Increase In Total Exposure Research Articles

Effect of Opicapone on Levodopa Pharmacokinetics in Patients with Fluctuating Parkinson's Disease.

Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with Parkinson's disease (PD) experiencing motor fluctuations. To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens. A total of 24 patients with PD and motor fluctuations were enrolled in an exploratory, open-label, modified cross-over trial. Participants first received levodopa/carbidopa 500/125 mg (five intakes) for 2 weeks and were then randomly assigned (1:1) to levodopa/carbidopa 400/100 mg given over either four or five daily intakes plus opicapone 50 mg for an additional 2 weeks. Levodopa 12-hour pharmacokinetics was the primary outcome (ie, excluding the effect of last/evening levodopa/carbidopa intake), with motor complications evaluated as secondary outcomes. Over 12-hour pharmacokinetics and compared with five-intake levodopa/carbidopa 500/125 mg without opicapone, maximal levodopa concentrations were similar or nonsignificantly higher on both levodopa/carbidopa 400/100 mg regimens plus opicapone. Despite a 100 mg lower total levodopa/carbidopa daily dose, adding opicapone 50 mg at least doubled the levodopa plasma half-life and minimal concentrations, with a significant ≈30% increase in total exposure. The levodopa fluctuation index was only significantly lower for the five intakes plus opicapone regimen (difference of -71.8%; P< 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time. Combining opicapone 50 mg with a 100 mg lower daily dose of levodopa provides higher levodopa bioavailability with avoidance of trough levels. Despite the lower levodopa dose, modifying the levodopa pharmacokinetic profile with opicapone was associated with decreased off time and increased on time. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Changes in population exposure to extreme precipitation in the Yangtze River Delta, China

Precipitation extremes are expected to increase in a warming world, which could have substantial impacts on the environment, social property, and human health, especially in densely populated regions. In this study, the Yangtze River Delta (YRD) was used as a case study to investigate the spatiotemporal characteristics of daily, daytime, and nighttime extreme precipitation events (EPEs), and the population exposure to EPEs based on observational precipitation and population data. The EPEs both in days (duration) and amount (magnitude) showed obvious south-north gradients, with high values occurring in the south and low values in the north. A few stations in the northern parts of the YRD showed weak decreasing trends in extreme precipitation days and amounts during 1961–2018, whereas most of the stations showed positive trends. The stations with significantly increasing trends were mainly located in the central and eastern parts of the YRD. All the EPE indices for the whole area showed increasing trends during 1961–2018. Population exposure to daily, daytime, and nighttime extreme precipitation days (amounts) increased by 37% (40%), 34% (39%), and 41% (41%), respectively, from the early period (1984–1993) to the later period (2009–2018). The significant increase in total exposure to EPEs was dominated by the effect of rapid population growth during 1984–2018. An atmospheric circulation analysis of the EPEs in 2016 showed that the anomalously strong warm and wet southwesterly water–vapor transport from April to October (except for August) on the northwest side of the West Pacific subtropical high merged with cold air, resulting in abnormally more EPEs and exposure in 2016 than any other years of the study period in the YRD. The findings provide information useful to adaptation and mitigation policymaking for regions with conditions similar to the YRD.

Exposure to Hurricane Sandy and Risk of Opioid Abuse

Background Given both the increased prevalence of natural disasters in recent years and the crippling opioid epidemic, identifying at-risk groups for substance abuse post-disaster is imperative to survivor mental health. The objective of this study was to examine the association between exposure to Hurricane Sandy and risk of opioid abusive behavior. Methods We conducted a retrospective analysis using data from two cross-sectional studies that examined the impact of Hurricane Sandy on mental health from October 2013- August 2016. Patient demographics, hurricane exposure and mental health history were obtained via self-report questionnaires. Opioid abuse risk was determined and categorized using adaptations from the Opioid Risk Tool (ORT). Multinomial logistic regression was used to examine the relationship between hurricane exposure and opioid abuse risk. Results Data was available on 1,687 Hurricane Sandy survivors, the majority being female (59.3%), white (52.0%) and an average age of 46.1 years (std. 19.2). Approximately 9.0% of survivors were classified as being ‘High’ risk for opioid abuse. For every increase in total exposure reported, the odds of being classified as high risk was 1.09 greater (95% CI 1.05, 1.14) compared to low risk, after adjusting for covariates. Among personal exposures only (i.e. injury to self or family member), for every increase in reported exposure the adjusted odds of being classified as high risk was 1.25 times greater (95% CI 1.15, 1.37) compared to low risk. Conclusions These findings suggest that exposure to a natural disaster, specifically personal exposures, are associated with increased risk for opioid abusive behavior.

Effect of Hepatic Impairment on the Pharmacokinetics of Itacitinib.

Itacitinib is a potent, selective JAK-1 inhibitor currently in development for the treatment of chronic graft-vs-host-disease in combination with corticosteroids. Itacitinib is primarily eliminated via cytochrome P450 3A metabolism with minimal renal elimination. The purpose of this open-label study was to investigate the effect of hepatic impairment, as determined by Child-Pugh grade, on itacitinib pharmacokinetics. All participants received a single 300-mg dose of itacitinib orally in the fasted state. Blood samples were collected serially through 96 hours after dosing; 4 hours after dosing, an additional sample was collected for protein binding determination. Participants with moderate hepatic impairment (N = 8) had an approximate 2.5-fold increase in total exposure (area under the plasma concentration-time curve from time 0 to infinity [AUC0-∞ ]) and an approximate 2-fold increase in maximal exposure (Cmax ) compared to those with normal hepatic function (N = 8) (geometric mean ratio, 2.51 [90% confidence interval (CI), 1.54-4.08] for AUC0-∞ and 1.95 [90%CI, 1.14-3.35] for Cmax ). Participants with severe hepatic impairment (N = 6) had an approximate 4-fold increase in total exposure (AUC0-∞ ) and an approximate 3.5-fold increase in maximal exposure compared to participants with normal hepatic function (geometric mean ratio, 4.08 [90%CI, 2.41-6.89] for AUC0-∞ and 3.48 [90%CI, 1.94-6.23] for Cmax ). Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hepatic function, with average unbound fractions (percent free) of 25.7%, 31.5%, and 25.6%, respectively. There were no serious or fatal treatment-related adverse events. The results of this study combined with exposure, efficacy, and safety data from the pivotal study in the relevant patient population will inform final dosing recommendations.

The elite player performance plan: the impact of a new national youth development strategy on injury characteristics in a premier league football academy

ABSTRACTThe objective of this study was to investigate the injury incidence and patterns in elite youth football at a category 1 Premier League Academy before and after the introduction of a new development strategy, the Elite Player Performance Plan (EPPP). A prospective study was performed over six consecutive seasons encompassing three years before and after the introduction of the EPPP. The findings revealed a most likely moderate increase in total exposure per player per season when the post-EPPP football exposure (640.86 ± 83.25 hours per player per year) was compared with the pre-EPPP football exposure (539.08 ± 71.59). The total injury incidence pre-EPPP was 3.0/1000 hours compared to 2.1/1000 hours post-EPPP (rate ratio 1.43). 6% of all injuries were re-injuries (20.24 ± 33.43 days) but did not result in a substantially longer absence (16.56 ± 15.77 days). The injury burden decreased for the U12-U15 from pre- to post-EPPP, whereas the injury burden increased for the U16-U18 (respectively 125 and 47% higher). These findings suggest that following the introduction of the EPPP there has been a reduction in injuries in the younger age groups U12-U15 but in the older age groups U16-U18 there has been an increase in the severity of the injuries sustained at this club.

Tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator AZD1656, after single ascending doses in healthy subjects during euglycemic clamp

AZD1656 is a novel glucokinase activator with a postulated dual mechanism of action by activating glucokinase in both the pancreas and the liver, and with the potential to deliver effective glucose-lowering in Type 2 diabetes mellitus. Here, we present the tolerability, pharmacokinetics and pharmacodynamics of AZD1656 in two single-blind, randomized, placebo-controlled studies, one with Western and the other with Japanese healthy adult male subjects. Both studies evaluated oral single ascending doses of AZD1656 of up to 180 mg, administered during euglycemic clamp conditions to explore a wide dose range without risking hypoglycemia. Safety, pharmacokinetics and effects on serum insulin and glucose infusion rate were assessed. A population pharmacokinetics analysis was also conducted. AZD1656 was well tolerated in single doses up to 180 mg in both populations. AZD1656 was rapidly absorbed, and a dose-proportional increase in total exposure was observed for AZD1656 and the equipotent metabolite, AZD5658. Taking differences in body weight into account, there were no differences in pharmacokinetic parameters between Western and Japanese subjects. A dose-dependent blood glucose lowering effect was indirectly demonstrated by the increased glucose infusion rate required to maintain euglycemia, which was of similar magnitude in both populations. Dose-dependent increases in insulin secretion were also observed. No safety concerns were raised. AZD1656 displayed uncomplicated pharmacokinetics and dose-dependent pharmacodynamics effects were observed. The results suggest no ethnic differences in AZD1656 tolerability, pharmacokinetics or pharmacodynamics.

Radiation Worker Protection by Exposure Scheduling

The discovery of the protective adaptive response of cells to a low dose of radiation suggests applications to radiation worker/first responder protection. Its use in cancer radiotherapy has been discussed in a separate publication. This paper describes simple changes in scheduling that can make use of these beneficial adaptive effects for protection. No increase in total exposure is necessary, only a simple change in the timing of radiation exposure. A low dose of radiation at a sufficient dose rate will trigger the adaptive response. This in turn will offer a considerable protection against the damage from a subsequent high dose. A simple scenario is discussed as well as a brief review of the experimental basis of the adaptive response.

The Effects of Paroxetine on the Pharmacokinetics of Paliperidone Extended-release Tablets

Co-morbid medical and psychiatric conditions are common in individuals with schizophrenia. As such, selecting antipsychotic medications with a low potential for drug-drug interactions (DDIs) is crucial, as many are extensively metabolized by hepatic cytochrome P450 (CYP) isozymes. This randomized, crossover study examined the effects of paroxetine (a potent CYP2D6 inhibitor) on the pharmacokinetic parameters of a single dose of the novel antipsychotic agent, paliperidone extended-release tablets (paliperidone ER), in healthy subjects. The mean C (max) and AUC of paliperidone were slightly higher and paliperidone clearance was slightly lower following co-administration of paliperidone ER with paroxetine. There was a ratio of geometric treatment means of 116.48% for AUC (infinity) [90% CI: 104.49-129.84]. However, the increase in total exposure to paliperidone was not considered clinically relevant. The incidence of adverse events was lower when subjects received the combination of paliperidone ER and paroxetine compared with paroxetine alone. Results suggest that no clinically relevant pharmacokinetic interaction occurs when paroxetine and paliperidone ER are co-administered and, therefore, initiation or discontinuation of concomitant treatment with CYP2D6-inhibiting drugs does not appear to warrant an adjustment in paliperidone ER dosage.

Effect of febuxostat on pharmacokinetics of desipramine, a CYP2D6 substrate, in healthy subjects

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase (NP-SIXO) being developed for the management of hyperuricemia in patients with gout. Background In-vitro data showed that febuxostat had no significant effect on CYP1A2, CYP2C9, CYP2C19 or CYP3A4 activity (Ki>100 μM), and a weak inhibitory effect on CYP2D6 (Ki=40 μM). Aim The effect of febuxostat on desipramine pharmacokinetics (PK) was evaluated. Methods A phase-1, two-period, crossover, double-blind study was conducted in 18 CYP2D6 extensive-metabolizer subjects. Each subject received a single 25 mg oral dose of desipramine (DES) after multiple oral dosing with febuxostat (FBX) 120 mg or placebo (PLA) once daily. Blood samples were collected to assess the PK of DES and 2-hydroxydesipramine (2-HD). Results The results are shown in the table below. The increase in total exposure to DES and the concomitant decrease in the 2-HD/DES AUC ratio suggest that the metabolism of DES to 2-HD via CYP2D6 was mildly inhibited. However, this effect was not considered to be clinically significant. The incidence of adverse events was similar between treatment regimens with the majority being mild and moderate in severity. Conclusion No dose adjustment is expected for CYP2D6 substrates when co-administered with febuxostat. Clinical Pharmacology & Therapeutics (2005) 77, P43–P43; doi: 10.1016/j.clpt.2004.12.059 Table 1. Mean±SD Plasma PK for DES and 2-HD, Point Estimates (PE) and Confidence Intervals (CI) Parameter DES + FBX DES + PLA PE (90% CI)1 1 Ratio of DES+FBX to DES+PLA 2 AUC Ratio: 2-HD/DES AUC ratio DES Cmax (ng/mL) 9.6 ± 3.5 8.4 ± 3.2 1.16 (1.10–1.23) AUC∞ (ng h/mL) 295 ± 194 263 ± 249 1.22 (1.11–1.35) 2-HD Cmax (ng/mL) 6.2 ± 2.0 6.6 ± 2.3 0.96 (0.90–1.02) AUC∞ (ng h/mL) 163 ± 30 166 ± 62 1.02 (0.93–1.11) AUC Ratio2 0.74 ± 0.40 0.88 ± 0.49 0.83 (0.76–0.91}

A pilot study to rate determinants of exposure from videotaped work activities of farmers' use of pesticides.

Industrial hygienists often observe workers to determine who should be measured based on a predicted exposure level. Such evaluations are usually based on real-time observation, yet surprisingly little research has been conducted on what determinants of exposure industrial hygienists use to rank workers and whether the ranking is accurate. Accuracy of the ranking may also be affected by the observation process, which is limited when conditions in the workers' immediate environment are rapidly changing. An alternative to real-time observation is videotaping workers and evaluating the tapes at a later date. A pilot study was conducted using previously collected data to determine if workers could be ranked by exposure level utilizing a scoring system to rate videotaped work practices. Six farmers had been videotaped and their dermal exposures measured as they applied insecticide to hogs. In this study, scores were developed to rate the farmers' working conditions by exposure level. Two types of determinants were used to describe exposure: touching and work practices. Touching included the number of times parts of the body had contact with surfaces possibly contaminated with insecticide. Work practices included the types of clothing and protective equipment worn as well as specific practices used by the farmer (e.g., application method). Two raters conducted independent assessments of the videotape using the same criteria. One rater reviewed the tape twice. Agreement between the raters for the "touching" score was weak (intra-class coefficient (ICC) = 0.28), but there was excellent agreement between the two raters (ICC = 0.92) for overall quality of work practices. As expected, a greater number of touches was moderately correlated with an increase in total exposure (rs = 0.60) and there was a weak inverse relationship between protective work practices and the exposure under the clothing (rs = -0.26). All other relationships with exposure level were contrary to what was expected. Since videotapes provide the industrial hygienist with a record of work events and can capture details that might otherwise be missed or not considered they may play a useful role in exposure assessment, especially if carefully developed procedures are followed to overcome the limitations found by this pilot study.