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Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and in pathological processes such as tumor growth, rheumatoid arthritis, and ocular neovascularization. A recombinant humanized monoclonal antibody (rhuMAb), rhuMAb VEGF, has been developed to inhibit the effects of VEGF in the treatment of solid tumors. Intravenous and s.c. pharmacokinetic studies were conducted in mice, rats, and cynomolgus monkeys. In addition, the tissue distribution of i.v. 125I-rhuMAb VEGF was investigated in rabbits. At a dose of approximately 10 mg/kg, the clearance of rhuMAb VEGF from the serum was 15.7 ml/day/kg in mice, 4.83 ml/day/kg in rats, and 5.59 ml/day/kg in cynomolgus monkeys, and the terminal half-life ranged from 6 to 12 days in all species. After s.c. administration, rhuMAb VEGF had a bioavailability of 69% in rats and 100% in mice and cynomolgus monkeys. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of rhuMAb VEGF using allometric scaling in humans. The predicted serum clearance of rhuMAb VEGF in humans was 2.4 ml/day/kg and the terminal half-life was 12 days. Two hours after i.v. bolus administration of125I-rhuMAb VEGF in rabbits, trichloroacetic acid-precipitable radioactivity was noted primarily in the plasma, with lesser amounts in highly perfused tissues such as kidneys, testes, spleen, heart, and lungs. At 48 h after dosing, trichloroacetic acid-precipitable radioactivity was noted in plasma with minimal distribution to testes, bladder, heart, lungs, and kidneys. Tissue distribution and pharmacokinetic data indicate that rhuMAb VEGF is cleared slowly and distributes to specific sites in the body.

The purpose of this study was to characterize the bradycardic effects of 5-hydroxytryptamine (5-HT)1A receptor agonists in the chloralose-anesthetized spinal cat and to determine if tolerance develops to the bradycardia produced by these drugs. 5-HT1A receptor agonists studied included 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone, gepirone, flesinoxan and U-93385E (cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benz[e]indole-9 - carboxamide). These compounds reduced heart rate by 20 to 30% in the spinal cat and lowered arterial blood pressure. The hypotension resulted from a decrease in cardiac output. Atropine reversed and vagotomy prevented the bradycardia produced by a single dose of U-93385E. The decrease in heart rate produced by i.v. bolus doses of flesinoxan or U-93385 was reversed by administration of the 5-HT1A receptor antagonists spiperone or WAY 100135. Administration of a single dose of U-93385E (either 0.3, 1.0 or 3.0 mg/kg i.v.) resulted in a 20 to 30% decrease in heart rate. In contrast, cumulative dosing of U-93385E (0.01-3.0 mg/kg i.v.) failed to lower heart rate in the spinal cat. Similarly, infusion of 1 mg/kg of U-93385E over a 2-hr period failed to lower heart rate and prevented a bradycardic effect of a single bolus dose of U-93385E or flesinoxan. In contrast, the alpha-2 receptor agonist clonidine decreased heart rate in animals receiving the U-93385E infusion. Finally, single bolus doses of flesinoxan or U-93385E failed to decrease heart rate in cats treated for 7 days with U-93385E and then saline for 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and in pathological processes such as tumor growth, rheumatoid arthritis, and ocular neovascularization. A recombinant humanized monoclonal antibody (rhuMAb), rhuMAb VEGF, has been developed to inhibit the effects of VEGF in the treatment of solid tumors. Intravenous and s.c. pharmacokinetic studies were conducted in mice, rats, and cynomolgus monkeys. In addition, the tissue distribution of i.v. 125I-rhuMAb VEGF was investigated in rabbits. At a dose of approximately 10 mg/kg, the clearance of rhuMAb VEGF from the serum was 15.7 ml/day/kg in mice, 4.83 ml/day/kg in rats, and 5.59 ml/day/kg in cynomolgus monkeys, and the terminal half-life ranged from 6 to 12 days in all species. After s.c. administration, rhuMAb VEGF had a bioavailability of 69% in rats and 100% in mice and cynomolgus monkeys. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of rhuMAb VEGF using allometric scaling in humans. The predicted serum clearance of rhuMAb VEGF in humans was 2.4 ml/day/kg and the terminal half-life was 12 days. Two hours after i.v. bolus administration of 125I-rhuMAb VEGF in rabbits, trichloroacetic acid-precipitable radioactivity was noted primarily in the plasma, with lesser amounts in highly perfused tissues such as kidneys, testes, spleen, heart, and lungs. At 48 h after dosing, trichloroacetic acid-precipitable radioactivity was noted in plasma with minimal distribution to testes, bladder, heart, lungs, and kidneys. Tissue distribution and pharmacokinetic data indicate that rhuMAb VEGF is cleared slowly and distributes to specific sites in the body.

The effects of the putative serotonin (5-HT)1A receptor antagonists WAY-100135 (WAY) and spiperone on the neuronal activity recorded from medullary and dorsal raphe 5-HT neurons and the inferior cardiac sympathetic nerve were investigated in chloralose anesthetized cats. We also determined the effectiveness of WAY and spiperone to antagonize the sympathoinhibitory effects of the 5-HT1A agonist 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH DPAT). Intravenous administration of both WAY and spiperone produced a dose-related inhibition of the firing of medullary 5-HT neurons. WAY also inhibited firing of serotonergic neurons in the dorsal raphe nucleus. WAY treatment had no significant effect on inferior cardiac sympathetic nerve discharge (SND), whereas spiperone treatment caused a small, but significant, increase in SND. WAY treatment did not significantly affect 8-OH DPAT-induced inhibition of unit firing. Spiperone, however, did display antagonist activity at the presynaptic autoreceptor site. WAY and spiperone pretreatments resulted in significant rightward shifts in the 8-OH DPAT inhibition of SND dose-response curves and reversed the depressant effects of 8-OH DPAT. These results suggest that WAY and spiperone act as 5-HT1A antagonists postsynaptically, but WAY appears to have more potent agonist efficacy at the 5-HT1A presynaptic autoreceptor site in the cat. However, because all drugs were administered intravenously, conclusions regarding direct effects of WAY and spiperone on 5-HT1A receptors must be made cautiously.