Pharmacokinetics of long-acting lenacapavir in participants with hepatic or renal impairment.

Lenacapavir is a novel, first-in-class, multistage inhibitor of HIV-1 capsid function approved for the treatment of multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced people with HIV. Two Phase 1, open-label, parallel-group, single-dose studies assessed the pharmacokinetics (PK) of lenacapavir in participants with moderate hepatic impairment [Child-Pugh-Turcotte (CPT) Class B: score 7-9] or severe renal impairment [15 ≤ creatinine clearance (CLcr) ≤29 mL/min] to inform lenacapavir dosing in HIV-1-infected individuals with organ impairment. In both studies, a single oral dose of 300 mg lenacapavir was administered to participants with normal (n = 10) or impaired (n = 10) hepatic/renal function who were matched for age (±10 years), sex, and body mass index (±20%). Lenacapavir exposures [area under the plasma concentration-time curve from time 0 to infinity (AUCinf) and maximum concentration (Cmax)] were approximately 1.47- and 2.61-fold higher, respectively, in participants with moderate hepatic impairment compared to those with normal hepatic function, whereas lenacapavir AUCinf and Cmax were approximately 1.84- and 2.62-fold higher, respectively, in participants with severe renal impairment compared to those with normal renal function. Increased lenacapavir exposures with moderate hepatic or severe renal impairment were not considered clinically meaningful. Lenacapavir was considered generally safe and well tolerated in both studies. These results support the use of approved lenacapavir dosing regimen in patients with mild (CPT Class A: score 5-6) or moderate hepatic impairment as well as in patients with mild (60 ≤ CLcr ≤ 89 mL/min), moderate (30 ≤ CLcr ≤ 59 mL/min), and severe renal impairment.

Lenacapavir: A Novel, Potent, and Selective First-in-Class Inhibitor of HIV-1 Capsid Function Exhibits Optimal Pharmacokinetic Properties for a Long-Acting Injectable Antiretroviral Agent.

Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.

Trends and advances in pre- and post-harvest processing of linseed oil for quality food and health products.

Linseed is an ancient crop used for diverse purposes since the beginning of civilization. In recent times, linseed has emerged as a superfood due to its high content of health-promoting omega-3 fatty acids and other bioactive compounds. Among primary health effects, it has potential to manage hypertension, diabetes, osteoporosis, atherosclerosis, cancer, arthritis, neurological, cardiovascular diseases including blood cholesterol levels, constipation, diarrhea, and autoimmune disorders etc. due to the presence of omega-3 fatty acid, lignans, high dietary fibers, and proteins, whereas, secondary health effects comprise of relieving from various skin disorders. Due to these health-beneficial properties, interest in linseed oil necessitates the intensification of research efforts on various aspects. These include cultivation technology, varietal and genetic improvement, post-harvest processing, profiling of nutrients and bioactive compounds, pre-clinical and clinical studies, etc. The present review discussed the advances in linseed research including pre- and post-harvest processing. However, focus on the bioactive compounds present in linseed oil and their health effects are also presented. Linseed cultivation, pre- and post-harvest processing aspects are covered including climatic, edaphic, agronomic factors, type of cultivar and storage conditions etc, which impact the overall oil yield and its nutritional quality. Various emerging applications of linseed oil in functional food, nutraceutical, pharmaceutical, and cosmeceutical preparations were also presented in detail. Further, recommendations were made on linseed oil research in the field of genetics, breeding germplasm resources and genome editing for exploring its full applications as a nutrition and health product.

Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir.

BACKGROUND: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. METHODS: CAPELLA enrolled viremic HTE PWH with resistance to ≥3 of 4 of the main antiretroviral (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline resistance was evaluated in participants experiencing virologic failure. RESULTS: At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one-third of participants having exhausted all drugs from ≥3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. CONCLUSIONS: LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.

Role of Mutant Phosphate Solubilizing Microorganism on Growth of Brassica juncea (L.) cv RH 30.

Phosphorus is the second major plant nutrient and the availability of this element to plants is a major challenge due to conversion to insoluble form by chemical reactions with metal cations depending upon the soil pH. Total of sixty eight isolates of phosphate solubilizing bacteria from rhizosphere of mustard grown in different region of Haryana was studied. The isolates were mutagenised by giving treatment of Nitrosoguanidine (50 ug/ml). Three PSB strains (15M, 22M and 25M) and six mutants (15M2, 15M6, 22M28, 22M29, 25M11 and 25M30) were evaluated for their establishment in the rhizosphere, their effect on biomass production in mustard (Brassica juncea). Total bacterial count in rhizosphere increased after 30 and 40 days of sowing while decrease in growth was observed at 60 days of sowing. The phosphate solubilizing bacterial count in the rhizosphere varied from 1 to 24, 2 to 20 and 1 to 11 at 30, 45 and 60 days after sowing. Phosphate uptake also increased upto 11-21% which shows thatmutants had significant effect on increase in plant dry biomass and P-uptake under pot house conditions.

Production, Characterization and Prebiotic Potential of Xylooligosaccharides Produced from Wheat Bran using Enterobacter hormaechei KS1 Xylanase.

In the present investigation, xylooligosaccharides were produced from wheat bran and wheat bran extracted xylan through enzymatic hydrolysis using xylanase from novel Enterobacter hormaechei KS1. Xylooligosaccharides/reducing sugars production from wheat bran was found maximum (374 mg/g) when 4.0% of wheat bran was treated with 375 units (IU/mL) of Enterobacter hormaechei KS1 xylanase at pH 6.0 and incubated at 50 °C for 24 h of incubation. In case of wheat bran extracted xylan 419 mg/g of xylooligosaccharides were produced when 3% of extracted xylan was incubate for 8 h. Analysis of the enzymatic hydrolysate through high performance liquid chromatography equipped with refractive index detector showed the presence of xylose, xylopentose and xylohexose. The decrease in pH with 1.0% dose of xylooligosacchaides produced from extracted xylan hydrolysis using E. hormaechei KS1 xylanase showed more decrease with L. rhamnosus (6.72 to 5.94) followed by L. brevis (6.71 to 6.15) and L. plantarum (6.71 to 6.41). In case of increase in optical density both wheat bran and wheat bran extracted xylan generated xylooligosaccharides exhibited similar pattern i.e., L. rhamnosus > L. plantarum > L. brevis.

Risk of Negative Health Outcomes and High Costs for People With Diabetes and Unmet Psychological Needs in the United States.

Measuring the population-level relationship between compromised mental health and diabetes care remains an important goal for clinicians and health care decision-makers. We evaluated the impact of self-reported unmet psychological need on health care resource utilization and total health care expenditure in people with type 2 diabetes. Patients who reported unmet psychological needs were more likely than those who did not to incur a higher annual medical expenditure, have greater resource utilization, and have a higher risk of all-cause mortality.

Is aspirin a substrate of MDR1/P-glycoprotein?

Aspirin (acetyl salicylic acid) is widely used co-medication in patients with cardiovascular and cerebrovascular diseases. Given the prevalence of acetyl salicylic acid's use as a co-medication and conflicting reports in the literature on it being a substrate of P-glycoprotein (P-gp). There is a potential risk for its interaction with compounds with P-gp liability, therefore, we have conducted a detailed investigation to determine substrate potential of acetyl salicylic acid towards P-gp. We observed significantly lower cellular uptake of acetyl salicylic acid in MDR1 transfected LLC-PK1 cells compared to LLC-PK1 wild-type (WT) cells, however, the in vitro efflux of acetyl salicylic acid in MDR1 transfected LLC-PK1 cells was not inhibited by known inhibitors under various conditions. Acetyl salicylic acid did not show active asymmetrical transport across MDR1 transfected LLC-PK1 cells compared to LLC-PK1-WT cells in transwell assay. Moreover, no difference in plasma and brain exposure of acetyl salicylic acid and its metabolite salicylic acid was observed between FVB-WT and Mdr1a/b knockout (KO) mice. Taken together, our findings indicate that acetyl salicylic acid is not a substrate of P-gp.

A novel semi-mechanistic tumor growth fraction model for translation of preclinical efficacy of anti-glypican 3 antibody drug conjugate to human.

The growing fraction (GF) of tumor has been reported as one of the predictive markers of the efficacy of chemotherapeutics. Therefore, a semi-mechanistic model has been developed that describes tumor growth on the basis of cell cycle, allowing the incorporation of the GF of a tumor in pharmacokinetic/pharmacodynamic (PK/PD) modeling. Efficacy data of anti-glypican 3 (GPC3) antibody drug conjugate (ADC) in a hepatocellular carcinoma (HCC) patient derived xenograft (PDX) model was used for evaluation of this proposed model. Our model was able to describe the kinetics of growth inhibition of HCC PDX models following treatment with anti-GPC3 ADC remarkably well. The estimated tumurostatic concentrations were used in tandem with human PKs translated from cynomolgus monkey for prediction of the efficacious dose. The projected efficacious human dose of anti-GPC3 ADC was in the range 0.20-0.63 mg/kg for the Q3W dosing regimen, with a median dose of 0.50 mg/kg. This publication is the first step in evaluating the applicability of GF in PK/PD modeling of ADCs. The authors are hopeful that incorporation of GF will result in an improved translation of the preclinical efficacy of ADCs to clinical settings and thereby better prediction of the efficacious human dose.

Democracy, Capacity, and Coercion in Pandemic Response: COVID-19 in Comparative Political Perspective.

The COVID-19 pandemic has challenged governments around the world. It also has challenged conventional wisdom and empirical understandings in the comparative politics and policy of health. Three major questions present themselves: First, some of the countries considered to be most prepared-having the greatest capacity for outbreak response-have failed to respond effectively to the pandemic. How should our understanding of capacity shift in light of COVID-19, and how can we incorporate political capacity into thinking about pandemic preparedness? Second, several of the mechanisms through which democracy has been shown to be beneficial for health have not traveled well to explain the performance of governments in this pandemic. Is there an authoritarian advantage in disease response? Third, after decades in which coercive public health measures have increasingly been considered counterproductive, COVID-19 has inspired widespread embrace of rigid lockdowns, isolation, and quarantine enforced by police. Will these measures prove effective in the long run and reshape public health thinking? This article explores some of these questions with emerging examples, even amid the pandemic, when it is too soon to draw conclusions.

Correction to: Release of an enantioselective nitrilase from Alcaligenes faecalis MTCC 126: a comparative study.

In the original version of our paper entitled "Release of an enantioselective nitrilase from Alcaligenes faecalis MTCC 126: a comparative study" (2005) 27:415-424, some references to already published articles were inadvertently left out.

Ceftaroline efficacy against high-MIC clinical Staphylococcus aureus isolates in an in vitro hollow-fibre infection model.

Objectives: The current CLSI and EUCAST clinical susceptible breakpoint for 600 mg q12h dosing of ceftaroline (active metabolite of ceftaroline fosamil) for Staphylococcus aureus is ≤1 mg/L. Efficacy data for S. aureus infections with ceftaroline MIC ≥2 mg/L are limited. This study was designed to generate in-depth pharmacokinetic/pharmacodynamics (PK/PD) understanding of S. aureus isolates inhibited by ≥ 2 mg/L ceftaroline using an in vitro hollow-fibre infection model (HFIM). Methods: The PK/PD target of ceftaroline was investigated against 12 diverse characterized clinical MRSA isolates with ceftaroline MICs of 2 or 4 mg/L using q8h dosing for 24 h. These isolates carried substitutions in the penicillin-binding domain (PBD) and/or the non-PBD. Additionally, PD responses of mutants with ceftaroline MICs ranging from 2 to 32 mg/L were evaluated against the mean 600 mg q8h human-simulated dose over 72 h. Results: The mean stasis, 1 log10-kill and 2 log10-kill PK/PD targets were 29%, 32% and 35% f T>MIC, respectively. In addition, these data suggest that the PK/PD target for MRSA is not impacted by the presence of substitutions in the non-PBD commonly found in isolates with ceftaroline MIC values of ≤ 2 mg/L. HFIM studies with 600 mg q8h dosing demonstrated a sustained long-term bacterial suppression for isolates with ceftaroline MICs of 2 and 4 mg/L. Conclusions: Overall, efficacy was demonstrated against a diverse collection of clinical isolates using HFIM indicating the utility of 600 mg ceftaroline fosamil for S. aureus isolates with MIC ≤4 mg/L using q8h dosing.

Altered Expression of Sphingosine-1-Phosphate Metabolizing Enzymes in Oral Cancer Correlate With Clinicopathological Attributes.

We have determined the gene expression of sphingosine-1-phosphate (S1P) metabolizing enzymes (SphK1, SphK2, SGPL1, SGPP1, SGPP2, PPAP2A, PPAP2B, and PPAP2C) by quantitative real-time polymerase chain reaction in tumor tissues and adjacent normal tissues of 50 oral squamous cell carcinoma (OSCC) patients. Expression of SphK1 and SGPP1 genes was up-regulated significantly in 70% and 75% OSCC tumors respectively. Importantly, expression of SphK2 and PPAP2B was down-regulated in the tumor tissues of 70% OSCC patients. Expression of SphK2 and PPAP2B negatively correlated with tumor-node-metastasis (TNM) staging and tumor volume respectively. Furthermore, LPP1 is an independent predictor of TNM staging and lymph node ratio.

Cost-Effective and Handmade Paper-Based Immunosensing Device for Electrochemical Detection of Influenza Virus.

Although many studies concerning the detection of influenza virus have been published, a paper-based, label-free electrochemical immunosensor has never been reported. Here, we present a cost-effective, handmade paper-based immunosensor for label-free electrochemical detection of influenza virus H1N1. This immunosensor was prepared by modifying paper with a spray of hydrophobic silica nanoparticles, and using stencil-printed electrodes. We used a glass vaporizer to spray the hydrophobic silica nanoparticles onto the paper, rendering it super-hydrophobic. The super-hydrophobicity, which is essential for this paper-based biosensor, was achieved via 30-40 spray coatings, corresponding to a 0.39-0.41 mg cm-2 coating of nanoparticles on the paper and yielding a water contact angle of 150° ± 1°. Stencil-printed carbon electrodes modified with single-walled carbon nanotubes and chitosan were employed to increase the sensitivity of the sensor, and the antibodies were immobilized via glutaraldehyde cross-linking. Differential pulse voltammetry was used to assess the sensitivity of the sensors at various virus concentrations, ranging from 10 to 104 PFU mL-1, and the selectivity was assessed against MS2 bacteriophages and the influenza B viruses. These immunosensors showed good linear behaviors, improved detection times (30 min), and selectivity for the H1N1 virus with a limit of detection of 113 PFU mL-1, which is sufficiently sensitive for rapid on-site diagnosis. The simple and inexpensive methodologies developed in this study have great potential to be used for the development of a low-cost and disposable immunosensor for detection of pathogenic microorganisms, especially in developing countries.

Identification and Characterization of FabA from the Type II Fatty Acid Synthase of Streptomyces coelicolor.

FabA is proposed to catalyze the dehydration step of chain elongation in fatty acid and undecylprodiginine biosynthesis in Streptomyces coelicolor. Analysis of the S. coelicolor genome has revealed a fabA gene (SCO4636-SCO4637, encoding a heterodimer 3-hydroxyacyl-ACP dehydratase). Herein, we report the identification and characterization of the corresponding gene products. Kinetic analysis has demonstrated that FabA is capable of utilizing various chain lengths of straight- and branched-chain 3-hydroxyacyl-NAC substrates. Additionally, FabA does not discriminate between acyl carrier proteins (ACPs) from primary and secondary metabolism. These data provide the first experimental evidence that FabA has 3-hydroxyacyl-ACP dehydratase activity and processes intermediates for both biosynthetic pathways.

Effects of bisphenol-A on male reproductive success in adult Kadaknath chicken.

Bisphenol-A (BPA) adversely affects human and animal reproductive success in many ways, but this information is scant on birds. In the present study, we investigated the reproductive toxicity of BPA in adult Kadaknath chicken using two BPA dosages orally (1 or 5 mg/kg body weight) for seven weeks. In order to assess BPA toxicity, sperm functions, fertilizing ability, serum testosterone concentration and testis histopathology were measured in treated and control chickens. The semen volume was highest in birds exposed to 1mg/kg body weight BPA compared to other groups. 5 mg/kg body weight BPA reduced sperm concentration significantly more than other treatment and controls. However, overall fertility and testis histology were unaffected. These results indicate that BPA adversely affects sperm characteristics in adult kadaknath chicken without affecting fertilization potential.

Characterization of FabG and FabI of the Streptomyces coelicolor dissociated fatty acid synthase.

Streptomyces coelicolor produces fatty acids for both primary metabolism and for biosynthesis of the secondary metabolite undecylprodiginine. The first and last reductive steps during the chain elongation cycle of fatty acid biosynthesis are catalyzed by FabG and FabI. The S. coelicolor genome sequence has one fabI gene (SCO1814) and three likely fabG genes (SCO1815, SCO1345, and SCO1846). We report the expression, purification, and characterization of the corresponding gene products. Kinetic analyses revealed that all three FabGs and FabI are capable of utilizing both straight and branched-chain ß-ketoacyl-NAC and enoyl-NAC substrates, respectively. Furthermore, only SCO1345 differentiates between ACPs from both biosynthetic pathways. The data presented provide the first experimental evidence that SCO1815, SCO1346, and SCO1814 have the catalytic capability to process intermediates in both fatty acid and undecylprodiginine biosynthesis.

Pharmacokinetics/pharmacodynamics of a ß-lactam and ß-lactamase inhibitor combination: a novel approach for aztreonam/avibactam.

OBJECTIVES: The combination of aztreonam/avibactam has promising activity against MDR Gram-negative pathogens producing metallo-ß-lactamases (MBLs), such as New Delhi MBL-1. Pharmacokinetic (PK)/pharmacodynamic (PD) understanding of this combination is critical for optimal clinical dose selection. This study focuses on the determination of an integrated PK/PD approach for aztreonam/avibactam across multiple clinical Enterobacteriaceae strains. METHODS: Six clinical Enterobacteriaceae isolates expressing MBLs and ESBLs were studied in an in vitro hollow-fibre infection model (HFIM) using various dosing regimens simulating human-like PK for aztreonam/avibactam. The neutropenic murine thigh infection model was used for in vivo validation against two bacterial strains. RESULTS: MIC values of aztreonam/avibactam for the isolates ranged from 0.125 to 8 mg/L. Using a constant infusion of avibactam at 4 mg/L, the aztreonam PK/PD index was observed as % fT >MIC. Studies performed in the presence of a fixed dose of aztreonam revealed that the efficacy of avibactam correlates best with percentage of time above a critical threshold concentration of 2-2.5 mg/L. These conclusions translated well to the efficacy observed in the murine thigh model, demonstrating in vivo validation of the in vitro PK/PD target. CONCLUSIONS: PK/PD evaluations for aztreonam/avibactam in HFIM yielded a single target across strains with a wide MIC range. This integrated approach could be easily applied for forecasting clinically efficacious doses for ß-lactam/ß-lactamase inhibitor combinations.

Comparative expression analysis of embryonic development-related genes at different stages of parthenogenetic and in vitro fertilized embryos in caprine.

Aberrant gene expression occurs in parthenogenetic embryos due to abnormal epigenetic modifications in the genome that probably diminish viability and enhance developmental abnormalities in these embryos. In the present study, five developmentally important genes (HPRT1, Cx43, Sox2, Mest and IGF2R) were analysed at different stages in parthenotes (haploid and diploid) and compared with similar stages in in vitro fertilized (IVF) embryos. The results indicated that in haploid parthenotes expression of HPRT1 was upregulated (P < 0.05) only at the 2-4-cell stage whereas Cx43 expression was significantly (P < 0.05) downregulated in all stages as compared with the control. However, expression of this gene was upregulated (P < 0.05) in 2-4-cell and morula stages of diploid parthenotes. Expression of Sox2 was significantly (P < 0.05) downregulated in morula stage haploid parthenotes, whereas it was upregulated (P < 0.05) in 8-16-cell stage diploid embryos. The expression of Mest was upregulated (P < 0.05) at the 2-4-cell stage of both haploid and diploid parthenotes, whereas it was downregulated in 8-16-cell stage diploid embryos as compared with control. IGF2R expression was upregulated (P < 0.05) only in morula stage haploid and diploid parthenote as compared with control. These results indicate that parthenogenetic embryos showed aberrant gene expression of developmentally important genes such as HPRT1, Cx43, Sox2, Mest and IGF2R in comparison with IVF embryos, this finding may be one of the major reasons for the poor developmental competence of parthenogenetic embryos.

Isolation and propagation of neural stem cells in caprine (Capra hircus).

Neural stem cells (NSCs) can self-renew and give rise to neurons, astrocytes and oligodendrocytes; they are found in the nervous system of mammalian organisms, representing a promising resource for both fundamental research and therapeutics. There have been few investigations on NSCs in the livestock species. Therefore, we have successfully isolated and characterised NSCs from the foetal brain of a small domestic animal, the goat (called GNSCs). These cells from the foetal brain showed self-renewal, rapid proliferation with a population doubling time of 88 h, were morphologically homogeneous and maintained normal chromosome throughout the culture period. The cells expressed NSC-specific markers (Sox2, Pax6 and Mushashi), but were negative for CD34 and CD45. They were capable of multi-differentiation into neurons, astrocytes, oligodendrocytes, as well as adipocytes and osteocytes. The availability of such cells may hold great interest for basic and applied neuroscience.