Understanding the Hysteresis Loop Conundrum in Pharmacokinetic / Pharmacodynamic Relationships

This is the published version. Copyright 2014 Canadian Society for Pharmaceutical SciencesHysteresis loops are phenomena that sometimes are encountered in the analysis of pharmacokinetic and pharmacodynamic relationships spanning from pre-clinical to clinical studies. When hysteresis occurs it provides insight into the complexity of drug action and disposition that can be encountered. Hysteresis loops suggest that the relationship between drug concentration and the effect being measured is not a simple direct relationship, but may have an inherent time delay and disequilibrium, which may be the result of metabolites, the consequence of changes in pharmacodynamics or the use of a non-specific assay or may involve an indirect relationship. Counter-clockwise hysteresis has been generally defined as the process in which effect can increase with time for a given drug concentration, while in the case of clockwise hysteresis the measured effect decreases with time for a given drug concentration. Hysteresis loops can occur as a consequence of a number of different pharmacokinetic and pharmacodynamic mechanisms including tolerance, distributional delay, feedback regulation, input and output rate changes, agonistic or antagonistic active metabolites, uptake into active site, slow receptor kinetics, delayed or modified activity, time-dependent protein binding and the use of racemic drugs among other factors. In this review, each of these various causes of hysteresis loops are discussed, with incorporation of relevant examples of drugs demonstrating these relationships for illustrative purposes. Furthermore, the effect that pharmaceutical formulation has on the occurrence and potential change in direction of the hysteresis loop, and the major pharmacokinetic / pharmacodynamic modeling approaches utilized to collapse and model hysteresis are detailed

Diversidad genética de ovinos criollos colombianos

Ojective. genetical characterization the creole Colombian sheep and their relationships with breeds of European origins. Materials and methods. Blood samples of 261 sheeps from the following populations were collected: Criollos de Lana (CL), Mora Colombiana (MC), Criollo de Pelo (CP), criollos mestizos (Mes), Hampshire (Hamp), Corriedale (Corr), Katahdin (Kath), Pelibuey (Pel), in 40 farms of 8 departments (Córdoba, Magdalena, Cesar, Atlántico, Valle del Cauca, Nariño, Boyacá, Tolima) and 30 samples of Merino Spanish, Merino Precoz (MP), Merinofleischschaf (MF), Segureño (Seg) and Uda (UD) de Nigeria. A total of 15 microsatellites markers were included inthis study. Results. In creole sheep, the average number of alleles was found 6.20±1.48 (CL), 7.27±1.39 (CP) y 3.60±1.55 (MC); high genetic diversity found (high heterozygosities 75%), negative values in the FIS revealed high degree of introgression; furthermore the FST revealed genetic structure in both: Creole sheep (FST=0.02**) and departments (FST=0.039**).According to genetic distance, the creole Colombian sheep differs with outsider sheep. Conclusions. The results recommend protecting the Creole sheep production because it has been threatened by constant cross with foreign breeds, which would lead to the loss of genetic identity and adapting traits of creole sheep.themselves.Objetivo. Caracterizar genéticamente los ovinos criollos colombianos y sus relaciones con razas de origen europeo. Materiales y métodos. 261 muestras de sangre de las siguientes poblaciones, fueron colectadas: Criollos de Lana (CL), Mora Colombiana (MC), Criollo de Pelo (CP), mestizos (Mes), Hampshire (Hamp), Corriedale (Corr), Katahdin (Kath), Pelibuey (Pel), En 40 fincas de ocho departamentos (Córdoba, Magdalena, Cesar, Atlántico, Valle del Cauca, Nariño, Boyacá y Tolima) y 30 muestras de Merino Español (ME), Merino Precoz (MP), Merinofleischschaf (MF), Segureño (Seg) y Uda (UD) de Nigeria. Un total de 15 marcadores microsatélites fueron incluidos en este estudio. Resultados. En ovinos criollos, el número promedio de alelos encontrado fue 6.20±1.48 (CL), 7.27±1.39 (CP) y 3.60±1.55 (MC); hallándose también alta diversidad genética en ellos (heterocigosidades superiores al 75%), valores negativos en el FIS revelaron alto grado de introgresión; además el FST reveló estructura genética tanto en los grupos criollos (FST=0.02**), como en los departamentos muestreados (FST=0.039**). Según la distancia genética, los ovinos criollos colombianos presentan diferencias con los ovinos foráneos. Conclusiones. Los resultados obtenidos recomiendan proteger la ovinocultura criolla puesto que se encuentra amenazada por los constantes cruzamientos con razas foráneas, lo que conllevaría a pérdida de la identidad genética y de los rasgos de adaptación propios de los animales criollos

Inhibition of experimental colorectal cancer and reduction in renal and gastrointestinal toxicities by copper-indomethacin in rats

Purpose: To evaluate, for the first time, the efficacy of copper–indomethacin in the inhibition of aberrant crypt foci formation using the azoxymethane-induced adenocarcinoma model, to examine cell viability in the HCT-116 colorectal cancer cell line, gastrointestinal permeability, mitochondrial oxidative damage, and renal toxicity in rat models. Methods: Azoxymethane-induced adenocarcinoma rats were dosed with indomethacin and copper–indomethacin for 28 days and aberrant crypt foci were evaluated. HCT-116 colorectal cancer cells were exposed to indomethacin and copper–indomethacin at 0–250 μg/mL (0–698 μM for indomethacin, and 0–147 μM for copper–indomethacin), and cell viability was measured. Acute gastrointestinal toxicity was measured using gastrointestinal permeability markers, gastrointestinal ulceration and bleeding, and measurement of an acute-phase protein haptoglobin. Effects of acute and chronic administration of indomethacin and copper–indomethacin on urinary electrolyte concentrations were examined. Results: Both indomethacin and copper–indomethacin resulted in a significant reduction in aberrant crypt foci in azoxymethane-treated rats. In parallel, high concentrations of indomethacin and copper–indomethacin also reduced cell viability in HCT-116 colorectal cancer cells. However, copper–indomethacin was considerably safer in all measures of gastrointestinal toxicity compared to indomethacin. In addition, indomethacin reduced urinary electrolytes at an ulcerogenic dose of 10 mg/kg acutely and chronically at 3.0 mg/kg for 28 days, whereas copper–indomethacin at equimolar doses of indomethacin affected urine electrolytes after acute dosing but not after chronic dosing for 28 days. Conclusions: Copper–indomethacin has both gastrointestinal and renal sparing properties while maintaining efficacy in experimental adenocarcinoma

Effect of recombinant zoster vaccine on incidence of Herpes zoster after autologous stem cell transplantation : a randomized clinical trial

IMPORTANCE Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster. OBJECTIVE To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients. DESIGN, SETTING, AND PARTICIPANTS Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT. INTERVENTIONS Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n=922) or placebo (n=924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter. MAIN OUTCOMES AND MEASURES The primary end point was occurrence of confirmed herpes zoster cases. RESULTS Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P<.001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P=.02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P=.02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P=.01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points. CONCLUSIONS AND RELEVANCE Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0161041

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation A Randomized Clinical Trial

IMPORTANCE Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster. OBJECTIVE To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients. DESIGN, SETTING, AND PARTICIPANTS Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT. INTERVENTIONS Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n=922) or placebo (n=924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter. MAIN OUTCOMES AND MEASURES The primary end point was occurrence of confirmed herpes zoster cases. RESULTS Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P&lt;.001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P=.02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P=.02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P=.01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points. CONCLUSIONS AND RELEVANCE Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0161041

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation A Randomized Clinical Trial

IMPORTANCE Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster. OBJECTIVE To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients. DESIGN, SETTING, AND PARTICIPANTS Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT. INTERVENTIONS Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n=922) or placebo (n=924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter. MAIN OUTCOMES AND MEASURES The primary end point was occurrence of confirmed herpes zoster cases. RESULTS Among 1846 autologous HSCT recipients (mean age, 55 years; 688 {[}37\%] women) who received 1 vaccine or placebo dose, 1735 (94\%) received a second dose and 1366 (74\%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95\% CI, 0.22-0.44; P<.001), equivalent to 68.2\% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95\% CI, 0.00-0.78; P=.02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95\% CI, 0.04-0.81; P=.02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95\% CI, 0.42-0.89; P=.01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86\% of vaccine and 10\% of placebo recipients, of which pain was the most common, occurring in 84\% of vaccine recipients (grade 3: 11\%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points. CONCLUSIONS AND RELEVANCE Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0161041

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUN

Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

BACKGROUN