Reduction of site-specific CYP3A-mediated metabolism for dual angiotensin and endothelin receptor antagonists in various in vitro systems and in cynomolgus monkeys.

2-{Butyryl-[2'-(4,5-dimethyl-isoxazol-3-ylsulfamoyl)-biphenyl-4-ylmethyl]-amino}-N-isopropyl-3-methyl-butyramide (BMS-1) is a potent dual acting angiotensin-1 and endothelin-A receptor antagonist. The compound was subject to rapid metabolic clearance in monkey and human liver microsomes and exhibited low systemic exposure and marked interanimal variability in cynomolgus monkeys after p.o. administration. The variability pattern was identical to that of midazolam given p.o. in the same monkeys, as measured by area under the curve and Cmax values, suggesting that CYP3A-mediated metabolism might play a role in the rapid clearance and observed interanimal variability. Subsequent in vitro metabolism studies using human liver microsomes and cDNA-expressed human cytochrome P450 (P450) enzymes revealed that BMS-1 was a CYP3A4 substrate and was not metabolized by other human P450 enzymes. Mass spectral and NMR analyses of key metabolites led to the identification of the dimethyl isoxazole group as a major metabolic soft spot for BMS-1. Replacement of the 4-methyl group on the isoxazole ring with halogens not only improved overall metabolic stability but also decreased CYP3A-mediated hydroxylation of the isoxazole 5-methyl group. As exemplified by 2-{butyryl-[2'-(4-fluoro-5-methyl-isoxazol-3-ylsulfamoyl)-biphenyl-4-ylmethyl]-amino}-N-isopropyl-3-methyl-butyramide (BMS-3), a fluorinated analog of BMS-1, the structural modification resulted in an increase in the systemic exposure relative to previous analogs and a dramatic reduction in interanimal variability in the monkeys after p.o. administration. In addition, BMS-3 could be metabolized by both CYP2C9 and CYP3A4, thus avoiding the reliance on a single P450 enzyme for metabolic clearance. Integration of results obtained from in vitro metabolism studies and in vivo pharmacokinetic evaluations enabled the modulation of site-specific CYP3A-mediated metabolism, yielding analogs with improved overall metabolic profiles.     

Lipid Metabolism,Disorders and Therapeutic Drugs – Review

Different lifestyles have an impact on useful metabolic functions, causing disorders. Different lipids are involved in the metabolic functions that play various vital roles in the body, such as structural components, storage of energy, in signaling, as biomarkers, in energy metabolism, and as hormones. Inter-related disorders are caused when these functions are affected, like diabetes, cancer, infections, and inflammatory and neurodegenerative conditions in humans. During the Covid-19 period, there has been a lot of focus on the effects of metabolic disorders all over the world. Hence, this review collectively reports on research concerning metabolic disorders, mainly cardiovascular and diabetes mellitus. In addition, drug research in lipid metabolism disorders have also been considered. This review explores lipids, metabolism, lipid metabolism disorders, and drugs used for these disorders.     

The Design and Validation of a New Algorithm to Identify Incident Fractures in Administrative Claims Data

Our study validated a claims-based algorithm for the identification of incident and recurrent fractures in administrative data. We used Centers for Medicare and Medicaid (CMS) claims from 2005 to 2014 linked to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) database. Case qualifying (CQ) fractures were identified among participants with ≥12 months of fee-for-service coverage before first fracture claim and ≥6 months after. Recurrent fractures were defined as the first CQ fracture that occurred following a clean period of at least 90 days from the last claim associated with the preceding incident fracture. We used medical records (discharge summary, imaging, and surgical report) to adjudicate fractures. We calculated positive predictive values (PPVs) for incident and recurrent fractures. Our study was not designed to assess the algorithm sensitivity or negative predictive value. We identified 2049 potential incident fractures from claims among 1650 participants. Record retrieval was attempted for 728 (35.5%) suspected incident fractures (prioritizing more recent CQ fractures associated with osteoporosis, but without explicitly requiring any osteoporosis ICD-9 diagnosis code). Our final sample included 520 claims-identified fractures with medical records, of which 502 (96.5%) were confirmed. The PPVs (95% CI) of the hip, wrist, humerus, and clinical vertebra—all exceeded 95%. We identified 117 beneficiaries with 292 ≥2 CQ fracture episodes at the same site, and attempted retrieval on 105 (36.0%) episodes. Our analytic sample included 72 (68.5%) CQ episodes from 33 participants. The PPVs for identifying recurrent clinical vertebral, hip/femur, and nonvertebral fractures with a 90-day clean period exceeded 95%. Although we could not ascertain sensitivity, our updated fracture identification algorithms had high PPV for the identification of incident and recurrent fractures of the same site. Although medical record review and clinical adjudication remain a gold standard, our claims-based algorithm provides an alternative approach to fracture ascertainment when high PPV is desired. © 2019 American Society for Bone and Mineral Research.     

An NMR based panorama of the heterogeneous biology of acute respiratory distress syndrome (ARDS) from the standpoint of metabolic biomarkers

Acute respiratory distress syndrome (ARDS), manifested by intricate etiology and pathophysiology, demands careful clinical surveillance due to its high mortality and imminent life support measures. NMR based metabolomics provides an approach for ARDS which culminates from a wide spectrum of illness thereby confounding early manifestation and prognosis predictors. ¹H NMR with its manifold applications in critical disease settings can unravel the biomarker of ARDS thus holding potent implications by providing surrogate endpoints of clinical utility. NMR metabolomics which is the current apogee platform of omics trilogy is contributing towards the possible panacea of ARDS by subsequent validation of biomarker credential on larger datasets. In the present review, the physiological derangements that jeopardize the whole metabolic functioning in ARDS are exploited and the biomarkers involved in progression are addressed and substantiated. The following sections of the review also outline the clinical spectrum of ARDS from the standpoint of NMR based metabolomics which is an emerging element of systems biology. ARDS is the main premise of intensivists textbook, which has been thoroughly reviewed along with its incidence, progressive stages of severity, new proposed diagnostic definition, and the preventive measures and the current pitfalls of clinical management. The advent of new therapies, the need for biomarkers, the methodology and the contemporary promising approaches needed to improve survival and address heterogeneity have also been evaluated. The review has been stepwise illustrated with potent biometrics employed to selectively pool out differential metabolites as diagnostic markers and outcome predictors. The following sections have been drafted with an objective to better understand ARDS mechanisms with predictive and precise biomarkers detected so far on the basis of underlying physiological parameters having close proximity to diseased phenotype. The aim of this review is to stimulate interest in conducting more studies to help resolve the complex heterogeneity of ARDS with biomarkers of clinical utility and relevance.     

Synthesis and antibacterial activity of some imidazole-5-(4H)one derivatives

In the present study, several substituted oxazolones were synthesized by condensation of benzoylglycine with different aldehydes. From such oxazolones, substituted imidazolones were synthesized by condensation with ethylenediamine, urea and 4-N,N-dimethylaminoaniline. All these synthesized compounds produced significant antibacterial activities. Furthermore, compounds containing -CH(2)CH(2)NH(2), -CONH(2) and -C(6)H(4)-N(CH(3))(2) groups as substitutents on the imidazolones were found to be potent antibacterial agents. Thus, among the twelve compounds, 1-(2-aminoethyl)-2-phen yl-4-(4-(dimethylamino)benzylidene)imidazole-5-(4H)one (4d), 1-carboxamido-2-phenyl-4-(4-(dimethylamino)benzylidene)imidazole-5-(4H)one (4e) and 1-(4-(N,N-dimethylamino)phenyl)-2-phenyl-4-(4-(dimethylamino)benzylidene)imidazole-5-(4H)one (4f) were found to have a significant higher antibacterial activity than the other substituted imidazolones. Compound 4e was the most active one in this series.     

The positive effect of pregnancy in rheumatoid arthritis and the use of medications for the management of rheumatoid arthritis during pregnancy

Inflammopharmacology - Rheumatoid arthritis (RA) is an autoimmune systemic inflammatory disorder that is mostly characterised by progressive symmetrical joint destruction, particularly in the wrist...     

Risk Assessment at 11–14-Week Antenatal Visit: A Tertiary Referral Center Experience from South India

Background

Present study carried out in a tertiary referral hospital in South India attempts to determine the predictive value of integrated screening at 11–14-week antenatal visit.

Objectives

To determine the detection rate of fetal abnormalities at 11–14 weeks and also to predict the placental dysfunction disorders based on early integrated evaluation.

Method

Integrated screening performed on 440 women between 11 and 14 weeks, including detailed maternal history [medical history, bad obstetric history (BOH)], body mass index (BMI), mean arterial pressure (MAP), detailed ultrasound and maternal serum biochemistry as part of combined first-trimester screening for aneuploidy.

Results

There were two proven Down’s syndrome foetuses; both detected with combined screening test. There were 12 fetuses with major anomalies, out of whom 7 (58.3%) detected in 11–14-week scan. Among 440, 114 pregnancies (25.9%) developed complications in pregnancy, including 33 (7.5%) gestational hypertension, 8 (1.8%) pre-eclampsia, 41 (9.38%) SGA, 13 (2.9%) abortions, 22 (5%) indicated and 9 (2.04%) spontaneous preterm deliveries, 38 (8.63%) GDM and 3 (0.6%) stillbirth/IUD. Among the risk factors, age >35 years, BMI >23 kg/m², BOH, MAP >105 mmHg and PAPP-A <0.5 MoM correlated well with adverse outcome. Using early integrated screening, 78.9% of obstetric complications could be predicted although 306 (69.5%) were labeled high risk, among whom 90 (29.4%) developed adverse pregnancy outcomes.

Conclusions

Majority of fetal abnormalities can be detected, and majority adverse pregnancy outcomes can be predicted at 11–14-week antenatal visit, although this study shows high screen positivity and low specificity in a tertiary referral unit.

     

Modeling chronic olanzapine exposure using osmotic minipumps: pharmacological limitations

Animal models can face unique challenges in mirroring what occurs in humans. This is the case for antipsychotics in rodents, where these drugs are metabolized much more rapidly. One strategy to address this issue has been the use of osmotic minipumps to ensure continuous antipsychotic exposure over prolonged intervals, which is routinely the case when these same drugs are administered to humans. More recently, it has been identified that with olanzapine this approach may be compromised by oxidative degradation, a process that can be observed within days. Further, in vivo evidence has reported progressive decreases in plasma levels over a 1-month interval. To address this issue in vitro, osmotic minipumps (n = 4), with olanzapine at a concentration resulting in a dose of 7.5 mg/kg/day in vivo, were placed in saline-filled Falcon tubes and immersed in a water bath. Olanzapine concentrations were assessed in the minipumps as well as the surrounding water bath at baseline, 1 h, and days 1, 7, 14, 21, and 28. Minipump results indicated a monophasic exponential decay and a half-life of 14.8 days (95% CI = 13.1-17.1 days). Results from the water bath demonstrated a linear increase in olanzapine up to and including day 21, followed thereafter by a decrease to day 28. It is concluded that administration of olanzapine via osmotic minipump is viable in animal models to mirror what occurs in humans, although the interval should be confined to 2 weeks. As well, strategies in dissolving olanzapine to diminish oxidation are discussed.