Relative Potency Estimates Research Articles

Distributed Opioids in Morphine Equivalent: A Global Measure of Availability for Palliative Care

ContextEstimates of serious health-related suffering (SHS) demonstrate immense unmet need for palliative care, predominately in low- and middle-income countries (LMICs). Because opioids are essential medicines in palliative care (PC), measuring their availability can be used to evaluate the capacity of health systems to meet need. ObjectivesPresent the methodology for calculating Distributed Opioids in Morphine Equivalents (DOME)— introduced in the Lancet Commission on Global Access to Palliative Care and Pain Relief report - and how it can be used as a simple indicator to quantify unmet pain relief and PC need. MethodsUsing International Narcotics Control Board (INCB) data, DOME applies relative potency estimates to convert the annualized quantities of clinically appropriate opioids procured by a country to oral morphine equivalent milligrams. To quantify unmet need, an expert group proposed health condition-specific estimates for opioid need and used available data on the burden of SHS to posit the annual opioid quantity required by country for symptomatic treatment of pain or breathlessness. Comparing this to DOME generates DOME%SHSNEED, the proportion of opioids needed for palliative care that can be fulfilled by the opioid procured by a country during a year. ResultsDOME and DOME%SHSNEED can be used to measure, over time, the capacity of countries to meet PC need, as a key component of universal health coverage. Identifying access gaps disproportionately impacting LMICs can promote better health system performance and guide countries and institutions in policy making. ConclusionDOME and DOME%SHSNEED can be used to monitor health system progress to redress disparities and promote access to medically indicated opioid therapy in palliative care.

Systematic update to the mammalian relative potency estimate database and development of best estimate toxic equivalency factors for dioxin-like compounds

The World Health Organization (WHO) assesses potential health risks of dioxin-like compounds using Toxic Equivalency Factors (TEFs). This study systematically updated the relative potency (REP) database underlying the 2005 WHO TEFs and applied advanced methods for quantitative integration of study quality and dose-response. Data obtained from fifty-one publications more than doubled the size of the previous REP database (∼1300 datasets). REP quality and relevance for these data was assessed via application of a consensus-based weighting framework. Using Bayesian dose-response modeling, available data were modeled to produce standardized dose/concentration-response Hill curves. Study quality and REP data were synthesized via Bayesian meta-analysis to integrate dose/concentration-response data, author-calculated REPs and benchmark ratios. The output is a prediction of the most likely relationship between each congener and its reference as model-predicted TEF uncertainty distributions, or the ‘best estimate TEF’ (BE-TEF). The resulting weighted BE-TEFs were similar to the 2005 TEFs, though provide more information to inform selection of TEF values as well as to provide risk assessors and managers with information needed to quantitatively characterize uncertainty around TEF values. Collectively, these efforts produce an updated REP database and an objective, reproducible approach to support development of TEF values based on all available data.

Development and application of a systematic and quantitative weighting framework to evaluate the quality and relevance of relative potency estimates for dioxin-like compounds (DLCs) for human health risk assessment

The toxic equivalency factors (TEFs) approach for dioxin-like chemicals (DLCs) is currently based on a qualitative assessment of a heterogeneous data set of relative estimates of potency (REPs) spanning several orders of magnitude with highly variable study quality and relevance. An effort was undertaken to develop a weighting framework to systematically evaluate and quantitatively integrate the quality and relevance for development of more robust TEFs. Six main-study characteristics were identified as most important in characterizing the quality and relevance of an individual REP for human health risk assessment: study type, study model, pharmacokinetics, REP derivation method, REP derivation quality, and endpoint. Subsequently, a computational approach for quantitatively integrating the weighting framework parameters was developed and applied to the REP2004 database. This was accomplished using a machine learning approach which infers a weighted TEF distribution for each congener. The resulting database, weighted for quality and relevance, provides REP distributions from >600 data sets (including in vivo and in vitro studies, a range of endpoints, etc.). This weighted database provides a flexible platform for systematically and objectively characterizing TEFs for use in risk assessment, as well as providing information to characterize uncertainty and variability. Collectively, this information provides risk managers with information for decision making.

Comparative Dose-Response Study on the Infusion of Norepinephrine Combined with Crystalloid Coload versus Colloid Coload for Preventing Hypotension During Spinal Anesthesia for Cesarean Delivery.

BackgroundAlthough the optimal infusion dose of norepinephrine combined with crystalloid coload for preventing spinal anesthesia-induced hypotension (SAIH) for cesarean delivery has been established, the infusion regimen of norepinephrine combined with colloid coload has not been fully quantified. The objective of this study was to compare and determine the median effective dose (ED50) and 90% effective dose (ED90) of norepinephrine infusion combined with crystalloid coload versus colloid coload for preventing SAIH during cesarean delivery.MethodsTwo hundred parturients were randomly assigned to receive norepinephrine infusion at 0.02, 0.04, 0.06, 0.08, or 0.10 µg/kg/min in combination with 10 mL/kg crystalloid coload or colloid coload to prevent SAIH. The study period was defined as the interval from the commencement of intrathecal injection to delivery of the neonate. The primary outcome was non-occurrence of hypotension, defined as systolic blood pressure (SBP) less than 80% of the baseline before delivery. The ED50 and ED90 of norepinephrine infusion dose were determined using probit regression analysis. By calculating the 95% confidence intervals (CIs) of relative median potency to determine whether the prophylactic infusion of norepinephrine requirement was different between the two groups.ResultsThe derived ED50 and ED90 of norepinephrine infusion combined with crystalloid coload were 0.030 (95% CIs 0.020 to 0.038) and 0.097 (95% CIs 0.072 to 0.157) µg/kg/min, respectively. The ED50 and ED90 of norepinephrine infusion combined with colloid coload were 0.021 (95% CIs 0.013 to 0.029) and 0.070 (95% CIs 0.053 to 0.107) µg/kg/min, respectively. The estimate of relative median potency for norepinephrine between the two groups was 1.37 (95% CIs 0.94 to 2.23).ConclusionUnder the conditions of this study, 10 mL/kg colloid coload reduced the dose of prophylactic norepinephrine infusion by approximately 30% in parturients during spinal anesthesia for cesarean delivery compared with the crystalloid coload.

Local lymph node assay: 5-bromo-d-deoxyuridine-ELISA method for comparative study in assessing chemical potencies and skin sensitization in BALB/c and CBA/J strains

Local lymph node assay (LLNA) is a predictive in vivo method to provide estimates of relative potency and to contribute to risk assessment/risk management regarding skin sensitizing potency of chemicals and formulations as a stand-alone alternative test. In addition, LLNA is relatively rapid and cost-effective compared to the Buehler method (Guinea pig test), and confers important animal welfare benefits. CBA/J and BALB/c strains are widely commercially available and have been evaluated by formal LLNA validation studies. However, the LLNA method using BrdU with ELISA, unlike other LLNA methods (OECD TG 429, 442 A, 442B), has not been previously validated. Therefore, in this study a validation method was performed to evaluate if the LLNA:BrdU-ELISA method could also be used to identify sensitizers among chemicals listed in OECD TG 429 using CBA/J and BALB/c strains. Here, we newly found that the LLNA:BrdU-ELISA validation method correctly identified 12 of 13 sensitizers in the BALB/c, 11 of 13 sensitizers in the CBA/J, and 3 of 5 non-sensitizers were identified in the two strains. Collectively, we found that the results of LLNA:BrdU-ELISA method provide a similar level of performance for accuracy and sensitivity in two mouse strains BALB/c and CBA/J.

Circadian Variation in the Median Effective Dose of Epidural Ropivacaine for Labor Analgesia.

Background: Labor pain perception has been demonstrated to exhibit a circadian rhythm with lower pain scores during the day compared with the night. This study aimed to determine and compare the median effective dose (ED50) of ropivacaine in parturients having epidural labor analgesia during the day vs. during the night.Methods: The study group consisted of 60 nulliparous healthy parturients who were assigned to one of two groups according to the time they requested labor analgesia: Day Group (7:01 am to 7:00 pm) and Night Group (7:01 pm to 7:00 am). A bolus of.15% ropivacaine was administered epidurally and effective analgesia was defined as the attainment of a visual analog scale (VAS) pain score ≤ 10 mm within 30 min. The dose of ropivacaine for the first parturient in each group was 18 mg. The dose for each subsequent parturient was varied with increments or decrements of 3 mg based on the response of the previous subject. The ED50 was calculated using up-down sequential analysis. Probit regression was used to estimate the relative mean potency of ropivacaine between groups.Results: The ED50 (mean [95% CI]) of ropivacaine was lower in the Day Group (17.9 [16.5–19.4] mg) than in the Night Group (20.9 [19.2–22.7] mg) (P = 0.003). The estimate of relative potency for ropivacaine for the Night Group vs. the Day Group was 0.85 (95% CI:0.56–0.98).Conclusions: Under the conditions of this study, the dose requirement for epidural ropivacaine for labor analgesia was ~ 15% greater during the night than during the day.Clinical Trials Registration: Chinese Clinical Trial Registry (No.: ChiCTR1900025269. http://www.chictr.org.cn/showprojen.aspx?proj=36993).

The First WHO International Standard for Harmonizing the Biological Activity of Bevacizumab.

Several Bevacizumab products are approved for clinical use, with many others in late-stage clinical development worldwide. To aid the harmonization of potency assessment across different Bevacizumab products, the first World Health Organization (WHO) International Standard (IS) for Bevacizumab has been developed. Two preparations of a Bevacizumab candidate and comparator were assessed for their ability to neutralize and bind vascular endothelial growth factor (VEGF) using different bioassays and binding assays in an international collaborative study. Relative potency estimates were similar across different assays for the comparator or the duplicate-coded candidate sample. Variability in relative potency estimates was reduced when the candidate standard was used for calculation compared with various in-house reference standards, enabling harmonization in bioactivity evaluations. The results demonstrated that the candidate standard is suitable to serve as an IS for Bevacizumab, with assigned unitages for VEGF neutralization and VEGF binding activity. This standard coded 18/210 was established by the WHO Expert Committee on Biological Standardization, which is intended to support the calibration of secondary standards for product development and lifecycle management. The availability of IS 18/210 will help facilitate the global harmonization of potency evaluation to ensure patient access to Bevacizumab products with consistent safety, quality and efficacy.

Relative potency of intravenous oxymorphone compared to other µ opioid agonists in humans - pilot study outcomes.

Intravenous (IV) misuse of the µ opioid analgesic oxymorphone has caused significant public health harms; however, no controlled data on its IV abuse potential are available. The primary aims of this pilot study were to directly compare IV oxymorphone to IV oxycodone, morphine, and hydromorphone on a subjective measure of drug liking and to assess relative potency. Participants (n = 6) with opioid use disorder, physical dependence, and current IV use completed this two-site, within-subject, double-blind, placebo-controlled, inpatient pilot study. During each session, one IV dose (mg/70kg) was administered: oxymorphone (1.8, 3.2, 5.6, 10, 18, 32), hydromorphone (1.8, 3.2, 5.6, 10, 18), oxycodone (18, 32, 56), morphine (18, 32), and placebo. Data were collected before and for 6h after dosing. Primary outcomes included safety/physiological effects, subjective reports of drug liking, and relative potency estimates. All active test drugs produced prototypical, dose-related µ opioid agonist effects (e.g., miosis). Oxymorphone was more potent than the comparator opioids on several measures, including drug liking and respiratory depression (p < 0.05). Across abuse-related subjective outcomes, oxymorphone was 2.3-2.8-fold more potent than hydromorphone and 12.5-14-fold more potent than oxycodone (p < 0.05). Despite the relatively small sample size, this pilot study detected robust oxymorphone effects. Oxymorphone was far more potent than the comparator opioids, particularly on abuse potential outcomes. Overall, these findings may help explain surveillance reports that demonstrate, after adjusting for prescription availability, oxymorphone is injected at the highest frequency, relative to other prescription opioids.

Linking Coregulated Gene Modules with Polycyclic Aromatic Hydrocarbon-Related Cancer Risk in the 3D Human Bronchial Epithelium.

Exposure to polycyclic aromatic hydrocarbons (PAHs) often occurs as complex chemical mixtures, which are linked to numerous adverse health outcomes in humans, with cancer as the greatest concern. The cancer risk associated with PAH exposures is commonly evaluated using the relative potency factor (RPF) approach, which estimates PAH mixture carcinogenic potential based on the sum of relative potency estimates of individual PAHs, compared to benzo[a]pyrene (BAP), a reference carcinogen. The present study evaluates molecular mechanisms related to PAH cancer risk through integration of transcriptomic and bioinformatic approaches in a 3D human bronchial epithelial cell model. Genes with significant differential expression from human bronchial epithelium exposed to PAHs were analyzed using a weighted gene coexpression network analysis (WGCNA) two-tiered approach: first to identify gene sets comodulated to RPF and second to link genes to a more comprehensive list of regulatory values, including inhalation-specific risk values. Over 3000 genes associated with processes of cell cycle regulation, inflammation, DNA damage, and cell adhesion processes were found to be comodulated with increasing RPF with pathways for cell cycle S phase and cytoskeleton actin identified as the most significantly enriched biological networks correlated to RPF. In addition, comodulated genes were linked to additional cancer-relevant risk values, including inhalation unit risks, oral cancer slope factors, and cancer hazard classifications from the World Health Organization's International Agency for Research on Cancer (IARC). These gene sets represent potential biomarkers that could be used to evaluate cancer risk associated with PAH mixtures. Among the values tested, RPF values and IARC categorizations shared the most similar responses in positively and negatively correlated gene modules. Together, we demonstrated a novel manner of integrating gene sets with chemical toxicity equivalence estimates through WGCNA to understand potential mechanisms.

Efficient experimental design for dose response modelling

The logit binomial logistic dose response model is commonly used in applied research to model binary outcomes as a function of the dose or concentration of a substance. This model is easily tailored to assess the relative potency of two substances. Consequently, in instances where two such dose response curves are parallel so one substance can be viewed as a dilution of the other, the degree of that dilution is captured in the relative potency model parameter. It is incumbent that experimental researchers working in fields including biomedicine, environmental science, toxicology and applied sciences choose efficient experimental designs to run their studies to both fit their dose response curves and to garner important information regarding drug or substance potency. This article provides far-reaching practical design strategies for dose response model fitting and estimation of relative potency using key illustrations. These results are subsequently extended here to handle situations where the assessment of parallelism and the proper dose-scale are also of interest. Conclusions and recommended strategies are supported by both theoretical and simulation results.

Statistical inferences on nonconstant relative potency with quantal response data.

Relative potency is widely used in toxicological and pharmacological studies to characterize potency of chemicals. The relative potency of a test chemical compared to a standard chemical is defined as the ratio of equally effective doses (standard divided by test). This classical concept relies on the assumption that the two chemicals are toxicologically similar-that is, they have parallel dose-response curves on log-dose scale-and thus have constant relative potency. Nevertheless, investigators are often faced with situations where the similarity assumption is deemed unreasonable, and hence the classical idea of constant relative potency fails to hold; in such cases, simply reporting a single constant value for relative potency can produce misleading conclusions. Relative potency functions, describing relative potency as a function of the mean response (or other quantities), is seen as a useful tool for handling nonconstant relative potency in the absence of similarity. Often, investigators are interested in assessing nonconstant relative potency at a finite set of some specific response levels for various regulatory concerns, rather than the entire relative potency function; this simultaneous assessment gives rise to multiplicity, which calls for efficient statistical inference procedures with multiplicity adjusted methods. In this paper, we discuss the estimation of relative potency at multiple response levels using the relative potency function, under the log-logistic dose-response model. We further propose and evaluate three approaches to calculating multiplicity-adjusted confidence limits as statistical inference procedures for assessing nonconstant relative potency. Monte Carlo simulations are conducted to evaluate the characteristics of the simultaneouslimits.

PFAS and cholesterol in epidemiological studies: causality, biomarkers, mixtures and relative potency

Concern continues about adverse effects, including raised cholesterol, associated with perfluorinated substances (PFAS) in general and perfluoro-octanoic acid (PFOA) in particular, and whether all associations are truly causal. There have been numerous epidemiological studies of blood concentrations (usually cross-sectional studies of serum concentrations) of PFOA and cholesterol. In addition to the usual sources of potential confounding, using serum PFOA as the exposure raises the possibility of confounding by physiology, for example, enterohepatic recirculation and correlated absorption of both PFAS and bile acids or cholesterol. Mechanistic toxicology studies of the pharmacodynamics of PFOA and cholesterol may shed light on the plausibility of these various causal and artefactual contributions to the associations, but the large and complex C8 dataset offers the possibility of assessing directly the strength of the epidemiological evidence in favour of this association being causal.District level measures of exposure offer a way of addressing exposure response immune from confounding by physiology, acting as instrumental variables for exposure. For 40,000 adults 18+ in the C8 study population, there was a strong and significant association of cholesterol, in relation to serum PFOA, adjusting for sex, age, race and other measured potential confounders. New results using the instrumental variable approach by water district contamination level showed a similar, significant dose response, and the concordance of the two approaches strongly supports a causal interpretation of the association. Comparison of slopes suggests that about half of the association with PFOA in single pollutant models is explained by confounding. A similar change in slope is achieved in cross sectional analyses by adding adjustment for other PFASs in the blood. Slopes for each PFAS in multi-pollutant models thus allow the estimation of relative potency which is helpful for risk assessment in populations with mixed PFAS exposure.

Comparative dose-response study of hyperbaric ropivacaine for spinal anesthesia for cesarean delivery in singleton versus twin pregnancies

Study objectiveIt is controversial whether local anesthetic dose requirement for spinal anesthesia for cesarean delivery differs between patients with singleton and patients with multiple gestation pregnancies. The aim of this study was to determine and compare the ED50 and ED90 for hyperbaric ropivacaine used for spinal anesthesia for cesarean delivery in patients with singleton pregnancies versus patients with twin pregnancies. DesignProspective, randomized, comparative dose-finding study. SettingOperating room, Women's Hospital, Zhejiang University School of Medicine. Patients100 patients with singleton pregnancies (Group S) and 100 patients with twin pregnancies (Group T) presenting for scheduled cesarean delivery under combined spinal-epidural anesthesia were enrolled in the study. InterventionsPatients in Group S or Group T were randomly allocated to receive 9.5, 11, 12.5, 14 or 15.5 mg of hyperbaric ropivacaine intrathecally. A dose was considered effective when it achieved a bilateral sensory block level at the T6 dermatome or above within 10 min after intrathecal injection, there was no numerical rating scale (NRS) pain score ≥ 3 intraoperatively, and there was no requirement for epidural supplementation at any time during anesthesia and operation. Values for ED50 and ED90 for ropivacaine were determined using probit regression. The difference in ropivacaine dose requirement between patients with singleton pregnancies and patients with twin pregnancies was assessed by calculating relative median potency. MeasurementsSuccess rates for different intrathecal doses of ropivacaine, side effects and neonatal outcomes were recorded. Main resultsThe estimated (95% confidence interval) values for ED50 and ED90 of intrathecal ropivacaine in patients with singleton pregnancies were 11.2 (10.2 to 12.0) mg and 15.7 (14.4 to 18.3) mg, respectively. The values for ED50 and ED90 in patients with twin pregnancies were 10.5 (9.5 to 11.3) mg and 14.8 mg (13.6 to 17.0) mg, respectively. The estimate of relative median potency for ropivacaine between patients with singleton and twin pregnancies was 0.94 (95% confidence interval 0.83 to 1.04). ConclusionPatients with singleton and twin pregnancies have similar dose requirement for hyperbaric ropivacaine used for spinal anesthesia for cesarean delivery in the setting of combined spinal-epidural (CSE) anesthesia, no opioids, low weight cohort, insertion with the patients in the right lateral position, and norepinephrine boluses.

Comparisons of outlier tests for potency bioassays.

Potency bioassays are used to measure biological activity. Consequently, potency is considered a critical quality attribute in manufacturing. Relative potency is measured by comparing the concentration-response curves of a manufactured test batch with that of a reference standard. If the curve shapes are deemed similar, the test batch is said to exhibit constant relative potency with the reference standard, a critical requirement for calibrating the potency of the final drug product. Outliers in bioassay potency data may result in the false acceptance/rejection of a bad/good sample and, if accepted, may yield a biased relative potency estimate. To avoid these issues, the USP<1032> recommends the screening of bioassay data for outliers prior to performing a relative potency analysis. In a recently published work, the effects of one or more outliers, outlier size, and outlier type on similarity testing and estimation of relative potency were thoroughly examined, confirming the USP<1032> outlier guidance. As a follow-up, several outlier detection methods, including those proposed by the USP<1010>, are evaluated and compared in this work through computer simulation. Two novel outlier detection methods are also proposed. The effects of outlier removal on similarity testing and estimation of relative potency were evaluated, resulting in recommendations for best practice.

A Prospective, Randomized, Double-Blinded Study of the Effect of Intravenous Ondansetron on the Effective Dose in 50% of Subjects of Prophylactic Phenylephrine Infusions for Preventing Spinal Anesthesia-Induced Hypotension During Cesarean Delivery.

Ondansetron has been shown to reduce the incidence of hypotension and vasopressor requirement during spinal anesthesia for obstetric and nonobstetric surgery. However, the magnitude of this effect has not been fully quantified. In this parallel-group, randomized, double-blinded study, we determined the effective dose in 50% of subjects (ED50) of a prophylactic phenylephrine infusion for preventing hypotension in patients who received a single dose of intravenous ondansetron 4 mg or saline control before combined spinal-epidural anesthesia for elective cesarean delivery. ED50 values obtained were compared to estimate the effect of ondansetron versus placebo on vasopressor requirement. Sixty parturients were randomly assigned to receive ondansetron (group O) or saline control (group C) 10 minutes before positioning for induction of spinal anesthesia. A prophylactic phenylephrine infusion was used to prevent hypotension. The first patient in each group received a phenylephrine infusion at the rate of 0.5 µg/kg/min. The infusion rate for each subsequent patient was varied with increments or decrements of 0.05 µg/kg/min based on the response of the previous patient, and the effective dose of the phenylephrine infusion for preventing hypotension in 50% of patients (ED50) was calculated for each group and compared using up-down sequential analysis. Probit regression was applied as a backup and sensitivity analysis was used to compare ED50 values for phenylephrine between groups by comparing calculated relative mean potency. The ED50 (mean [95% confidence interval (CI)]) of the rate of phenylephrine infusion was lower in group O (0.24 µg/kg/min [0.10-0.38 µg/kg/min]) compared with group C (0.32 µg/kg/min [0.14-0.47 µg/kg/min]) (P < .001). The total consumption of phenylephrine (mean ± standard deviation [SD]) until delivery was lower in group O (316.5 ± 25.9 µg) than in group C (387.7 ± 14.7 µg, P = .02). The estimate of relative median potency for phenylephrine for group O versus group C was 0.74 (95% CI, 0.37-0.95). Under the conditions of this study, intravenous ondansetron 4 mg reduced the ED50 of a prophylactic phenylephrine infusion by approximately 26% in patients undergoing cesarean delivery under combined spinal-epidural anesthesia.

Relative Effect Potency Estimates for Dioxin-Like Compounds in Pregnant Women with Gestational Diabetes Mellitus and Blood Glucose Outcomes Based on a Nested Case-control Study.

To improve the applicability of the toxic equivalents principle for human health risk assessment, systemic relative effect potencies (REPs) for dioxin-like compounds (DLCs) deriving from human in vivo data are required. A prospective nested case-control study was performed to determine REPs from the human serum concentration of DLCs using gestational diabetes mellitus (GDM) and fasting blood glucose (FBG) as the end points of concern. Serum concentration of 29 DLCs from 77 cases and 154 controls were measured. Logistic and linear regression were used to estimate the effects of individual congeners on GDM and FBG, respectively. The REPs based on GDM and FBG were calculated from the ratios of regression coefficients, βi(DLCs)/βTCDD. Two sets of consistent human serum-based REPs, that is, GDM-REP and FBG-REP, were established and largely agree with REPs from other human studies. These human-serum REPs show much smaller variation compared to the 4 to 5 orders of magnitude span in REPs database for the present WHO-TEF determination. Moreover, the established REPs fitted well with WHO-TEFs, especially for polychlorinated dibenzo- p-dioxins, furans. These REPs reflecting real human exposure scenarios exhibited validity and could be used to improve health risk assessment of human body burden of DLCs.

Evaluation of the Larvicidal Potential of the Leaf Extracts of Hyptis suaveolens Poit against Anopheles Mosquitoes

This study evaluated the larvicidal potential of the ethanolic and aqueous leaf extracts of Hyptis suaveolens Poit on the 4th larval instar of laboratory-reared Anopheles spp at varying concentrations of 0.1ml, 0.2ml, 0.3ml, 0.4ml and 0.5ml for specified periods of 24hrs, 48hrs and 72hrs. Qualitative phytochemical screening of the leaf extracts identified bioactive components like alkaloid, saponin, phenol, anthraquinone and flavonoid. The LC50 and LC90 values obtained indicate that the ethanolic leaf extracts of Hyptis suaveolens Poit had the greatest toxicity on the test organisms within 24hrs of exposure at median LC50 value of 0.485ml compared to the LC50 value of 0.625ml by its aqueous extract. The relative median potency estimates indicate that within 24 hrs, the ethanolic Hyptis suaveolens Poit was 0.161 times more potent on the test organism than aqueous Hyptis suaveolens Poit. The result of this research, therefore, underscores the efficacy of Hyptis suaveolens Poit as an eco-friendly alternative in Anopheles mosquito control. It is, therefore, recommended that quantitative phytochemical screening, application of column chromatography as well as thin layer chromatography be carried out on the extracts to isolate and purify toxic phytochemicals with larvicidal potentiality.

Effect of a statistical outlier in potency bioassays.

The USP<1032> guidelines recommend the screening of bioassay data for outliers prior to performing a relative potency (RP) analysis. The guidelines, however, do not offer advice on the size or type of outlier that should be removed prior to model fitting and calculation of RP. Computer simulation was used to investigate the consequences of ignoring the USP<1032> guidance to remove outliers. For biotherapeutics and vaccines, outliers in potency data may result in the false acceptance/rejection of a bad/good lot of drug product. Biological activity, measured through a potency bioassay, is considered a critical quality attribute in manufacturing. If the concentration-response potency curve of a test sample is deemed to be similar in shape to that of the reference standard, the curves are said to exhibit constant RP, an essential criterion for the interpretation of a RP. One or more outliers in the concentration-response data, however, may result in a failure to declare similarity or may yield a biased RP estimate. Concentration-response curves for test and reference were computer generated with constant RP from four-parameter logistic curves. Single outlier, multiple outlier, and whole-curve outlier scenarios were explored for their effects on the similarity testing and on the RP estimation. Though the simulations point to situations for which outlier removal is unnecessary, the results generally support the USP<1032> recommendation and illustrate the impact on the RP calculation when application of outlier removal procedures are discounted.

Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 - 10 States, July-December 2016.

Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from 3,105 in 2013 to approximately 20,000 in 2016 (1,2). Illicitly manufactured fentanyl, a synthetic opioid 50-100 times more potent than morphine, is primarily responsible for this rapid increase (3,4). In addition, fentanyl analogs such as acetylfentanyl, furanylfentanyl, and carfentanil are being detected increasingly in overdose deaths (5,6) and the illicit opioid drug supply (7). Carfentanil is estimated to be 10,000 times more potent than morphine (8). Estimates of the potency of acetylfentanyl and furanylfentanyl vary but suggest that they are less potent than fentanyl (9). Estimates of relative potency have some uncertainty because illicit fentanyl analog potency has not been evaluated in humans. This report describes opioid overdose deaths during July-December 2016 that tested positive for fentanyl, fentanyl analogs, or U-47700, an illicit synthetic opioid, in 10 states participating in CDC's Enhanced State Opioid Overdose Surveillance (ESOOS) program.* Fentanyl analogs are similar in chemical structure to fentanyl but not routinely detected because specialized toxicology testing is required. Fentanyl was detected in at least half of opioid overdose deaths in seven of 10 states, and 57% of fentanyl-involved deaths also tested positive for other illicit drugs, such as heroin. Fentanyl analogs were present in >10% of opioid overdose deaths in four states, with carfentanil, furanylfentanyl, and acetylfentanyl identified most frequently. Expanded surveillance for opioid overdoses, including testing for fentanyl and fentanyl analogs, assists in tracking the rapidly changing illicit opioid market and informing innovative interventions designed to reduce opioid overdose deaths.

Estimation of relative potency using parallel line analysis.

2種類の薬物の効力を比較する場合，平行線検定を用いて効力比を求めることがよく行われている．薬物間の効力比をその信頼区間とともに求めれば，その効果の違いを具体的な数値パラメータとして扱える上に，効力比の信頼区間が1を含まないならば，効果の有意な違いを統計学的に示すことができる．また，適当な同等性マージンを設定すれば2種の薬物の効力の同等性を示すこともできる．従来，平行線検定は直線をあてはめるものが主流であったが，近年ではシグモイド曲線を用いた非線形回帰分析での平行線検定が可能な統計解析ソフトウエアが利用可能で，シグモイド曲線にしたがうことが多い薬理学での利便性が高まった．一方，本手法の前提となる2つの用量反応直（曲）線の平行性に関しては，2つの直線の傾きの違いをみるF検定で有意差が無いことで検討してきたが，米国薬局方の生物学的アッセイ法の新しいガイドラインではそれに代わって，傾きの差や比の信頼区間を用いる方法が提唱されている．本稿ではこれらの新しい流れを紹介し，実地で活用する際の注意点に関して考察する．