Electrocardiographic Effects of a Supratherapeutic Dose of Oritavancin.

The purpose of this study was to measure oritavancin's electrocardiographic effects at a supratherapeutic dose of 1600 mg given intravenously (IV) over 3 hours. A cohort of 150 healthy volunteers were randomized to receive placebo, oritavancin, or oral moxifloxacin 400 mg in a parallel designed thorough QT study. A supratherapeutic mean maximum oritavancin concentration (Cmax ) of 232 µg/mL was achieved. There was no significant effect on baseline and placebo corrected (dd) QTcF, QRS, or heart rate; ddPR was slightly increased at most time points, with a maximum mean change of 7.7 milliseconds 1 hour after infusion. Linear PK-PD modeling predicted a 3.2-millisecond change in the PR interval for the Cmax (138 µg/mL) observed in pivotal phase 3 studies after 1200 mg of oritavancin. Moxifloxacin produced the expected increase in ddQTcF, validating assay sensitivity. At plasma concentrations above the clinical exposures of oritavancin, no clinically or statistically significant effect on QTcF, QRS, or heart rate was observed. The increase in PR is considered clinically insignificant, given the rapid decline in initial plasma concentration of oritavancin after infusion and the expected lower Cmax in patients. A therapeutic 1200-mg single dose of oritavancin is not anticipated to cause any clinically significant effect on cardiac electrophysiology.

Tolerability and efficacy of two synergistic ratios of oral morphine and oxycodone combinations versus morphine in patients with chronic noncancer pain.

OBJECTIVES: Analgesic synergy and improved tolerability have been reported for flexible dose morphine and oxycodone combinations. This report describes two studies with similar double-blind, randomized, 7-day crossover designs (up to 7 days per arm) conducted to 1) explore the analgesic and safety benefit offixed ratio of morphine (M) and oxycodone (0) combinations (MOX) and 2) define the optimal ratio for morphine and oxycodone combination. SETTING: Clinical study centers in Australia. PATIENTS: Patients with chronic noncancer pain. INTERVENTION: Eligible patients were randomly assigned to receive flexible doses of either M or fixed ratio of MOX (M3:02 in study A; M1:02 in study B). The starting doses of M or MOX were the morphine equivalent doses (MEDs) converted from the analgesics received before entering double-blind treatment. At each crossover period, the doses were titrated to achieve analgesia at steady state, which was defined as when the same total daily dose (+/-10 percent) had been given consecutively for 3 days. MAIN OUTCOME MEASURE: The primary endpoint was the study medication dose (MED), which produced adequate pain control at steady state. RESULTS: Analgesic synergy in MOX was observed in both studies. On an MED basis, 61.6 percent (study A, M:0 = 3:2) or 46.8 percent (study B, M:0 = 1:2) more MED were needed forM monotherapy to achieve steady-state pain control when compared with MOX. Patient tolerability profiles were also generally better in the MOX groups. CONCLUSION: A 3:2 or 1:2 fixed ratio combination of morphine and oxycodone (MOX) produced analgesic synergy and a tolerability profile improvement in patients with chronic noncancer pain.

Modeling tardive dyskinesia: predictive 5-HT2C receptor antagonist treatment.

Tardive dyskinesia (TD), a movement disorder produced by long-term treatment with a classical antipsychotic drug, is generally considered to be a disorder of dopamine (DA) systems, since classical antipsychotics are potent DA D(2) receptor blockers. Also, acute DA D(1) agonist treatment of rats is known to produce vacuous chewing movements (VCMs), a behavioral feature resembling the oral dyskinesia that is so prominent in most instances of TD. In this paper we outline a series of studies in a new animal model of TD in which DA D(1) receptor supersensitivity was produced by neonatal 6-hydroxydopamine (6-OHDA) -induced destruction of nigrostriatal DA fibers. In rats so-lesioned 5-HT receptor supersensitivity is additionally produced, and in fact 5-HT receptor antagonists attenuate enhanced DA D(1) induction of VCMs. Moreover, in 6-OHDA-lesioned rats treated with haloperidol for one year, there a 2-fold increase in numbers of VCMs (vs intact rats treated with haloperidol); and this high frequency of VCMs persists for more than 6 months after discontinuing haloperidol treatment. During this stage, 5-HT(2) receptor antagonists, but not DA D(1) receptor antagonists, attenuate the incidence of VCMs. This series of findings implicates the 5-HT neuronal phenotype in TD, and promotes 5-HT(2) receptor antagonists, more specifically 5-HT(2C) receptor antagonists, as a rational treatment approach for TD in humans.