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L’environnement de l’entreprise présente des opportunités et des menaces auxquelles il appartient aux dirigeants de l’entreprise de prendre des mesures adaptées. En R.D. Congo, le climat des affaires étant défavorable, il paraît difficile de voir ce secteur connaitre un essor considérable, capable de contribuer de manière attendue au développement socio-économique du pays. Comme le témoigne le rapport de la Banque Mondiale sur le Doing Business, les indicateurs retenus classent la R.D. Congo dans une situation défavorable. Cependant, les efforts constants s’entreprennent au jour le jour pour tenter de changer la donne. Depuis un certain temps, l’amélioration du climat des affaires en R.D. Congo devient une préoccupation majeure pour les gouvernements afin de le rendre incitatif aux investisseurs et favoriser son développement. Une analyse des caractéristiques environnementales externes et internes permettra de cerner la situation.

Magnesium-based multicomponent alloys with different compositions, namely Mg60Al20Zn5Cu10Mn5 (Mg60 alloy), Mg70Al15Zn5Cu5Mn5 (Mg70 alloy), and Mg80Al5Cu5Mn5Zn5 (Mg 80) alloys, were prepared using the disintegrated melt deposition technique. The DMD technique is a distinctive method that merges the benefits from gravity die casting and spray forming. This approach facilitates high solidification rates, process yields, and reduced metal wastage, resulting in materials with a fine microstructure and minimal porosity. Their potential as biodegradable materials was assessed through corrosion in different simulated body fluids (SBFs), microstructure, and cytotoxicity tests. It was observed that the Mg60 alloy exhibited low corrosion rates (~× 10−5 mm/year) in all SBF solutions, with a minor amount of corrosive products, and cracks were observed. This can be attributed to the formation of the Mg32(AlZn)49 phase and to its stability due to Mg(OH)2 film, leading to excellent corrosion resistance when compared to the Mg70 and M80 alloys. Conversely, the Mg80 alloy exhibited high corrosion rates, along with more surface degradation and cracks, due to active intermetallic phases, such as Al6Mn, Al2CuMg, and Al2Cu phases. The order of corrosion resistance for the Mg alloy was found to be ASS > HBSS > ABP > PBS. Further, in vitro cytotoxicity studies were carried out using MDA-MB-231 tumor cells. By comparing all three alloys, in terms of proliferation and vitality, the Mg80 alloy emerged as a promising material for implants, with potential antitumor activity.

Objective: Spinal and bulbar muscular atrophy is characterized by slow-progressive muscle weakness, decreased functional performance and falls. Research into the use of exercise in spinal and bulbar muscular atrophy has shown equivocal to negative results, although authors suggest that patients with spinal and bulbar muscular atrophy may benefit from both increased exercise intensity and shorter bout duration. The aim of this case report is to explore the safety of a moderate-intensity strength training programme coupled with dynamic balance and function-specific training in a patient with spinal and bulbar muscular atrophy. Case report: A 56-year-old man with spinal and bulbar muscular atrophy presented with multiple falls and declining performance in physical, vocational, and recreational activities. Examination revealed several musculoskeletal impairments that were sub-clinical to mild compared with an SBMA natural history cohort. Intervention and outcome: A 15-week moderate-intensity exercise programme combining weightlifting and functional exercises was performed under clinical supervision. Exercise volume, frequency and intensity were adjusted based on patient-reported outcomes and muscle damage blood markers. Performance-based and selfreported functional improvements occurred that exceeded the minimal clinically important difference. The intervention was well tolerated and the patient nearly doubled his baseline 10-repetition maximums for weight-lifting exercises. Conclusion: Exercise therapy combining weightlifting and upright functional training led to meaningful performance improvements in this case of a patient with spinal and bulbar muscular atrophy and relatively low disease burden. LAY ABSTRACT Spinal and bulbar muscular atrophy (SBMA) is a rare neuromuscular disease characterized by slow-progressive muscle weakness, decreased functional performance, and falling. With limited research for guidance, medical practitioners often advise patients with SBMA to avoid weight lifting or intensive exercise. The patient was a high-functioning 56-year-old man with SBMA who struggled with performing daily activities and intensive physical work demands. He participated in a closely monitored 15-week exercise program that combined weight lifting and functional exercises. The patient safely tolerated the program, self-reported physical improvements, and nearly doubled the weight for lifting exercises. This case report highlights one individual with SBMA who benefitted from moderate-intensity exercise, including weight lifting, under careful clinical supervision. More research is needed before this intervention can be recommended for people with SBMA.

ObjectiveReal-world data characterizing differences between African American (AA) and White women with metastatic triple-negative breast cancer (mTNBC) are limited. Using 9 years of data collected from community practices throughout the United States, we assessed racial differences in the proportion of patients with mTNBC, and their characteristics, treatment, and overall survival (OS).MethodsThis retrospective study analyzed de-identified data from 2,116 patients with mTNBC in the Flatiron Health database (January 2011 to March 2020). Characteristics and treatment patterns between AA and White patients with mTNBC were compared using descriptive statistics. OS was examined using Kaplan-Meier analysis and a multivariate Cox proportional hazards regression model.ResultsAmong patients with metastatic breast cancer, more AA patients (23%) had mTNBC than White patients (12%). This difference was particularly pronounced in patients who lived in the Northeast, were aged 45–65, had commercial insurance, and had initial diagnosis at stage II. AA patients were younger and more likely to have Medicaid. Clinical characteristics and first-line treatments were similar between AA and White patients. Unadjusted median OS (months) was shorter in AA (10.3; 95% confidence interval [CI]: 9.1, 11.7) vs. White patients (11.9; 95% CI: 10.9, 12.8) but not significantly different. After adjusting for potential confounders, the hazard ratio for OS was 1.09 (95% CI: 0.95, 1.25) for AA vs. White patients.ConclusionsThe proportion of patients with mTNBC was higher in AA than White mBC patients treated in community practices. Race did not show an association with OS. Both AA and White patients with mTNBC received similar treatments. OS was similarly poor in both groups, particularly in patients who had not received any documented anti-cancer treatment. Effective treatment remains a substantial unmet need for all patients with mTNBC.

Background Respiratory care programs are under pressure to recruit and retain students in both undergraduate and graduate programs. Factors that influence undergraduate students' decisions to continue their education into an advanced degree program are not fully understood. The purpose of this study is to determine students' perceived self-efficacy, outcome expectations, barriers, and support to attend a Master of Science in Respiratory Care (MSRC) program. Methods This study used a survey from a previous study that included questions on undergraduate student self-efficacy, outcome expectations, perceived barriers and was utilized to assess students' perceptions of the support to attend an MSRC and its impact on their career goals. Student self-efficacy is defined as a person's beliefs and ability about his/her capacity to succeed in a specific situation. All undergraduate students (n = 89) in the Bachelor of Science in Respiratory Care program at Texas State University were invited to participate in the study. Results A total of 87 surveys were collected (42 juniors and 45 seniors) with a response rate of 97.7%. Ninety percent of study participants were female, and the average age was 22.54 ± 3.50 years. Self-efficacy results indicate that 88.5% of our undergraduate students believe they would be successful if enrolled in the MSRC program. Only 58.6% are interested in pursuing the MSRC, possibly because 51.7% do not think the MSRC is required for the job they want. However, 98.8% believe the MSRC will create more opportunities for them. Cost (34%), tired of schoolwork (20%), and marriage (10%) are the three main reasons not to attend the MSRC. Of those interested in an MSRC program, 71.3% reported that they do not know if they can receive financial support for graduate studies, 71% are unaware of how to contact a graduate program coordinator, and 89% fear difficulty in navigating graduate school and networking with others. Conclusion Respiratory care students have self-efficacy to attend an MSRC program and believe it will provide more opportunities for them. However, cost and resource awareness are the main barriers to enrolling in the graduate program. This study highlights students' perceived barriers and challenges in advancing their knowledge and continuing their education with an MSRC degree and the need for student support.

Understanding the sources, prevalence, phenotypic and genotypic characteristics of mcr gene-harbouring bacteria (MGHB) in the poultry sector is crucial to supplement existing information. Through this, the plasmid-mediated colistin resistance (PMCR) could be tackled to improve food safety and reduce public health risks. Therefore, we conducted a literature synthesis of potential sources and characteristic occurrence of MGHB recovered from the poultry sector specific to the high-income countries (HICs). Colistin (COL) is a last-resort antibiotic used for treating deadly infections. For more than 60 years, COL has been used in the poultry sector globally, including the HICs. The emergence and rapid spread of mobile COL resistance (mcr) genes threaten the clinical use of COL. Currently, ten mcr genes (mcr-1 to mcr-10) have been described. By horizontal and vertical transfer, the mcr-1, mcr-2, mcr-3, mcr-4, mcr-5, and mcr-9 genes have disseminated in the poultry sector in HICs, thus posing a grave danger to animal and human health, as harboured by Escherichia coli, Klebsiella pneumoniae, Salmonella species, and Aeromonas isolates. Conjugative and non-conjugative plasmids are the major backbones for mcr in poultry isolates from HICs. The mcr-1, mcr-3 and mcr-9 have been integrated into the chromosome, making them persist among the clones. Transposons, insertion sequences (IS), especially ISApl1 located downstream and upstream of mcr, and integrons also drive the COL resistance in isolates recovered from the poultry sector in HICs. Genes coding multi-and extensive-drug resistance and virulence factors are often co-carried with mcr on chromosome and plasmids in poultry isolates. Transmission of mcr to/among poultry strains in HICs is clonally unrestricted. Additionally, the contact with poultry birds, manure, meat/egg, farmer’s wears/farm equipment, consumption of contaminated poultry meat/egg and associated products, and trade of poultry-related products continue to serve as transmission routes of MGHB in HICs. Indeed, the policymakers, especially those involved in antimicrobial resistance and agricultural and poultry sector stakeholders-clinical microbiologists, farmers, veterinarians, occupational health clinicians and related specialists, consumers, and the general public will find this current literature synthesis very useful.

Background Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.Methods Three cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.Results High PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p

Abstract Objective To conduct a follow-up on the rate and related risk factors of probable disaster-related psychiatric disorders such as depressive disorder (major depressive episode, MDE), stress disorders, post-traumatic (posttraumatic stress disorder, PTSD), and the quality of life of the survivors of a fossil gas explosion in Taiwan 18 months after the event. Methods A community-based survey of residents of a community that experienced a petrochemical gas explosion with cross-sectional assessments was conducted 18 months after the event. Two screening tools, including the Disaster-Related Psychological Screening Test (DRPST) and Short Form 12v2 (SF-12v2), were used to survey a representative sample of 388 participants. Results The average age of 388 participants is 43.27 ± 15.98 years (males: 203, average age: 41.44 ± 15.74 years; females: 185; average age: 45.27 ± 16.03 years). Probable PTSD, probable MDE, probable PTSD and MDE, and non-PTSD or non-MDE (non-P or -M) were present in 34 (8.8%), 14 (3.6%), 9 (2.3%), and 331 (85.3%) participants, respectively. The significant associated factor for probable PTSD or MDE among those who experienced disaster was financial problems. The associated factors on different quality of life subscales were old age, physical injury, employment, educational level, financial problems, probable PTSD and probable MDE. Conclusion While participants’ psychiatric status improved after 18 months, their quality of life continued to be affected, especially the quality of life of those with probable PTSD combined with MDE. Postdisaster treatment and follow-up should be addressed to a greater degree, especially for victims with mental illness, physical injuries and financial problems.

A MIMO GB-SAR system called MELISSA was put in place to monitor landslides in Italy and the sinking of the Costa Concordia cruise liner in France. It comprises 12 pyramidal horn antennas placed in a linear geometry for transmission, and these are used in the detection of the motion of a target (for example a landslide or other terrestrial deformation). The low half power beam width (19.76° at θ = 90°) of the transmitting radiation pattern of MELISSA results in low coverage area of the target. This paper proposes two alternative types of horn antenna for the current transmitter module of MELISSA, namely the cantenna and coaxial cavity horn antenna, for installation in a 2×6 planar antenna array. A higher value of the 3 dB beamwidth is observed using these arrays (38.320 at θ = 90° and 104.80 at φ = 0° for the cantenna array and 410 at θ = 90° and 140.40 at φ = 0° for the coaxial cavity horn antenna array). The overall gain of the proposed systems is around 10 dBi, and the efficiencies are between 85% and 90%. Using the Dolph Chebyshev beamforming technique on the proposed antenna arrays yields a zero sidelobe level, which improves the overall peak sidelobe ratio of the system and in turn the quality of the images obtained. Our proposed design for the transmitting section of the MELISSA system has applications terrestrial deformation monitoring with higher area coverage.

Antimicrobial resistance is a growing public health problem and a threat to effective treatment and prevention of an array of infections caused by bacteria. Africa is already faced with many socio-economic and health crises. Many countries in Africa can seldom boast of a standardized health care facility comparable to those in developed countries. Yet, the non-therapeutic use of COL has been banned in developed countries. However, in Africa, except for South Africa, COL is an over-the-counter (OTC) medication sold and dispensed by non-professionals/without a veterinarian’s supervision. The ban of non-therapeutic COL in developed countries has proven to reduce the development of mobile colistin resistance (MCR) in humans and animals. The unregulated use of COL has been proven to select pathogenic and commensal bacteria resistance. A transmissible plasmid-mediated colistin determinant, mobile COL resistance (mcr) gene, which is rapidly transferred/acquired horizontally or laterally intra/inter-species/genera, has been reported. A highly promiscuous mobile genetic element like plasmids containing transposons, insertion sequences, and integrons aid the carriage/rapid transfer and acquisition of these mcr genes. Hence, we highlight the danger posed by escalating colistin (COL) resistance in the continent and the impetus to halt the indiscriminate and non-therapeutic use of COL to protect public health.

Introduction. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder that leads to progressive weakness of bulbar and extremity muscles. Dynamic balance during functional tasks has not been reported in people with SBMA. Objectives. (1) To evaluate the ability to safely complete a forward lunge (FL), step quick turn (SQT), and step up and over (SUO), (2) to determine the presence and severity of dynamic balance impairments by comparing performance to normative data, and (3) to investigate the relationship between lower extremity strength and ability to complete each task. Design. Cross-sectional analysis. Participants. Fifty-three people with SBMA were included in a cross-sectional analysis. Normative datasets provided by the NeuroCom manufacturer and isometric strength literature facilitated patient comparisons. Outcome Measures. Force plate-based dynamic balance measures included FL (distance, impact index, contact time, and force impulse), SQT (turn time and turn sway), and SUO (lift up index, movement time, and impact index). Maximal isometric contractions of knee extensors, ankle dorsiflexors, ankle plantar flexors, and hip extensors were measured with fixed frame dynamometry. Results. The most difficult test, per completion rate, was SUO (52%), followed by FL (57%) and SQT (65%). t-tests revealed significant abnormalities in eight of nine balance variables (p

In this research, a finite element (FE) technique was used to predict the residual stresses in laser-peened aluminum 5083 at different power densities. A dynamic pressure profile was used to create the pressure wave in an explicit model, and the stress results were extracted once the solution was stabilized. It is shown that as power density increases from 0.5 to 4 GW/cm2, the induced residual stresses develop monotonically deeper from 0.42 to 1.40 mm. However, with an increase in the power density, the maximum magnitude of the sub-surface stresses increases only up to a certain threshold (1 GW/cm2 for aluminum 5083). Above this threshold, a complex interaction of the elastic and plastic waves occurring at peak pressures above ≈2.5 Hugoniot Elastic Limit (HEL) results in decreased surface stresses. The FE results are corroborated with physical experiments and observations.

Chloride intracellular channel (CLIC) 4 is an ion channel, localized in the cytoplasm, and first identified as an actin binding protein. Here, Chou et al.knockout CLIC4 in mice and observe tubulogenesis and renal proximal tubule dilation defects, which is caused by irregular actin and endosomal trafficking.

Summary: Background: Sub-Saharan Africa has the highest incidence, prevalence, and fatality from stroke globally. Yet, only little information about context-specific risk factors for prioritising interventions to reduce the stroke burden in sub-Saharan Africa is available. We aimed to identify and characterise the effect of the top modifiable risk factors for stroke in sub-Saharan Africa. Methods: The Stroke Investigative Research and Educational Network (SIREN) study is a multicentre, case-control study done at 15 sites in Nigeria and Ghana. Cases were adults (aged ≥18 years) with stroke confirmed by CT or MRI. Controls were age-matched and gender-matched stroke-free adults (aged ≥18 years) recruited from the communities in catchment areas of cases. Comprehensive assessment for vascular, lifestyle, and psychosocial factors was done using standard instruments. We used conditional logistic regression to estimate odds ratios (ORs) and population-attributable risks (PARs) with 95% CIs. Findings: Between Aug 28, 2014, and June 15, 2017, we enrolled 2118 case-control pairs (1192 [56%] men) with mean ages of 59·0 years (SD 13·8) for cases and 57·8 years (13·7) for controls. 1430 (68%) had ischaemic stoke, 682 (32%) had haemorrhagic stroke, and six (

INTRODUCTION:Stroke is a prominent cause of death, disability, and dementia in sub-Saharan Africa (SSA). The Stroke Investigative Research and Education Network works collaboratively with stroke survivors and individuals serving as community controls to comprehensively characterize the genomic, sociocultural, economic and behavioral risk factors for stroke in SSA. PURPOSE:In this paper, we aim to: i) explore the attitudes, beliefs, and practices related to stroke in Ghana and Nigeria using the process of qualitative description; and ii) propose actions for future research and community-based participation and education. METHODS:Stroke survivors, their caregivers, health care professionals, and community representatives and faith-based leaders participated in one of twenty-six focus groups, which qualitatively explored community beliefs, attitudes and practices related to stroke in Ghana and Nigeria. Arthur Kleinman's Explanatory Model of Illness and the Social Ecological Model guided the questions and/or thematic analysis of the qualitative data. We hereby describe our focus group methods and analyses of qualitative data, as well as the findings and suggestions for improving stroke outcomes. RESULTS AND DISCUSSION:The major findings illustrate the fears, causes, chief problems, treatment, and recommendations related to stroke through the views of the participants, as well as recommendations for working effectively with the SIREN communities. Findings are compared to SIREN quantitative data and other qualitative studies in Africa. As far as we are aware, this is the first paper to qualitatively explore and contrast community beliefs, attitudes, and practices among stroke survivors and their caregivers, community and faith-based leaders, and health professionals in multiple communities within Nigeria and Ghana.

Health services are increasingly under pressure to develop information systems that are responsive to changing health needs and appropriate to service objectives. Developing an essential data set provides managers with a clearly defined set of indicators for monitoring and evaluating services. This article describes a process that resulted in the creation of an essential data set at district level. This had a significant impact on neighbouring districts and resulted in the development of a regional essential data set, which in turn helped to influence the creation of a provincial and then national essential data set. Four key lessons may be drawn from the process. The development of an essential data set both requires and can contribute to a process that allows the reporting requirements to be adjusted over time in response to changing circumstances. In addition, it contributes to (and requires) the integration of programme reporting requirements into a coherent information system. While the case study describes a bottom-up approach, a top-down consultative process is advocated because it establishes a framework within which information needs can be reviewed. Lastly, the use of surveys can aid efforts to keep the essential elements to a minimum. In conclusion, the development of an essential data set contributes to strengthening health services because it necessitates dialogue between programme managers and defines indicators to be monitored by them.

Smart mobile phones are widely popularized and advanced mobile communication services are provided increasingly often, such that ubiquitous computing environments will soon be a reality. However, there are many security threats to mobile networks and their impact on security is more serious than that in wireline networks owing to the features of wireless transmissions and the ubiquity property. The secret information which mobile users carry may be stolen by malicious entities. To guarantee the quality of advanced services, security and privacy would be important issues when users roam within various mobile networks. In this manuscript, an anonymous authentication scheme will be proposed to protect the security of the network system and the privacy of users. Not only does the proposed scheme provide mutual authentication between each user and the system, but also each user’s identity is kept secret against anyone else, including the system. Although the system anonymously authenticates the users, it can still generate correct bills to charge these anonymous users via a credit-based solution instead of debit-based ones. Furthermore, our protocols also achieve fair privacy which allows the judge to revoke the anonymity and trace the illegal users when they have misused the anonymity property, for example, if they have committed crimes. Finally, in this paper, we also carry out complete theoretical proofs on each claimed security property.

Abstract This study investigates ovulation and egg deposition behaviors in the anuran Eleutherodactylus coqui from Puerto Rico in response to stimulation with gonadotropin and gonadotropin releasing hormones. Five hormones were tested by injection over a range of doses, including mammalian LHRH, avian LHRH, fish LHRH, D-Ala6, des-Gly10 ethylamide LHRH and hCG. We report a low level of ovulation and egg deposition in response to all hormones, with the most complete and consistent results from the non-natural D-Ala6, des-Gly10 ethylamide LHRH derivative. To confirm the viability of eggs produced in this manner we performed in vitro fertilization experiments that resulted in the development of normal frogs. Reproductive behaviors in E. coqui are apparently not controlled by a mammalian form of LHRH as reported in other common laboratory anuran species. D-Ala6, des-Gly10 ethylamide LHRH induces ovulation and deposition of mature and fertilizable eggs in E. coqui.

We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor ( 1 ), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues. Compound 28a was chosen for further profiling, because of its excellent in vitro profile and liver selectivity. This compound significantly increased hemoglobin levels in rats, following chronic QD oral administration, and displayed selectivity over systemic effects., Competing Interests: The authors declare no competing financial interest.

Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

Two novel metabolites of the dipeptidyl peptidase inhibitor sitagliptin (MK-0431, (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)-butan-2-amine), were identified after purification from dog urine. The metabolites (referred to as M2 and M5) were characterized by hydrogen/deuterium exchange tandem mass spectrometry and NMR spectroscopy nuclear Overhauser effect experiments as the cis and trans stereoisomers formed by cyclization of the primary amino group with the alpha carbon of the piperazine ring, following oxidative desaturation.

The pharmacokinetics, metabolism, and excretion of sitagliptin [MK-0431; (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine], a potent dipeptidyl peptidase 4 inhibitor, were evaluated in male Sprague-Dawley rats and beagle dogs. The plasma clearance and volume of distribution of sitagliptin were higher in rats (40-48 ml/min/kg, 7-9 l/kg) than in dogs ( approximately 9 ml/min/kg, approximately 3 l/kg), and its half-life was shorter in rats, approximately 2 h compared with approximately 4 h in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. After administration of [(14)C]sitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile, and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, whereas metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32 to 39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.

The metabolism and excretion of [(14)C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 muCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.