Aims Following intravenous administration of its prodrug, L-758,298, we assessed the pharmacodynamics of L-754,030, a novel and highly selective NK 1 receptor antagonist, by examining systemic haemodynamics and the blood flow responses to intra-arterial substance P infusion. Methods Sixteen healthy male volunteers participated in a double-blind, randomised, placebo controlled crossover trial of L-758 298. Forearm blood flow was measured using venous occlusion plethysmography during intrabrachial substance P infusion (0.125-128 pmol min −1 ). In part 1, eight subjects received substance P infusions before and during placebo, 0.25 mg, 1 mg or 5 mg of L-758 298. In part 2, eight subjects received substance P infusions 24 h after placebo or 1.43 mg of L-758 298.Results L-758 298 caused dose dependent inhibition of substance P induced vasodilatation ( P<0.001). Placebo adjusted differences (95% CI) in baseline forearm blood flow, mean arterial pressure and heart rate showed no relevant changes with 5 mg of L-758 298 (>1400-fold shift in substance P response): 0.00 (−0.49 to +0.49) ml 100 ml −1 min −1 , 1.0 (−3.2 to +5.2) mmHg and 1.9 (−5.9 to +9.7)beats min −1 , respectively. Twenty-four hours after 1.43 mg of L-758,298, there was 34-fold shift in response to substance P induced vasodilatation ( P<0.008) at plasma L-754 030 concentrations of 2-3 ng ml −1 . L-758 298 was generally well tolerated without serious adverse events. Conclusions Substance P induced forearm vasodilatation is mediated by the endothelial cell NK 1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.Keywords: substance P, neurokinin 1 receptor, endothelium, haemodynamics, blood flow Substance P is a member of the tachykinin family of Introduction peptides and acts through stimulation of the neurokinin receptors, having a particularly high affinity for the Substance P is a widely distributed endecapeptide which is found principally in the neural tissue of the central, type 1 (NK 1 ) receptor [9]. When given intra-arterially, substance P is a potent vasodilator [10][11][12] through an peripheral and enteric nervous systems [1][2][3][4]. The physiological functions of substance P include neuroendothelium dependent mechanism [13] which is partly mediated by nitric oxide release [14, 15]. In animal transmission in primary sensory neurones with particular involvement in nociception and emesis. In addition to studies, this response is induced via stimulation of the endothelial cell NK 1 receptor [9] although, to date, this functioning as a neurotransmitter, it also acts as an inflammatory mediator [5][6][7] and neurohumoral regulator has not been confirmed in vivo in man. Substance P is found in perivascular neural tissue [16] and has been [1, 8].postulated to play a role in the regulation of vascular

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Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three‐period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC(0–8h) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC(0–24h) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC(0–8h) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC(0–24h) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

Aims Patients with migraine may receive the 5-HT 1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other b-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between b-adrenoceptor blockers and rizatriptan.Methods Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various b-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured.Results Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0,?) for rizatriptan by approximately 67% and the C max by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically signi®cant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not signi®cantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other signi®cant adverse experiences during coadministration of rizatriptan with any of the b-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other b-adrenoceptor blockers signi®cantly inhibited the production of the indole-acetic acid metabolite of rizatriptan and sumatriptan. Conclusions These results suggest that propranolol increases plasma concentrations of rizatriptan by inhibiting monoamine oxidase-A. When prescribing rizatriptan to migraine patients receiving propranolol for prophylaxis, the 5 mg dose of rizatriptan is recommended. Administration with other b-adrenoceptor blockers does not require consideration of a dose adjustment.

Rizatriptan is a potent, oral 5-HT(1B/1D) agonist with a rapid onset of action being investigated for the acute treatment of migraine. This study examined the clinical and pharmacolinetic interaction between rizatriptan and the selective serotonin reuptake inhibitor, paroxetine. In this two-period crossover study, 12 healthy young subjects (6 males and 6 females) received 1 mg rizatriptan following 14 days of treatment with placebo or paroxetine (20 mg once daily). Plasma was sampled for rizatriptan and N-monodesmethyl rizatriptan, a minor but active metabolite of rizatriptan. Safety evaluations included monitoring for adverse events, vital signs, and visual analog scale assessment of mood. Plasma levels of rizatriptan and N-monodesmethyl rizatriptan were not altered when rizatriptan was administered with paroxetine compared to the placebo. Clinically, coadministration of rizatriptan with paroxetine was well tolerated. Blood pressure, heart rate, and temperature changes during the observation period did not differ to a clinically significant degree when rizatriptan was administered with paroxetine compared to the placebo. No effects on mood occurred following treatment with the combination compared to rizatriptan alone. Adverse events following rizatriptan administration with paroxetine were similar to those reported when rizatriptan was given with the placebo.