years) for a period of 4 weeks. Baseline mean sitting blood pressures were 168/98 and 169/95 mm Hg in the carvedilol and nifedipine groups, respectively. Baseline mean areas under the curve (AUC) of the intravenous glucose tolerance test (IVGTT) for the carvedilol and nifedipine groups were 6,136 +/- 1,195 and 6,287 +/- 1,228 mg/dl/min, respectively. Demographic and efficacy variables were not statistically different between treatment groups. After 4 weeks of therapy, mean sitting blood pressure was significantly (p less than 0.02) reduced to 144/91 mm Hg in the carvedilol group and to 149/87 mm Hg in the nifedipine group. Week 4 IVGTT AUC values of 5,735 +/- 1,464 mg/dl/min in the carvedilol group and 5,988 +/- 993 mg/dl/min in the nifedipine group, representing mean reductions of 6.14% and 3.17%, respectively, were not statistically different from baseline. Both treatments were well tolerated. No patient experienced adverse events in the carvedilol treatment group, whereas two patients in the nifedipine group reported episodes of headache (one patient) and palpitations (one patient); each episode was mild in severity and considered to be related to study medication.(ABSTRACT TRUNCATED AT 250 WORDS)

The safety of adding carvedilol to hypertensive patients inadequately treated with diuretics.

A single-blind, single-center study was conducted to investigate the short-term safety and efficacy of carvedilol, a new cardiovascular agent, when added to 25 mg hydrochlorothiazide (HCTZ) as combination therapy for patients inadequately treated with HCTZ alone. A total of 18 patients entered the baseline study phase, during which they received 25 mg HCTZ once daily for 4 weeks; 16 of these patients (8 men and 8 women) entered the combination treatment phase. All patients had a supine diastolic blood pressure (DBP) of greater than or equal to 95 mm Hg prior to receiving the first dose of combination treatment. Combination treatment consisted of 25 mg HCTZ plus 12.5 mg carvedilol once daily for 2 days, followed by a forced titration of the carvedilol dose to 25 mg for 7 days. After 2 days of 12.5 mg carvedilol plus 25 mg HCTZ once daily, mean trough blood pressure was reduced as compared with baseline values. Of 16 patients, 6 (38%) achieved a trough supine DBP of less than 90 mm Hg. After 1 additional week of combination therapy with 25 mg carvedilol, 8 of 15 patients (53%) achieved a trough supine DBP of less than 90 mm Hg and 14 of 15 patients (93%) achieved that of less than 95 mm Hg. At each visit during the combination treatment phase, the acute reduction in blood pressure was greatest during the first 2 h after dosing. The heart rate was minimally affected by combination treatment with carvedilol at either trough levels or acutely after dosing. Nine patients experienced adverse events during combination treatment.(ABSTRACT TRUNCATED AT 250 WORDS)