Single- and Multiple-Dose Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist, in Healthy Adults.

Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials.

A Randomized, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of 3 Weeks of Orally Administered Gefapixant in Healthy Younger and Older Adults.

Purpose: Patients with chronic cough are typically female and have a mean age of ~ 60 years. However, initial pharmacokinetic (PK) characterization of the P2X3-receptor antagonist gefapixant, developed to treat refractory or unexplained chronic cough, was performed in healthy participants who were predominantly younger adult males. The objective of this Phase 1 study was to assess the safety, tolerability, and PK of gefapixant in younger (18-55 years) and older (65-80 years) males and females.

Gefapixant in two randomised dose-escalation studies in chronic cough.

Background And Objectives: Gefapixant has previously demonstrated efficacy in the treatment of refractory chronic cough at a high daily dose. The current investigations explore efficacy and tolerability of gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough using a dose-escalation approach.

Materials And Methods: Two randomised, double-blind, placebo-controlled, crossover, dose-escalation studies recruited participants with refractory chronic cough.

Cyclic estradiol treatment modulates the orexigenic effects of ghrelin in ovariectomized rats.

Data from a wide variety of mammalian species indicate that feeding behavior can be influenced by changes in endogenous estrogens and exogenous estrogenic treatments. Ghrelin is an important physiological signal for the regulation of energy balance, and ghrelin treatment increases eating and body weight in male rodents. The following studies evaluated the hypothesis that the inhibitory effects of estradiol on feeding involve interactions with orexigenic peptides by examining the ability of estradiol to modulate the behavioral effects of ghrelin in female rats.

Higher-order expansions for the entropy of a dimer or a monomer-dimer system on d-dimensional lattices.

Recently, an expansion as a power series in 1/d has been presented for the specific entropy of a complete dimer covering of a d-dimensional hypercubic lattice. This paper extends from 3 to 10 the number of terms known in the series. Likewise, an expansion for the entropy, dependent on the dimer density p, of a monomer-dimer system, involving a sum ∑(k)a(k)(d)p(k), has been offered recently.

High-temperature expansions of the higher susceptibilities for the Ising model in general dimension d.

The high-temperature expansion coefficients of the ordinary and the higher susceptibilities of the spin-1/2 nearest-neighbor Ising model are calculated exactly up to the 20th order for the general d-dimensional (hyper)simple-cubical lattices. These series are analyzed to study the dependence of critical parameters on the lattice dimensionality. Using the general d expression of the ordinary susceptibility, we have more than doubled the length of the existing series expansion of the critical temperature in powers of 1/d.

Yang-Lee edge singularities from extended activity expansions of the dimer density for bipartite lattices of dimensionality 2 ≤ d ≤ 7.

We have extended, in most cases through 24th order, the series expansions of the dimer density in powers of the activity in the case of bipartite [(hyper)-simple-cubic and (hyper)-body-centered-cubic] lattices of dimensionalities 2 ≤ d ≤ 7. A numerical analysis of these data yields estimates of the exponents characterizing the Yang-Lee edge singularities for lattice ferromagnetic spin models as d varies between the lower and the upper critical dimensionalities. Our results are consistent with, but more extensive and sometimes more accurate than, those obtained from the existing dimer series or from the estimates of related exponents for lattice animals, branched polymers, and fluids.

Triviality problem and high-temperature expansions of higher susceptibilities for the Ising and scalar-field models in four-, five-, and six-dimensional lattices.

High-temperature expansions are presently the only viable approach to the numerical calculation of the higher susceptibilities for the spin and the scalar-field models on high-dimensional lattices. The critical amplitudes of these quantities enter into a sequence of universal amplitude ratios that determine the critical equation of state. We have obtained a substantial extension, through order 24, of the high-temperature expansions of the free energy (in presence of a magnetic field) for the Ising models with spin s≥1/2 and for the lattice scalar-field theory with quartic self-interaction on the simple-cubic and the body-centered-cubic lattices in four, five, and six spatial dimensions.

Effects of estradiol on food intake and meal patterns for diets that differ in flavor and fat content.

Apart from the well known inhibitory effects of estradiol on food intake, meal size, and body weight in female rats that have been documented over the past thirty years, a more recent report presents the opposite finding; that a large dose of estradiol can increase food intake and weight gain in gonadally intact female rats presented with a palatable diet. The purpose of the present experiment was to further examine this hypothesis by evaluating the ability of estradiol to influence feeding behavior in ovariectomized rats presented with diets that differ in flavor and fat content. Female rats were given a cyclic regimen of estradiol benzoate treatment (5.

Estradiol and the control of food intake.

Gonadal steroids are among the many factors that influence food intake and body weight in mammals. Hormonal effects on these processes are particularly striking in female rats, which show large increases in food intake and body weight after ovariectomy. A key role of estradiol in the control of food intake and energy balance in humans is evidenced by the fact that the incidence of obesity increases greatly after menopause [American College of Obstetricians and Gynecologists.

Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain.

Unlabelled: Physical dependence or withdrawal is an expected effect of prolonged opioid therapy. Oxytrex (oxycodone + ultralow-dose naltrexone) is an investigational drug shown here to minimize physical dependence while providing strong analgesia with twice-daily dosing. In this 719-patient, double-blind, placebo- and active-controlled Phase III clinical trial in chronic low back pain, patients were randomized to receive placebo, oxycodone qid, or oxytrex qid or bid.

Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex.

Unlabelled: Oxytrex is a novel drug that combines oxycodone with ultralow-dose naltrexone, an opioid antagonist. Ultralow-dose opioid antagonists have been demonstrated to enhance and prolong opiate analgesia and alleviate opioid tolerance and withdrawal in rodents. This 3-week, Phase II clinical trial assessed safety and analgesic efficacy of Oxytrex in patients with moderate to severe pain from osteoarthritis.

Devazepide fails to reverse the inhibitory effect of interleukin-1beta on food intake in female rats.

Proinflammatory cytokines released during the course of infection elicit numerous behavioral and metabolic changes. The decrease in food intake that accompanies infection is mediated in part by interleukin-1 (IL-1). Cholecystokinin (CCK) is a neuropeptide released during a meal, decreases food intake, and previous research suggests that CCK mediates the anorectic action of IL-1.

Cyclic estradiol treatment enhances the effects of interleukin-1beta on food intake in female rats.

Proinflammatory cytokines elicit behavioral and physiological responses that include decreased food intake, fever, and a general disinterest in usual activities. Ovarian hormones modulate immune system activity and responsiveness to cytokines in female mammals, suggesting that sex differences in immune function may be influenced by gonadal steroids. In this experiment, female adult rats were ovariectomized and given two daily subcutaneous injections of 5.

Central implants of dilute estradiol enhance the satiety effect of CCK-8.

The following studies evaluated whether direct placement of estradiol into different brain areas could increase the satiating potency of CCK in female rats. In Experiment 1, estradiol implants in the PVN, but not in the VMN or third ventricle, significantly enhanced the satiety actions of CCK (5.0 micrograms/kg).

Antagonism of estrogenic effects on feeding behavior by central implants of anisomycin.

The following experiment determined whether the estrogenic suppression of food intake is dependent upon changes in protein synthesis within neurons of the paraventricular nucleus of the hypothalamus (PVN). Ovariectomized rats were treated centrally with anisomycin-filled or empty (control) cannulae in the PVN. Females were injected with either 2.

Modulation of the satiety effect of cholecystokinin by estradiol.

Data obtained from a wide variety of mammalian species indicate that feeding behavior can be influenced by changes in endogenous estrogens and by exogenous estrogenic treatments. The present experiment represents an initial investigation of the hypothesis that the suppression of food intake by estradiol is mediated by an enhancement of the satiety effect of cholecystokinin (CCK). Twenty-four female rats were ovariectomized and implanted either with a 5% estradiol silastic capsule or an empty capsule on the day of surgery.

Effects of PVN lesions on the responsiveness of female rats to estradiol.

Previous research has shown that the paraventricular nucleus of the hypothalamus (PVN) is an important site of action for the effects of estradiol on feeding behavior. The recent finding that estrogenic stimulation of the PVN lowers food intake without inducing lordosis suggests that the effects of estradiol on feeding and sexual behaviors are organized separately within the brain. Whether the effects of estradiol on food intake can be attenuated by PVN lesions is therefore a question of practical and theoretical interest.