Pharmacological inhibition of the hypertensive response to combretastatin A-4 phosphate in rats.

Combretastatin A-4 phosphate (CA4P) is a novel and promising anti-neoplastic agent. However, it is associated with transient hypertension in both animal and human models. In this study, we examined the potential cardiac toxicity and hypertensive effects of CA4P, and defined the most effective pharmacological inhibition of CA4P-induced hypertension in rats. There was a significant, concentration dependent increase in mean arterial blood pressure with a maximum increase of about 60% of the baseline MAP at 30 mg/kg of CA4P compared to the saline control. However, there was no significant increase in the cardiac troponin I level after CA4P injection. Nitroglycerin and the calcium channel blocker diltiazem effectively blocked the hypertensive effects of CA4P while the beta blocker metoprolol was ineffective. Furthermore, sublingual nitroglycerin administration demonstrated an additional anti-hypertensive effect in a setting of a low dose diltiazem infusion (10 microg/kg/min). We conclude that CA4P treatment resulted in a concentration dependent increase in blood pressure without significant myocardial damage in healthy rats. The hypertensive effect of CA4P was effectively blocked by both nitroglycerin and diltiazem, but not metoprolol.

Systematic discovery of multicomponent therapeutics.

Multicomponent therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of medicine, including cancer, infectious diseases, and CNS disorders. We have developed a high-throughput screening method for identifying effective combinations of therapeutic compounds. We report here that systematic screening of combinations of small molecules reveals unexpected interactions between compounds, presumably due to interactions between the pathways on which they act. Through systematic screening of approximately 120,000 different two-component combinations of reference-listed drugs, we identified potential multicomponent therapeutics, including (i) fungistatic and analgesic agents that together generate fungicidal activity in drug-resistant Candida albicans, yet do not significantly affect human cells, (ii) glucocorticoid and antiplatelet agents that together suppress the production of tumor necrosis factor-alpha in human primary peripheral blood mononu-clear cells, and (iii) antipsychotic and antiprotozoal agents that do not exhibit significant antitumor activity alone, yet together prevent the growth of tumors in mice. Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways and, when performed with reference-listed drugs, may result in the discovery of new combination drug regimens.