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Normally, preslaughter acute heat stress could accelerate postmortem glycolysis and impair chicken breast (pectoralis major muscle) quality. However, previous studies indicated that it might be different when the acute heat stress temperature rises to an extreme range (above 35 °C). Therefore, this study’s objectives were to compare the pH decline, glycolytic enzyme activity, and AMP-activated protein kinase (AMPK) phosphorylation at early postmortem among three extreme acute heat stress temperature settings: a control group (36 °C) and two experimental groups (38 °C and 40 °C). Although the temperature did not affect glycogen phosphorylase a and pyruvate kinase activity, there was a decrease in pH decline rate, phosphofructokinase-1 activity, and phospho-AMPK-α[Thr172] within 4 h postmortem when temperature increased from 36 to 40 °C. Temperature also affected hexokinase activity, with the 36 °C-group having the highest activity. The results of the current study, for the first time, indicated that postmortem metabolic rate in chicken breast muscle could be changed by acute heat stress temperature setting at extreme range.

The paliperidone pharmacokinetics after intramuscular administration of once‐monthly paliperidone palmitate in Japanese patients were studied in 3 phase 1 studies and in 2 phase 3 studies performed in Japan, Korea, and Taiwan. These data (Japanese, n = 509; Korean, n = 31; Taiwanese, n = 47) were used to describe the paliperidone palmitate pharmacokinetics in Japanese, to compare with non‐Japanese, and to validate the historical population pharmacokinetic (Pop‐PK) model for paliperidone palmitate, developed using data from studies in patients with schizophrenia outside Japan. The final historical Pop‐PK model, including all significant patient covariates of Japanese studies, was used to simulate paliperidone plasma concentration–time data using nonlinear mixed effects, followed by comparison with actual data. Visual predictive checks displayed considerable overlap between predicted and actual plasma concentrations; the majority of observations were within the 90% prediction interval. Japanese, Korean, and Taiwanese patients had comparable plasma concentrations. Covariate distributions demonstrated comparatively lower median body mass index in Japanese, Korean, and Taiwanese patients versus rest‐of‐world population. Prediction errors for the data set used for external validation were within cutoff values, confirming accuracy/precision of the model. Paliperidone pharmacokinetics were adequately predicted for Japanese studies using the historical Pop‐PK model, confirming its robustness. Pharmacokinetics in Japanese, Korean, and Taiwanese patients with schizophrenia were comparable with rest‐of‐world population.

Background Pharmacokinetic-pharmacodynamic (PK/PD) models were developed to describe the relationship between the time course of paliperidone plasma concentrations and the risk of relapse of schizophrenia symptoms following administration of paliperidone palmitate 1-month (PP1M) and 3-month (PP3M) long-acting injectables, and to identify relevant covariates for relapse and dropout events. Methods Patient data from two global phase 3, relapse prevention studies comparing PP3M to placebo (study A) and PP3M to PP1M (study B) were analyzed. Dropout and relapse data were assessed using survival analysis as two separate single time-to-event models. Baseline covariates included age, sex, race/country, duration of illness, previous hospitalizations, prior use of long-acting injectables and use of multiple (≥2) antipsychotics at screening. Results The PK/PD analysis data set included 305 patients who were randomized to receive PP3M or placebo in the double-blind phase of study A and 1002 patients randomized to receive PP3M or PP1M in the double-blind phase of study B. Risk of relapse decreased with increasing paliperidone concentrations for both PP1M and PP3M, while it appeared to increase in patients with higher number of previous hospitalizations and/or with higher prerandomization (trough) paliperidone concentration (study A), and in patients on concomitant benzodiazepine medication and/or at Japan centers (study B). These findings are reflective of different illness severity in the population and of differences in medical practice for Japanese patients. In model-based simulations, PP3M and PP1M displayed similar relapse rates over time. Conclusions This PK/PD analysis confirmed that PP1M and PP3M provide comparable efficacy in terms of relapse prevention, and that PP3M is superior to placebo. The PK/PD models presented here may as well be applied to studies with similar designs as either study A or B.

Background The Fontan procedure is the final step of the 3-stage palliative procedure commonly performed in children with single ventricle physiology. Thrombosis remains an important complication in children after this procedure. To date, guideline recommendations for the type and duration of thromboprophylaxis after Fontan surgery are mainly based on extrapolation of knowledge gained from adults at risk for thrombosis in other clinical settings. Warfarin is being used off-label, and because of its multiple interactions with other drugs and food, a new alternative is highly desirable. Rivaroxaban, a direct Factor Xa inhibitor with a predictable pharmacokinetic profile, is a candidate to address this medical need. Study design The UNIVERSE study is a prospective, open-label, active-controlled, multicenter study in children 2 to 8 years of age who have single ventricle physiology and had the Fontan procedure within the 4 months preceding enrollment. This study consists of 2 parts. In Part A, rivaroxaban pharmacokinetics, pharmacodynamics, safety, and tolerability are assessed to validate the pediatric dosing selected. In Part B, safety and efficacy of rivaroxaban versus acetylsalicylic acid are evaluated for thromboprophylaxis in children post–Fontan procedure. Children in each part will receive study drug for 12 months. Part A has been completed with 12 children enrolled. Enrollment into Part B is currently ongoing. Conclusions The UNIVERSE study aims to provide dosing, pharmacokinetics/pharmacodynamics, safety, and efficacy information on the use of rivaroxaban, an oral anticoagulant, versus acetylsalicylic acid, an antiplatelet agent, in children with single ventricle physiology after the Fontan procedure.

Weight loss has been shown to improve metabolic parameters and cardiovascular risk in people with type 2 diabetes mellitus (T2DM). This phase 2 study evaluated the safety and efficacy of JNJ-64565111, a dual agonist of GLP-1 and glucagon receptors, in individuals with T2DM and class II/III obesity. In this randomized, double-blind study, participants with T2DM (HbA1c 6.5%-9.5%), body mass index of 35 to 50 kg/m2 and stable weight were randomly assigned (1:1:1:1) to placebo or JNJ-64565111 (5.0 mg, 7.4 mg or 10.0 mg). The primary endpoint was percent change from baseline in body weight at week 12. Of 195 dosed participants, 144 (73.8%) completed treatment. At week 12, placebo-subtracted body weight changes were -4.6%, -5.9% and -7.2% with JNJ-64565111 5.0 mg, 7.4 mg and 10.0 mg, respectively. All JNJ-64565111 doses were associated with no change in HbA1c and slight numerical elevation of fasting insulin. Numerical increases in fasting plasma glucose were observed with JNJ-64565111 5.0 mg and 7.4 mg. Incidence of treatment-emergent adverse events, especially nausea and vomiting, was higher with JNJ-64565111 vs placebo. Overall, JNJ-64565111 significantly reduced body weight in a dose-dependent manner vs placebo but was associated with greater incidence of treatment-emergent adverse events, no HbA1c reductions, and increased fasting plasma glucose and fasting insulin.

Pulmonary hypertension is a noninfectious disease of cattle at altitudes > 1524 m (5,000 ft). Mean pulmonary arterial pressures (mPAP) ≥ 50 mmHg is used as an indicator for pulmonary hypertension in cattle. Meat quality attribute, such as color, critically influencing consumer purchase decision, is economically significant. However, the effect of pulmonary arterial pressures (PAP) on postmortem beef color has not been investigated. To examine this, instrumental color, metmyoglobin reducing activity (MRA), and lipid oxidation of aged strip loins (longissimus lumborum; LL) steaks from high PAP (98±13; n = 5) and low PAP score (41±3; n = 6) fattened Angus steers (i.e., live weight of ~600 kg) were evaluated during simulated retail display (day 1, 3, 5, 7, 9). A split-plot design was used to analyze the effects of PAP score and display day on instrumental color, MRA, and lipid oxidation. Data analysis was performed using R with the lme4 package as a mixed model, where PAP score (high or low), display day, and their interactions were the fixed effects, and random effect was individual steer. Differences between least square means (P < 0.05) were determined by Tukey’s multiple comparisons. An interaction (P < 0.05) between PAP score and display day for redness (a* value), chroma, hue, and MRA was observed. The LL steaks from high PAP score animal had lower (P < 0.05) redness, chroma, and hue, than from low PAP score steer on day 9. A main effect (P < 0.05) of display day on lipid oxidation of was observed, with lipid oxidation increasing as display days increased. The results of current study indicated that the LL steaks from steers with high PAP score have lower color stability than those from steers with low PAP score during simulated retail display. Research partially supported by USDA-NIFA grant: 2018-67015-28241.

Individuals with obesity have a heightened risk of developing serious comorbidities, and pharmacological treatments for people with obesity are limited. This phase 2 study assessed the safety and efficacy of JNJ-64565111, a dual agonist of glucagon-like peptide-1 and glucagon receptors, in individuals with class II/III obesity without type 2 diabetes. In this randomized, double-blind, placebo-controlled and open-label active-controlled, parallel-group, multicentre study, participants aged 18 to 70 years with a body mass index of 35 to 50 kg/m2 and stable weight were randomly assigned in a 1:1:2:2:2 ratio to blinded treatment with placebo; JNJ-64565111 (5.0, 7.4 or 10.0 mg, each with no dose escalation), or open-label liraglutide 3.0 mg. The primary efficacy endpoint was percent change from baseline in body weight at week 26. Four-hundred seventy four participants were randomized and 343 (72.4%) completed treatment. At week 26, placebo-subtracted body weight changes (adjusted for multiplicity) were -6.8%, -8.1% and -10.0% for the JNJ-64565111 5.0 mg, 7.4 mg and 10.0 mg groups, respectively, and -5.8% for the liraglutide group. Incidence of treatment-emergent adverse events, especially nausea and vomiting, was higher in each JNJ-64565111 treatment group compared to placebo and liraglutide. JNJ-64565111 significantly reduced body weight in a dose-dependent manner vs placebo but was associated with greater incidence of treatment-emergent adverse events.

BACKGROUND In adult epilepsy patients, nonadherence to treatment regimes has been found to be associated with high morbidity, raised mortality and higher health care costs. The present study was undertaken with an aim to evaluate the medication compliance among patients undergoing treatment for epilepsy and study the factors affecting medication compliance. MATERIALS AND METHODS The present study was carried out as a cross sectional study among 100 patients diagnosed with seizure disorders who are already on treatment for a period of at least six months. Drug noncompliance was studied with the help a self-reported questionnaire which was derived from the Brief Medication Questionnaire. The items in the questionnaire recorded information regarding: awareness of drug therapy in terms of dose, timings and name of the drugs, missed medication, factors affecting compliance, aids to compliance, frequency of drug default and relapse. All data was entered in Epidata and statistical analysis was done using the software SPSS version 22.0. Chi square test was applied to test for statistical significance in difference between proportions. A p value

Introduction The objective of this study was to estimate longitudinal changes in disease progression (measured by Alzheimer's disease assessment scale-cognitive 11-item [ADAS-cog/11] scale) after bapineuzumab treatment and to identify covariates (demographics or baseline characteristics) contributing to the variability in disease progression rate and baseline disease status. Methods A population-based disease progression model was developed using pooled placebo and bapineuzumab data from two phase-3 studies in APOE e4 noncarrier and carrier Alzheimer's disease (AD) patients. Results A beta regression model with the Richard's function as the structural component best described ADAS-cog/11 disease progression for mild-to-moderate AD population. This analysis confirmed no effect of bapineuzumab exposure on ADAS-cog/11 progression rate, consistent with the lack of clinical efficacy observed in the statistical analysis of ADAS-cog/11 data in both studies. Assessment of covariates affecting baseline severity revealed that men had a 6% lower baseline ADAS-cog/11 score than women; patients who took two AD concomitant medications had a 19% higher (worse) baseline score; APOE e4 noncarriers had a 5% lower baseline score; and patients who had AD for a longer duration had a higher baseline score. Furthermore, shorter AD duration, younger age, APOE e4 carrier status, and use of two AD concomitant medications were associated with faster disease progression rates. Patients who had an ADAS-cog/11 score progression rate that was not statistically significantly different from 0 typically took no AD concomitant medications. Discussion The beta regression model is a sensible modeling approach to characterize cognitive decline in AD patients. The influence of bapineuzumab exposure on disease progression measured by ADAS-cog/11 was not significant. Trial Registration ClinicalTrials.gov identifier: NCT00575055 and NCT00574132 .

This multicenter, randomized, open-label, parallel-group, phase-1 study assessed the pharmacokinetics (PK), safety, and tolerability of the investigational intramuscular paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia or schizoaffective disorder. A total of 328 patients (men or women, aged 18-65 years) were enrolled in 1 of 4 separately conducted panels (A to D). Each panel had 2 single-dose treatment periods (period 1, 1 mg intramuscular paliperidone immediate release [IR]; period 2, intramuscular PP3M 75-525 mg eq) separated by a washout of 7-21 days. Overall, 245 of 308 (79.5%) PP3M-dosed patients completed the study. Because the PK studies of panels A and C were compromised by incomplete injection in some patients, PK data from only panels B and D are presented. Safety data from all panels are presented. Peak paliperidone plasma concentration was achieved between 23 and 34 days, and apparent half-life was ∼2-4 months. Mean plasma AUC∞ and Cmax of paliperidone appeared to be dose-proportional. Relative bioavailability in comparison with paliperidone was ∼100% independent of the dose and injection site. Headache and nasopharyngitis were the most common (>7%) treatment-emergent adverse events. Overall, safety and tolerability were similar to those of the 1-month formulation. Results support a once-every-3-months dosing interval in patients with schizophrenia or schizoaffective disorder.

Paliperidone palmitate 3-month formulation (PP3M), a long-acting injectable atypical antipsychotic, was recently approved in the US and Europe for the treatment of schizophrenia in adult patients who have already been treated with paliperidone palmitate 1-month formulation (PP1M) for ≥4 months. This article reviews the pharmacokinetic rationale for the approved dosing regimens for PP3M, dosing windows, management of missed doses and treatment discontinuation, switching to other formulations, and dosing in special populations. Approved PP3M dosing regimens are based on the comparisons of simulations with predefined dosing regimens using paliperidone palmitate and oral paliperidone extended release (ER) population pharmacokinetic models (one-compartment model with two saturable absorption processes for PP3M; one-compartment model with parallel zero- and first-order absorption for PP1M; two-compartment model with sequential zero- and first-order absorption for ER) versus clinical trial data. Covariates were obtained by resampling subject covariates from the pharmacokinetics database for PP1M and PP3M. Simulation scenarios with varying doses and covariate values were generated. The population median and 90% prediction interval of the simulated concentration-time profiles were plotted for simulation outcomes evaluation. Simulations described in this paper provide (a) simulated plasma exposures for switching from PP1M to PP3M, (b) support for a once-every-3-months injection cycle, (c) information on dosing windows and managing missed doses of PP3M, (d) important guidance on PP3M dosing in special patient populations, and (e) key PP3M pharmacokinetic exposure metrics based on the population pharmacokinetic PP3M model. Population pharmacokinetics provided practical guidance to establish dosing regimens for PP3M.

Meat color is the most important quality trait influencing consumer purchase decisions. The interinfluential interactions between myoglobin and biomolecules govern color stability in meat. The advances in proteomics, such as high throughput analytical tools in mass spectrometry, 2-dimensional electrophoresis, and bioinformatics, offer themselves as robust techniques to characterize the proteome basis of muscle- and species-specific meat color phenomena. Differential abundance of chaperones and antioxidant proteins contributes to muscle-specific color stability in beef; the greater abundance of chaperones and antioxidant proteins in color-stable Longissimus lumborum than in color-labile Psoas major protects myoglobin and contributes to superior color stability of beef Longissimus steaks. Lipid oxidation-induced myoglobin oxidation is more critical to beef color than pork color due to the inherent differences in myoglobin chemistry; the number of nucleophilic histidine residues adducted by reactive aldehydes is greater in beef myoglobin than in pork myoglobin. Preferential adduction of secondary products of lipid oxidation to beef myoglobin accelerates metmyoglobin formation at a greater degree than in its pork counterpart. Mass spectrometric investigations revealed that although cherry-red carboxymyoglobin is more stable than oxymyoglobin, both redox forms undergo lipid oxidation-induced oxidation in model systems. The accuracy of mass spectrometry to detect the molecular mass of proteins has been applied to differentiate myoglobins from closely related meat animals, such as goats and sheep or emu and ostrich. In addition, this approach indicated that turkey myoglobin is 350 Da greater in molecular mass than beef myoglobin, and the unique biochemistry of turkey myoglobin could be responsible for its greater thermostability in model systems as well as the pink color defect observed in fully cooked uncured turkey products.

Background: Manuscript authors of scientific journals are expected to report if their studies were conducted according to international and national ethical guidelines and inform readers regarding ethics approval and informed consent obtained from participants and/or their legally acceptable representative/s. In the present study we assessed the reporting practices of ethics approval and informed consent (assent in case of pediatric studies) in four Indian journals. Materials and Methods: Original research articles published over a period of 4 years (2009-2012) in four major national clinical journals, viz. Journal of Association of Physicians of India (JAPI), Indian Journal of Surgery (IJS), Journal of Obstetrics and Gynecology of India (JOGI), and Indian Journal of Orthopedics (IJO) were reviewed with regard to documentation of ethics approval and written informed consent and assent in case of pediatric participants. Results: We reviewed 673 research articles and found that, overall ethical approval was mentioned in 163 (24.2%) and informed consent or assent was mentioned in 179 (26.5%) articles in all four journals. Individually we found, in JAPI of the 174 manuscripts reviewed, 74 (42.5%) reported having obtained approval from the ethics committee and 68 (39.1%) reported taking written informed consent from participants. In IJS of 123 manuscripts, 18 (14.6%) reported ethics committee approval and 20 (16.2%) reported informed consent from participants. In JOGI of 152 manuscripts, 21 (13.8%) reported ethics committee approval while 49 (32.2%) reported informed consent from participants. In IJO, of 224 manuscripts, 50 (22.3%) reported ethics committee approval and 42 (18.7%) reported obtaining informed consent. Conclusion: Majority of the publications did not provide information regarding compliance to ethical guidelines in spite of the availability of various guidelines. Thus, there is a need for awareness and training on bioethics for authors, reviewers, and editors of biomedical journals.

Summary Somatic X dosage compensation requires two mechanisms: X inactivation balances X gene output between males (XY) and females (XX), while X upregulation, hypothesized by Ohno and documented in vivo, balances X gene with autosomal gene output. Whether X dosage compensation occurs in germ cells is unclear. We show that mouse and human germ cells exhibit non-canonical X dosage states that differ from the soma and between the sexes. Prior to genome-wide reprogramming, X upregulation is present, consistent with Ohno's hypothesis. Subsequently, however, it is erased. In females, erasure follows loss of X inactivation, causing X dosage excess. Conversely, in males, erasure leads to permanent X dosage decompensation. Sex chromosomally abnormal models exhibit a “sex-reversed” X dosage state: XX males, like XX females, develop X dosage excess, while XO females, like XY males, develop X dosage decompensation. Thus, germline X dosage compensation states are determined by X chromosome number, not phenotypic sex. These unexpected differences in X dosage compensation states between germline and soma offer unique perspectives on sex chromosome infertility., Highlights • X dosage compensation in germ cells is reset during GWR • PGCs exhibit X upregulation before GWR, in keeping with Ohno's hypothesis • X upregulation is lost during GWR • Mouse and human germ cells exhibit X dosage states that are sexually dimorphic, Germ cells reset their epigenome and transcriptome prior to meiosis. Sangrithi et al. show that unique X chromosome dosage compensation states prevail in germ cells. These states are determined by the number of X chromosomes present rather than phenotypic sex, providing a different perspective on infertility associated with sex chromosome aneuploidy.

Alzheimer’s disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

Background Bapineuzumab, an anti-amyloid monoclonal antibody, was evaluated as a candidate for immunotherapy in mild-to-moderate Alzheimer's disease (AD) patients. Objective To assess the treatment effect of bapineuzumab therapy on disease-relevant biomarkers in patients with mild-to-moderate AD, using exposure-response modeling. Methods Biomarker data from two Phase III studies were combined to model the impact of bapineuzumab exposure on week-71 change from baseline in brain amyloid burden by 11C-labeled Pittsburgh compound B (PiB) PET imaging (global cortical average of the Standardized Uptake Value ratio values), cerebrospinal fluid (CSF) phosphorylated (p)-tau concentrations, and brain volumetrics (brain boundary shift integral) by magnetic resonance imaging. Bapineuzumab or placebo was administered as a 1-hour intravenous infusion every 13 weeks for 78 weeks. Pharmacokinetic/pharmacodynamic modeling helped determine the most appropriate exposure-response model and estimate the impact of disease-relevant covariates (baseline biomarker value, APOE*E4 allele copy number, and baseline disease status as measured by Mini-Mental State Examination score) on the three biomarkers. Results Linear exposure-response relationships with negative and significant slope terms were observed for PiB PET and CSF p-tau concentration. Baseline biomarker value and APOE*E4 carrier status were significant covariates for both biomarkers. No exposure-response relationship on brain boundary shift integral was detected. Conclusions Bapineuzumab treatment induced exposure-dependent reductions in brain amyloid burden. Effects on CSF p-tau concentrations were significant only in APOE*E4 carriers. No apparent influence of bapineuzumab exposure on brain volume could be demonstrated.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Amnestic mild cognitive impairment MCI) represents the prodromal stage of Alzheimer's dementia and this disease progresses in a non-linear fashion. • Disease progression depends on a variety of demographic, biochemical, genetic and cognitive factors. WHAT THIS STUDY ADDS • Baseline CSF biomarkers carry information about disease pathology and critical thresholds for these markers (Aβ and p-tau181P) have been identified that allow segregation of the population into MCI progressers and non-progressers. AIM The objective is to develop a semi-mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS-cog scores from the Alzheimer's disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for 3 years. METHOD Various covariates were tested on disease progression parameters and these variables fell into six categories: imaging volumetrics, biochemical, genetic, demographic, cognitive tests and CSF biomarkers. RESULTS CSF biomarkers were associated with both baseline disease score and disease progression rate in subjects with MCI. Baseline disease score was also correlated with atrophy measured using hippocampal volume. Progression rate was also predicted by executive functioning as measured by the Trail B-test. CONCLUSION CSF biomarkers have the ability to discriminate MCI subjects into sub-populations that exhibit markedly different rates of disease progression on the ADAS-cog scale. These biomarkers can therefore be utilized for designing clinical trials enriched with subjects that carry the underlying disease pathology.

One of the challenges in developing a viable therapy for Alzheimer's disease has been demonstrating efficacy within a clinical trial. Using this as motivation, we sought to re-examine conventional clinical trial practices in order to determine whether efficacy can be better shown through alternative trial designs and novel analysis methods. In this work, we hypothesize that the confounding factors which hamper the ability to discern a treatment signal are the variability in observations as well as the insidious nature of the disease. We demonstrate that a two-phase trial design in which drug dosing is administered after a certain level of disease severity has been reached, coupled with a method to account more accurately for the progression of the disease, may allow us to compensate for these factors, and thus enable us to make treatment effects more apparent. Utilizing data from two previously failed trials which involved the evaluation of galantamine for indication in mild cognitive impairment, we were able to demonstrate that a clear treatment effect can be realized through both visual and statistical means, and propose that future trials may be more likely to show success if similar methods are utilized.

Background: Inappropriate and indiscriminate use of fixed-dose drug combinations (FDCs) may lead to increased cost, unnecessary exposure to drugs, and adverse drug reactions. Government of India had issued a ban notification on manufacturing and sale of few FDCs which involved human risk and no therapeutic justification for their use. Despite the stringent steps from the health-care authorities, such FDCs are available in the market and are being prescribed extensively without considering the appropriate alternative in the form of a single drug formulation. Aims and Objective: This study was planned to find out the number FDCs prescribed by clinicians and find out the rationality with respect to the indication. Materials and Methods: Prescriptions of patients attending hospital pharmacy and indoor papers of patients admitted in the wards were screened for the presence of FDCs for a period of 6 months. A total of 3500 prescriptions were screened, and collected data were analyzed using descriptive statistics. Results: Out of 3500 prescriptions screened, 1000 (28.5%) had FDCs prescribed in it. Out of 1000 FDCs, 151 (15.1%) were prescribed by generic names and 849 (84.9%) were prescribed by brand names. A total of 596 (59.6%) FDCs were prescribed for infectious diseases followed by 195 (19.5%) FDCs prescribed for pain and inflammatory disorders and 169 (16.9%) FDCs were prescribed for diseases affecting the respiratory system. Out of 1000 FDCs, 818 (81.8%) were rational and 182 (18.2%) were irrational. Conclusion: The study revealed that the majority of prescriptions had rational FDCs prescribed by the treating doctors reflecting rational use of FDCs in our patients.

Background: The present study was undertaken to evaluate the incidence and pattern of adverse drug reaction (ADRs), causality, severity and preventability of ADRs.Methods: Data was collected and analyzed with the information such as patients’ demographic details, associated co-morbid conditions and detailed drug related information gathered from ADR reporting forms. World Health Organization (WHO) scale was used for assessing causality, modified Hartwig scale was used for assessing severity and modified Schumock and Thorntons scale were used for assessing preventability of ADRs. Data was analyzed using descriptive statistics.Results: Total 154 ADRs were reported in a period of one year (August 2016- July 2017). Out of 154 ADRs analyzed, 120 (77.9%) were in adults, 33 (21.4%) pediatric and 01 (0.7%) in geriatric patients. The most common ADR recorded was cutaneous reactions (43.5%) and the most common causative class of drugs for the same was found to be antimicrobials (46.7%) followed by non-steroidal anti-inflammatory drugs (15.6%). Causality assessment scale indicated 68.8% ADRs possible and 24% ADRs as probable. Severity assessment revealed that 45.5 % were mild, 50.6% moderate and 3.9% ADRs severe. Preventability assessment showed 84.4% of the cases were probably non-preventable.Conclusions: In this study it was found that, most of the ADRs were of possible category with mild to moderate severity and majority being non-preventable. Antimicrobial drugs being the most common offending drug class causing ADRs. Strategies targeting appropriate and cautious use of this class of drugs may benefit in reducing the number of ADRs and therefore the cost involved in the treatment.

Background: Coronary artery disease (CAD) is a major cause responsible for mortality more in younger age group than in elderly. Studies have reported underuse of four evidence based medicines namely aspirin, β-blockers, angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB), and statins in patients with CAD, particularly in developing countries. Therefore, this study was planned to analyse the prescriptions of patients with CAD to determine the appropriateness of the prescriptions.Methods: After obtaining the Institutional ethics committee permission, a cross sectional observational study was conducted at a tertiary care hospital. Total 150 patients were enrolled from the outpatient department, wards and intensive care unit of medicine department. Total 150 patients’ prescriptions presenting with varied category of CAD were screened and analysed.Results: The most common categories of CAD encountered was ST segment elevated myocardial infarction (N=50, 33%) followed by chronic stable angina (N=29, 20%). Among the drugs prescribed, antiplatelet drugs were prescribed to 135 (90%), hypolipidemics to 134 (89%), nitrates to 114 (76%), beta blockers to 97 (65%), ACE inhibitors to 94 (64%), anticoagulants to 60 (40%) and miscellaneous drugs to 52 (35%), patients. Of 68 (45%) patients with type 2 diabetes mellitus, 15 (22%) were prescribed only metoprolol and others were given ACE-I or ARBs.Conclusions: Among four evidence based drugs, use of 3 drugs, antiplatelets, beta blockers and hypolipidemics was apparent in 90% of prescriptions. Use of ACE inhibitors and ARBs was observed in type 2 diabetic patients with CAD, reflecting rational prescribing behavior of clinicians.

A population pharmacokinetic model of doripenem was constructed using data pooled from phase 1, 2, and 3 studies utilizing nonlinear mixed effects modeling. A 2-compartment model with zero-order input and first-order elimination best described the log-transformed concentration-versus-time profile of doripenem. The model was parameterized in terms of total clearance (CL), central volume of distribution ( V c ), peripheral volume of distribution ( V p ), and distribution clearance between the central and peripheral compartments ( Q ). The final model was described by the following equations (for j th subject): CL j (liters/h) = 13.6·(CL CR j /98 ml/min) 0.659 ·(1 + CL race j [0 for Caucasian]); V c j (liters) = 11.6·(weight j /73 kg) 0.596 ; Q j (liters/h) = 4.74·(weight j /73) 1.06 ; and V p j (liters) = 6.04·(CL CR j /98 ml/min) 0.417 ·(weight j /73 kg) 0.840 ·(age j /40 years) 0.307 . According to the final model, population mean parameter estimates and interindividual variability (percent coefficient of variation [% CV]) for CL (liters/h), V c (liters), V p (liters), and Q (liters/h) were 13.6 (19%), 11.6 (19%), 6.0 (25%), and 4.7 (42%), respectively. Residual variability, estimated using three separate additive residual error models, was 0.17 standard deviation (SD), 0.55 SD, and 0.92 SD for phase 1, 2, and 3 data, respectively. Creatinine clearance was the most significant predictor of doripenem clearance. Mean Bayesian clearance was approximately 33%, 55%, and 76% lower for individuals with mild, moderate, or severe renal impairment, respectively, than for those with normal renal function. The population pharmacokinetic model based on healthy volunteer data and patient data informs us of doripenem disposition in a more general population as well as of the important measurable intrinsic and extrinsic factors that significantly influence interindividual pharmacokinetic differences.

Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin (meticillin)-resistant staphylococci, was statistically noninferior to a combination of vancomycin plus ceftazidime in patients with complicated skin and skin structure infections (cSSSI). This analysis used data from this clinical trial to determine the relationship between therapeutic outcome and the percentage of time that the unbound ceftobiprole concentration exceeds the MIC (percent T>MIC). From the trial of ceftobiprole (500 mg every 8 h, 2-h infusion) for cSSSI due to gram-positive and/or gram-negative bacteria, data from 309 patients in the microbiological intent-to-treat analysis set with measured ceftobiprole concentrations and baseline MICs were used to assess the relationship between percent T>MIC and therapeutic outcome. Individual pharmacokinetic (PK) profiles were obtained from a three-compartment population PK model. The relationship between percent T>MIC and a clinical cure was determined. For the clinical trial dosing regimen, individual percent T>MICs were used to calculate fractional target attainment rates (TARs) for ≥30 and ≥50% T>MIC targets at various MICs. There was a statistically significant relationship between achieving a ≥30 or ≥50% T>MIC and a clinical cure ( P = 0.003 and P = 0.007, respectively; Pearson's χ 2 test). The fractional TAR was greater than 90% at a MIC of ≤4 mg/liter for patients with normal renal function. A relationship between percent T>MIC and a clinical cure with ceftobiprole was demonstrated. A ceftobiprole regimen of 500 mg every 8 h as a 2-h infusion has a high probability of achieving a target of ≥30 or ≥50% T>MIC for patients with cSSSI due to gram-positive and gram-negative pathogens.

Administration of synthetic glucocorticoids to women in premature labor has a clearly proven clinical benefit in decreasing the incidence of respiratory distress syndrome and intraventricular hemorrhage in the offspring if they are born prematurely.1 On the other hand, this treatment exposes the fetus to glucocorticoid concentrations higher than those that would normally be present in fetal blood at that stage of development. Fetal exposure at critical developmental stages to glucocorticoid concentrations that are inappropriate for that stage has been shown to have acute adverse effects on the central nervous2–6 and cardiovascular systems in the fetal sheep and baboon.7–11 In the cardiovascular system of sheep and nonhuman primates, synthetic glucocorticoids increase peripheral7–9,11 and cerebral vascular resistance,10 leading to increased mean fetal arterial blood pressure and decreased cerebral blood flow. Although the increased blood pressure may have harmful effects, the increase of cerebral vascular resistance may protect the brain from postasphyxic blood pressure peaks and intraventricular hemorrhage (Schwab M, Muller T, Loehle M, Coksaygan T, Antonow-Schlorke I, Wood CE, et al. Glucocorticoid induced maturation of cerebral autoregulation may explain the decreased incidence of intraventricular hemorrhage and increased risk of periventricular leukomalacia [abstract]. J Soc Gynecol Investig 2004;11 suppl: 355). Although it has been shown in sheep that repeated treatments may be of benefit for the lung,12 to our knowledge there has never been a study designed to examine a broad range of doses at the clinical level to determine the dose of maternal glucocorticoid that is optimal for the effects on the fetus in rodents, sheep, nonhuman primates or humans (PubMed, January 1966–January 2006; no language restrictions; search terms: antenatal or prenatal; glucocorticoids, steroids or betamethasone; dose or pharmacokinetics; lung or blood pressure). Recommendations1 for dose and timing of treatments are mainly based on the study of Liggins and Howie13 who chose the dose for clinical trials partly from the doses used in experiments with sheep. Retrospective data collected on mothers who received only a partial course of steroids, however, suggests that any exposure to an appropriate corticosteroid has beneficial effects on postnatal outcome.14 The present study was designed to estimate the time course of maternal and fetal betamethasone concentrations after maternal exposure to two doses and two different betamethasone preparations frequently used clinically in women in premature labor. Secondly, we evaluated the fetal arterial blood pressure responses to the different betamethasone doses and preparations as an index of cardiovascular adverse effects. Fetal arterial blood pressure changes in their time course are a sensitive measure of the biological activity of glucocorticoids.7–11 We hypothesized that the clinical doses of betamethasone produce supramaximal effects on the fetal cardiovascular system as an indicator that the doses used clinically may also need evaluation in relation to lung maturation.

Maternal administration of betamethasone to enhance fetal lung maturation for women who threaten preterm labor is common clinical practice. However, recommendations regarding the choice of betamethasone formulations for perinatal use are vague. The disposition of betamethasone from two commonly used antenatal formulations is poorly understood. We therefore designed a study to capture the true pharmacokinetic profiles of betamethasone from these fast acting and dual-release formulations. Betamethasone in sheep plasma was measured by a newly designed, highly sensitive liquid chromatography/tandem mass spectrometry assay after intramuscular injection (n = 4) of 0.25 mg/kg betamethasone phosphate and 0.5 mg/kg betamethasone phosphate/acetate formulations. Compartmental modeling was performed using the ADAPT II program. Betamethasone pharmacokinetics could be captured for 24 h for the phosphate and for 5 days for the phosphate/acetate formulations. The phosphate formulation profile had the appearance of a traditional Bateman function with a terminal half-life of 4 h, whereas the phosphate/acetate formulation produced a biexponential decline with a terminal half-life of 14 h. The latter is much longer than is commonly reported and has been missed in the literature due to assay limitations. Extrapolations to humans indicate that although both formulations might have similar therapeutic indices, the dual formulation might be associated with a lower safety profile. In light of this newly identified long terminal half-life for the betamethasone dual formulation, dosing practices for betamethasone in pregnancy need to be reassessed.

The pharmacokinetics of corticosteroids in pregnancy were analyzed to assess maternal/fetal disposition and factors controlling fetal exposure. Area/Moment equations and compartmental models for estimating pharmacokinetic parameters from single dose data during pregnancy were developed.Betamethasone in the maternal/fetal circulations of sheep was measured by HPLC after maternal intramuscular injection (n = 4) of 170 microg kg(-1) of a depot formulation. Additional data for beta-methasone in sheep and dexamethasone pharmacokinetics in rats were obtained from the literature. Area/Moment equations were derived using mass balance concepts, statistical moments, and Laplace theory. Area/Moment analysis, compartmental modeling, and allometric scaling to man for betamethasone were performed using WinNonlin and ADAPT II programs.Polyexponential maternal/fetal profiles for corticosteroids were observed. Clearance terms for corticosteroid transfer from fetus to mother were 4-fold higher than the clearance term for transfer in the opposite direction. A placental efflux process may restrict fetal access of corticosteroids which are known PGP substrates. The elimination clearance estimates indicate that fetal metabolism plays a minor role in corticosteroid elimination.Generalized and specific models for maternal/fetal pharmacokinetics were developed. An efflux transport mechanism, such as the known placental expression of PGP, could explain the limited fetal exposure of corticosteroids.

Background: Respiratory disorders are the most frequent cause of admission for neonatal intensive care in both term and preterm infants. The clinical diagnosis of respiratory distress in a newborn is suspected if the respiratory rate is greater than 60 per minute in a quite resting baby, presence of grunting and/or there are inspiratory subcostal/intracostal retractions Signs and symptoms of respiratory distress include cyanosis, grunting, nasal flaring, retractions, tachypnea, decreased breath sounds with or without rales and/or rhonchi, and pallor. Objectives of present study were to know the clinical profile and aetiology of neonates with respiratory distress and to study the morbidity and mortality of respiratory distress in neonatal intensive care unit (NICU). And to find out the predictors of survival in the neonates admitted with respiratory distress.Methods: Study is done on 281 neonates admitted in Neonatal Intensive Care Unit (NICU) as a Prospective Cohort and Descriptive Study and Simple Random sampling is used to include neonates in the study. All the neonates included in study were subjected to the following detailed perinatal history and thorough clinical examination of newborns was done.Results: Males outnumber the females in admission. Most of the affected neonates were weighing between 1500g to 2500g (185). Out of total patients of two hundred and eighty-one, there were 35 deaths (12.5%) and 246 patients survived (87.5%). In present study most common causes for respiratory distress were respiratory distress syndrome (31.3%), neonatal septicaemia including pneumonia (28.1%), TTBN (16.7%).Conclusions: The overall survival rate was 87.5%. Male outnumber female on admissions but the survival in females was better than males. Common causes of respiratory distress in our study are RDS, Neonatal septicaemia and TTBN. As the gestation increased the survival also improved. Term neonates had better survival as compared to preterm neonates. Antenatal corticosteroid administration improved the survival.

Background: In the year 2016, Government of India had banned 350 fixed dose combinations (FDCs) for the safety and efficacy purpose. The present study was conducted to assess the knowledge, attitude and practices of the clinicians and residents about the use of FDCs at a tertiary care hospital.Methods: A questionnaire based study was conducted at a tertiary care hospital after getting approval from institutional ethics committee. A pre-validated questionnaire comprising of 30 items was distributed to 100 participants. The questionnaire focused on the prescribing behaviour, knowledge on therapeutic efficacy, advantages and limitations of FDC use, clinician perception regarding FDC use and the strategies to improve the awareness about the regulatory updates of the marketed drugs.Results: Total 52/100 clinicians responded. Out of these, 88% prescribed FDCs in their practice, 62% prescribed FDCs only after ensuring therapeutic efficacy and 50% prescribed WHO approved FDCs. 64% were aware of the recent ban on some FDCs by DCGI. Internet was the most common source of latest updates on the regulatory status of the drug, as stated by 55% clinicians. All clinicians agreed that efforts are needed to ensure that prescribers remain up to date about the post-marketing regulatory status of the drugs.Conclusions: Even though many clinicians prescribe FDCs regularly, they appreciated the step of banning some FDCs; however, the clinicians need to be trained to update themselves regularly. The source and relevance of these updates should be taught to the undergraduate students during their training period which can be reemphasized during post graduate training period.

Background The objective of this analysis was to develop a nonlinear disease progression model, using an expanded set of covariates that captures the longitudinal Clinical Dementia Rating Scale–Sum of Boxes (CDR–SB) scores. These were derived from the Alzheimer’s Disease Neuroimaging Initiative ADNI-1 study, of 301 Alzheimer’s disease and mild cognitive impairment patients who were followed for 2–3 years. Methods The model describes progression rate and baseline disease score as a function of covariates. The covariates that were tested fell into five groups: a) hippocampal volume; b) serum and cerebrospinal fluid (CSF) biomarkers; c) demographics and apolipoprotein Epsilon 4 (ApoE4) allele status; d) baseline cognitive tests; and e) disease state and comedications. Results Covariates associated with baseline disease severity were disease state, hippocampal volume, and comedication use. Disease progression rate was influenced by baseline CSF biomarkers, Trail-Making Test part A score, delayed logical memory test score, and current level of impairment as measured by CDR–SB. The rate of disease progression was dependent on disease severity, with intermediate scores around the inflection point score of 10 exhibiting high disease progression rate. The CDR–SB disease progression rate in a typical patient, with late mild cognitive impairment and mild Alzheimer’s disease, was estimated to be approximately 0.5 and 1.4 points/year, respectively. Conclusions In conclusion, this model describes disease progression in terms of CDR–SB changes in patients and its dependency on novel covariates. The CSF biomarkers included in the model discriminate mild cognitive impairment subjects as progressors and nonprogressors. Therefore, the model may be utilized for optimizing study designs, through patient population enrichment and clinical trial simulations., Video abstract

To the Editor : A 6-mo-old girl presented with swelling of the left eye with discharge, fever, irritability and excessive cry of 8 d duration. There was no h/o of trauma, features suggestive of viral exanthamatous illness or upper respiratory tract infection (URTI) symptoms. Child was completely immunised with DPT vaccination as per national immunization schedule. On examination, child was febrile, irritable with excessive sweating, tachycardia, tachypnea, and SpO2 – 96 % at room air. On local ocular examination there was whitish membrane in left lower bulbar conjunctival sac with erythema and swelling of left eyelids (Fig. 1). The oral cavity did not reveal any patch over the tonsils. Systemic examination including cardiovascular, respiratory, abdominal and central nervous system were within normal limits. The investigations, complete blood count (CBC), random blood sugar (RBS), creatine phosphokinase-myocardium (CPK-MB), chest X-ray (CXR), two dimensional echocardiogram (2D ECHO) were within normal limits. The ocular swab test using Gram stain and Albert stain revealed Gram positive bacilli with colony resembling corynebacterium morphology, however culture did not grow any organism. Child was given crystalline penicillin and antidiphtheritic serum. During treatment on 4th day, child developed similar findings in the right eye. She was given 10 d of antibiotics and a total of 1 lakh units of antidiphtheritic serum (ADS); the repeat swab from conjunctiva after 10th day did not reveal Corynebacterium diphtheriae. Child is on follow up for last 4 mo without any complication. The index child, despite immunization, had membranous conjunctivitis without involvement of pharyngeal sites which is very unusual. Possible reason could be due to improper storage/ carriage or inadequate dose of the DPT vaccine [1, 2]. The other reason may due to droplet or fomite transmission from chronic adult carriers in the surroundings [3].

Free fatty acids (FFA) play essential roles in maintaining physiologic homeostasis in the newborn infant. Most of the FFA in serum is carried in complex with albumin, but a small fraction remains unbound in the aqueous phase.This study's goal is to report the values of serum levels of unbound free fatty acids (FFAu) in pregnant women and their newborn infants at term gestation.The measurements were made possible by the availability of the fluorescent probe for unbound FFA, acrylodated intestinal fatty acid binding protein (ADIFAB). Twenty-two mother-infant pairs were enrolled in the study. Maternal levels were obtained immediately before delivery, cord levels at the time of delivery, and infant levels after 24 hours of age.The level of FFAu measured in maternal samples was 11.8 +/- 4 nM, in cord samples 9.2 +/- 4 nM, and in infants 13.9 +/- 3 nM. These population averages are considerably greater than those observed in healthy adults (7.5 +/- 2.5 nM). No correlation was found between cord levels and birthweight, gestational age, labor duration, mode of deliver, and infant or maternal temperature.This investigation is the first to measure FFAu in a group of mothers and their infants and provides the technique for future investigations of the biologic activity of free fatty acids.

Background The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) has been used widely as a cognitive end point in Alzheimer's Disease (AD) clinical trials. Efforts to treat AD pathology at earlier stages have also used ADAS-Cog, but failure in these trials can be difficult to interpret because the scale has well-known ceiling effects that limit its use in mild cognitive impairment (MCI) and early AD. A wealth of data exists in ADAS-Cog from both historical trials and contemporary longitudinal natural history studies that can provide insights about parts of the scale that may be better suited for MCI and early AD trials. Methods Using Alzheimer's Disease Neuroimaging Initiative study data, we identified the most informative cognitive measures from the ADAS-Cog and other available scales. We used cross-sectional analyses to characterize trajectories of ADAS-Cog and its individual subscales, as well as other cognitive, functional, or global measures across disease stages. Informative measures were identified based on standardized mean of 2-year change from baseline and were combined into novel composite endpoints. We assessed performance of the novel endpoints based on sample size requirements for a 2-year clinical trial. A bootstrap validation procedure was also undertaken to assess the reproducibility of the standardized mean changes of the selected measures and the corresponding composites. Results All proposed novel endpoints have improved standardized mean changes and thus improved statistical power compared with the ADAS-Cog 11. Further improvements were achieved by using cognitive–functional composites. Combining the novel composites with an enrichment strategy based on cerebral spinal fluid beta-amyloid (Aβ 1-42 ) in a 2-year trial yielded gains in power of 20% to 40% over ADAS-Cog 11, regardless of the novel measure considered. Conclusion An empirical, data-driven approach with e xisting instruments was used to derive novel composite scales based on ADAS-Cog 11 with improved performance characteristics for MCI and early AD clinical trials. Together with patient enrichment based on Aβ 1-42 pathology, these modified endpoints may allow more efficient clinical trials in these populations and can be assessed without modifying current test administration procedures in ongoing trials.

Background There are no previous reports of paliperidone palmitate's (PP) long term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period. Methods In this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scale's total score ≤ 70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B. Results Of the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent (≥ 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients' psychoses remained stable. Conclusions Safety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range. Trial registration no ClinicalTrials.gov: NCT01150448

Sodium valproate is a well-established treatment in epilepsy and mood disorders. Its utility is compromised by its adverse effects such as tremor, weight gain, hair loss, and liver dysfunction. Hair loss may occur when drug is used in higher dose. Drug-induced hair loss is diffused and non-scarring, which is reversible upon withdrawal. But there are no case reports showing relation between serum levels of valproate and occurrence of hair loss. So we took interest in reporting this case report.

Doripenem dosing regimens for patients receiving continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF) were devised based on an established efficacy criterion (free plasma doripenem concentrations above the minimum inhibitory concentration [] of 1 mg/L for ≥35% of the dosing interval) while maintaining exposure below that with the highest studied dose of 1000 mg infused over 1 hour every 8 hours in healthy subjects. Simulations were utilized to assure ≥90% probability of achieving the efficacy criterion with the recommended doripenem regimens. Inflated intersubject variability of 40% (coefficient of variation) was used for pharmacokinetic parameters (representative of clinical variation) and nonrenal clearance was doubled to account for potential changes with acute renal insufficiency. Results indicate that a reduction in doripenem dose will be needed for critically ill patients receiving CVVH or CVVHDF. This work was conducted to fulfill a health authority request and resulted in the addition of dosing recommendations to the Doribax Summary of Product Characteristics.

The objectives were to develop a translational model that will help select doses for Phase-3 trials based on abbreviated Phase-2 trials and understand the competitive landscape for oral anti-diabetics based on efficacy, tolerability and ability to slow disease progression. Data for eight anti-diabetics with temporal profiles for fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) from 12 publications were digitized. The monotherapy data consisted of FPG and HbA1c profiles that were modeled using a transit compartment model. Evaluation of the competitive landscape utilized HbA1c literature data for 11 drugs. For the safety metric, tolerability issues with anti-diabetic drug classes were tabulated. For disease progression, the coefficient of failure method was used for assessing data from two long-term trials. The transit rate constants were remarkably consistent across 12 trials and represent system-specific/drug-independent parameters. The competitive landscape analysis showed that the primary efficacy metric fell into two groups of DeltaHbA1c: >0.8% or approximately 0.8%. On the safety endpoints, older agents showed some tolerability issues while the new agents were relatively safe. Among the different drug classes, only the thiazolidinediones appeared to slow disease progression but may also increase heart failure risk. In conclusion, the ability of system-specific parameters to predict HbA1c provides a tool to predict the expected efficacy profile from abbreviated dose-finding trials. To be commercially viable, new drugs should improve DeltaHbA1c by about 0.8% or more and possess safety profiles similar to newer anti-diabetic agents. Thus, this study proposes a suite of simple yet powerful tools to guide type-2-diabetes drug development.

Preterm birth produces neonatal respiratory distress syndrome, and dexamethasone (DEX) is administered maternally to induce fetal lung maturation in women at risk of preterm delivery. Antenatal DEX therapy is largely empirical, and administering multiple doses of DEX produces undesirable metabolic and developmental effects in the fetus. It is hypothesized that pharmacokinetic/pharmacodynamic (PK/PD) assessment of the maternal/fetal disposition and selected effects of corticosteroids will allow insight into optimal dosing methods. An optimal regimen was defined as a dosing schedule that would reproduce the endogenous prenatal steroid exposure and up-regulation of fetal lung maturational markers precociously. This report focuses on designing such a regimen from a PK standpoint in rats. The temporal profile of endogenous corticosterone in control rats was captured using a radioimmunoassay and showed that maternal and fetal corticosterone increased significantly during the last days of gestation. Six 1-mumol kg(-1) intramuscular DEX doses separated by 12-h intervals were administered maternally starting at gestational age 18, and PK was captured using a liquid chromatography-mass spectrometry assay. Unbound DEX exhibited a fetal to maternal concentration ratio of 0.55, had a free fraction of 0.2 in maternal and 0.4 in fetal plasma, and declined with a half-life of approximately 3 h. DEX PK and plasma protein binding were linear during the study, and DEX exposure caused severe adrenosuppression. These temporal steroid profiles in the fetal circulation will be used to drive the PD effects reported in a companion paper and an optimal steroid regimen will be proposed.

This study seeks a route of drug administration that would produce a pharmacokinetic profile for dexamethasone not significantly different from the intravenous route in female rats and would offer reproducible drug input with minimal stress to the animals. The intramuscular (i.m.) route of drug administration vs intravenous (i.v.) injection were compared in three female Wistar rats administered 1 mg/kg dexamethasone phosphate. Dexamethasone plasma concentrations were measured by a normal phase HPLC assay for 12 h after drug administration. Dexamethasone exhibited monoexponential behavior after intravenous dosing and was absorbed rapidly after intramuscular dosing (absorption half-life of 14 min) with 86% bioavailability. Dexamethasone had a terminal half-life of 2.3 h after drug administration by either route. The volume of distribution of 0.78 l/kg and the clearance of 0.23 l/h/kg are in good agreement with reported pharmacokinetic parameters in male rats. Intravenous dosing can be replaced by intramuscular dosing without causing any marked difference in dexamethasone pharmacokinetics.

Insulin is an important agent for the treatment of diabetes mellitus (DM). Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1) hypersensitivity reaction on the sites of subcutaneous injection of soluble and isophane insulin but insulin glargine was tolerated well and provided good glycemic control.

Mahesh N Samtani,1 John J Sheehan,2 Dong-Jing Fu,2 Bart Remmerie,3 Jennifer Kern Sliwa,2 Larry Alphs21Janssen Research and Development, Raritan, NJ, USA; 2Janssen Scientific Affairs, Titusville, NJ, USA; 3Janssen Research and Development, Division of Janssen Pharmaceutica, Beerse, BelgiumBackground: Medication nonadherence is a well described and prevalent clinical occurrence in schizophrenia. These pharmacokinetic model-based simulations analyze predicted antipsychotic plasma concentrations in nonadherence and treatment interruption scenarios and with treatment reinitiation.Methods: Starting from steady state, pharmacokinetic model-based simulations of active moiety plasma concentrations of oral, immediate-release risperidone 3 mg/day, risperidone long-acting injection 37.5 mg/14 days, oral paliperidone extended-release 6 mg/day, and paliperidone palmitate 117 mg (75 mg equivalents)/28 days were assessed under three treatment discontinuation/interruption scenarios, ie, complete discontinuation, one week of interruption, and four weeks of interruption. In the treatment interruption scenarios, pharmacokinetic simulations were performed using medication-specific reinitiation strategies.Results: Following complete treatment discontinuation, plasma concentrations persisted longest with paliperidone palmitate, followed by risperidone long-acting injection, while oral formulations exhibited the most rapid decrease. One week of oral paliperidone or risperidone interruption resulted in near complete elimination from the systemic circulation within that timeframe, reflecting the rapid elimination rate of the active moiety. After 1 and 4 weeks of interruption, minimum plasma concentrations were higher with paliperidone palmitate than risperidone long-acting injection over the simulated period. Four weeks of treatment interruption followed by reinitiation resulted in plasma levels returning to predicted therapeutic levels within 1 week.Conclusion: Due to the long half-life of paliperidone palmitate (25–49 days), putative therapeutic plasma concentrations persisted longest in simulated cases of complete discontinuation or treatment interruption. These simulations may help clinicians better conceptualize the impact of antipsychotic nonadherence on plasma concentrations, and the impact of medication-specific reinitiation strategies after intermittent nonadherence.Keywords: paliperidone palmitate, risperidone, long-acting injection, pharmacokinetics, nonadherence, plasma concentrationsErratum for this paper has been published

Objectives: Antimalarial drugs are commonly prescribed for the treatment of malaria and suspected cases of malaria in India. The recent trend is to prescribe ACT and the incidence of adverse reactions to this therapy is notwell-documented in Indian population. Therefore, this study was designed to assess ADR pattern of antimalarial drugs particularly ACT in India. Materials and Methods: Over a period of 1 year, 500 patients who were administered antimalarial drugs were enrolled in the study. The World Health Organization causality assessment scale was used for classifying the ADR. Results: In this study out of 500 patients, 251 complained of ADRs. The sex-wise difference in reporting of ADRs was statistically not significant (P=0.0943). The most common ADRs reported were nausea, anorexia and vomiting. ADRs were most commonly reported when chloroquine was coprescribed. Conclusions: This study indicates that ACT was commonlyused in the treatment of malaria. Results of the analysis suggest that all the ADRs were of moderate intensity and no serious ADR was observed. This baseline information will be useful to implement the ACT in India.

Fifty consecutive, unselected, endoscopically confirmed patients with bleeding esophageal varices received splenic artery and coronary vein occlusion as their primary treatment. This was accomplished surgically in the first 30 patients and by interventional angiography in the last 20. The in-hospital mortality rate was 22% and the actuarial 5-year survival rate was 52%. The incidence of recurrent gastrointestinal bleeding from all causes was 43.6% with a mortality rate of 13%.

Objective Disability assessment for dementia (DAD) measurements from two phase-3 studies of bapineuzumab in APOE e4 noncarrier and carrier Alzheimer's disease (AD) patients were integrated to develop a disease progression model. Methods We evaluated longitudinal changes in DAD scores, baseline factors affecting disease progression, and bapineuzumab effect on disease progression. Results A beta regression model best described DAD disease progression. The estimated treatment effect of bapineuzumab was not significant, consistent with lack of clinical efficacy observed in the primary analysis. The model suggested that progression of DAD tended to decrease with increase in bapineuzumab exposure. The exposure-response relationship was similar regardless of APOE e4 status but more pronounced in patients with mild AD. Baseline disease status, age, memantine use, and years since onset (YSO) had significant effects on baseline DAD scores. AD concomitant medication use, baseline disease status, and YSO had significant effects on disease progression rate, measured by DAD score. Conclusions The beta regression model is a sensible modeling approach to characterize functional decline in AD patients. This analysis suggested a possible effect of bapineuzumab exposure on DAD progression. Further evaluation may be warranted in future studies. Trial Registration ClinicalTrials.gov identifier: NCT00575055 and NCT00574132.