Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist.

INTRODUCTION: We assessed the effect of the prandial state on the pharmacokinetics, safety, and tolerability of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide 1 receptor agonist (GLP-1 RA), in two studies (A and B). METHODS: Study A and study B were phase 1, randomized, crossover studies in healthy adults aged 18-65 years and 21-70 years, respectively. Participants received single (3 mg, study A) or multiple (16 mg, study B) oral doses of orforglipron under fasted and fed conditions. Blood samples were collected pre- and postdose to assess area under the concentration-time curve (AUC), maximum observed drug concentration (Cmax), time of Cmax (tmax), and half-life (t1/2) associated with terminal rate constant. AUC and Cmax were analyzed using a linear mixed-effects model. Treatment differences were presented as ratios of geometric least squares means (GLSM). Treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse events were assessed. RESULTS: Study A included 12 participants (mean age 45.0 years; male 66.7%); study B included 34 participants (mean age 42.8 years; male 88.2%). GLSM AUC and Cmax were lower by 23.7% and 23.2% in study A, and 17.6% and 20.9% in study B, in the fed versus fasted states, respectively. In both studies, t1/2 and median tmax were comparable between fed and fasted states. The majority of TEAEs in both studies were gastrointestinal tract-related conditions. No serious adverse events or deaths were reported in either study. CONCLUSION: The observed pharmacokinetic differences due to the prandial state are unlikely to contribute to clinically meaningful differences in the efficacy of orforglipron. The safety profile was consistent with the known profiles of other GLP-1 RAs. Given the absence of prandial restrictions, orforglipron may emerge as a convenient oral treatment option for patients with type 2 diabetes or obesity. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03929744 and NCT05110794.

A Prospective Multi-centric Study of Acceptance, Insertion and Follow-Up of Postpartum Insertions of IUCD.

Purpose of the Study: The unmet need for contraception in the postpartum period is a major challenge in our country. Unintended pregnancies are highest in the first year after birth, and postpartum IUCD insertion is an effective way to counter this problem. This study was planned to build up data for acceptance and follow-up of postpartum IUCD insertions. Methods: The present study has included data of PPIUCD insertions and follow-up from seven institutions over a period of 6 months. The case recruitment lasted for 3 months, including only those who had PPIUCD insertions in this period, and they were followed up for a period of 6 months. The follow-up of patients was at 6 weeks and 6 months. All issues were addressed including side effects, expulsions, myths surrounding the device, etc., along with routine postnatal care. Results and Conclusion: There were 5227 deliveries and 1895 insertions. The acceptance rate was 36%, and a follow-up at 6 weeks and 6 months showed up an expulsion rate of approximately 4% and a removal rate of 5%. Overall, at the end of 6 months we have a continuation rate of 90%. This shows that a dedicated approach to postpartum contraception will definitely bring down incidence of unintended pregnancies.

Modulating target engagement of small molecules via drug delivery: approaches and applications in drug discovery and development.

Drug-delivery technologies for modified drug release have been in existence for decades, but their utilization has been largely limited to post-launch efforts improving therapeutic outcomes. Recently, they have gained renewed importance because the pharmaceutical industry is steadily shifting to a more integrated discovery-development approach. In discovery, modulating target engagement via drug-delivery technologies can enable crucial pharmacological studies for building well-defined criteria for molecular design. In development, earlier implementation of delivery technologies can enhance the value of drug products through reduced dosing frequency and improved tolerability and/or safety profile, thereby leading to better adherence and therapeutic effectiveness.

Synthesis and characterization of Zinc oxide nanoparticles utilizing seed source of Ricinus communis and study of its antioxidant, antifungal and anticancer activity.

ZnO nanoparticles have been synthesized using solution combustion technique and its antioxidant, antifungal, anticancer activity was studied. Ricinus communis plant seed extract used as fuel in synthesis by the solution combustion technique. Powder X-ray diffraction (PXRD) demonstrates the arrangement of a crystalline hexagonal stage (ICDD card number 89-1397) with space aggregate P63mc (186) and cell parameters a = b = 3.253, c = 5.213 Å. The normal crystallite measure is 20 nm which is ascertained by Debye - Scherer's formula. The Purity of the sample and metal to oxygen bond development was affirmed by utilizing Fourier transformation infrared (FTIR) spectroscopy and the particle size and shape was confirmed by HRTEM. Antifungal action of ZnO NPs was studied against Aspergillus and Penicillium by well dispersion strategy. The antifungal activity shows that ZnO NPs constitute as an effective fungicidal agent against both Aspergillus (4 ±â€¯0.5 mm) and Penicillium (3 mm ±â€¯0.4 mm) at 30 µg/mL fixation. ZnO nanoparticles were subjected to antioxidant activity. The objective of the study was to analyze the anticancer property of ZnO NPs on MDA-MB 231 cancer cells. To check the efficacy of the synthesized drug ZnO NPs MTT assay was performed, that determines % viability and/or cytotoxicity. IC50 of ZnO NPs in case of MDA-MB-231 breast cancer was 7.103 µg/mL. Anticancer outcome demonstrates that ZnO NPs is active against in MDA-MB-231 cells.

Ruthenium-decorated vanadium pentoxide for room temperature ammonia sensing.

Layer structured vanadium pentoxide (V2O5) microparticles were synthesized hydrothermally and successfully decorated by a facile wet chemical route, with ∼10-20 nm sized ruthenium nanoparticles. Both V2O5 and ruthenium nanoparticle decorated V2O5 (1%Ru@V2O5) were investigated for their suitability as resistive gas sensors. It was found that the 1%Ru@V2O5 sample showed very high selectivity and sensitivity towards ammonia vapors. The sensitivity measurements were carried out at 30 °C (room temperature), 50 °C and 100 °C. The best results were obtained at room temperature for 1%Ru@V2O5. Remarkably as short a response time as 0.52 s @ 130 ppm and as low as 9.39 s @ 10 ppm recovery time at room temperature along with high selectivity towards many gases and vapors have been noted in the 10 to 130 ppm ammonia concentration range. Short response and recovery time, high reproducibility, selectivity and room temperature operation are the main attributes of the 1%Ru@V2O5 sensor. Higher sensitivity of 1%Ru@V2O5 compared to V2O5 has been explained and is due to dissociation of atmospheric water molecules on 1%Ru@V2O5 as compared to bare V2O5 which makes hydrogen atoms available on Brønsted sites for ammonia adsorption and sensing. The presence of ruthenium with a thin layer of oxide is clear from X-ray photoelectron spectroscopy and that of water molecules from Fourier transform infrared spectroscopy.

Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1.

We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC80 of 24nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours.

Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors.

Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30µM, and failed to inhibit human mPGES-2 at 62.5µM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.

Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.

As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 µM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.

HIV with non-communicable diseases in primary care in Kibera, Nairobi, Kenya: characteristics and outcomes 2010-2013.

BACKGROUND: Antiretroviral therapy (ART) has increased the life expectancy of people living with HIV (PLHIV); HIV is now considered a chronic disease. Non-communicable diseases (NCDs) and HIV care were integrated into primary care clinics operated within the informal settlement of Kibera, Nairobi, Kenya. We describe early cohort outcomes among PLHIV and HIV-negative patients, both of whom had NCDs. METHODS: A retrospective analysis was performed of routinely collected clinic data from January 2010 to June 2013. All patients >14 years with hypertension and/or diabetes were included. RESULTS: Of 2206 patients included in the analysis, 210 (9.5%) were PLHIV. Median age at enrollment in the NCD program was 43 years for PLHIV and 49 years for HIV-negative patients (p<0.0001). The median duration of follow up was 1.4 (IQR 0.7-2.1) and 1.0 (IQR 0.4-1.8) years for PLHIV and HIV-negative patients, respectively (p=0.003). Among patients with hypertension, blood pressure outcomes were similar, and for those with diabetes, outcomes for HbA1c, fasting glucose and cholesterol were not significantly different between the two groups. The frequency of chronic kidney disease (CKD) was 12% overall. Median age for PLHIV and CKD was 50 vs 55 years for those without HIV (p=0.005). CONCLUSIONS: In this early comparison of PLHIV and HIV-negative patients with NCDs, there were significant differences in age at diagnosis but both groups responded similarly to treatment. This study suggests that integrating NCD care for PLHIV along with HIV-negative patients is feasible and achieves similar results.

Hepatitis C screening.

BACKGROUND: Hepatitis C screening is now recommended for all individuals born between the years 1945-1965 in addition to individuals who have high-risk factors. Although most clinicians have extensive experience with the diagnosis and treatment of the disease, they have limited experience screening for it. METHODS: We report current screening guidelines and methods. RESULTS: By identifying the disease as early as possible, screening and treatment can reduce morbidity and mortality. CONCLUSION: Screening for hepatitis C leads to the appropriate evaluation and treatment of individuals chronically infected with the hepatitis C virus and prevents the progression of liver disease to cirrhosis, hepatocellular carcinoma, and the associated morbidity and mortality. Screening for hepatitis C is also cost effective.

Progressive multifocal leukoencephalopathy (PML) associated with HIV Clade C--is not uncommon.

Progressive multifocal leukoencephalopathy (PML) is a rare, subacute, demyelinating disease of the central nervous system caused by JC virus. Studies of PML from HIV Clade C prevalent countries are scarce. We sought to study the clinical, neuroimaging, and pathological features of PML in HIV Clade C patients from India. This is a prospective cum retrospective study, conducted in a tertiary care Neurological referral center in India from Jan 2001 to May 2012. Diagnosis was considered "definite" (confirmed by histopathology or JCV PCR in CSF) or "probable" (confirmed by MRI brain). Fifty-five patients of PML were diagnosed between January 2001 and May 2012. Complete data was available in 38 patients [mean age 39 ± 8.9 years; duration of illness-82.1 ± 74.7 days). PML was prevalent in 2.8 % of the HIV cohort seen in our Institute. Hemiparesis was the commonest symptom (44.7 %), followed by ataxia (36.8 %). Definitive diagnosis was possible in 20 cases. Eighteen remained "probable" wherein MRI revealed multifocal, symmetric lesions, hypointense on T1, and hyperintense on T2/FLAIR. Stereotactic biopsy (n = 11) revealed demyelination, enlarged oligodendrocytes with intranuclear inclusions and astrocytosis. Immunohistochemistry revelaed the presence of JC viral antigen within oligodendroglial nuclei and astrocytic cytoplasm. No differences in clinical, radiological, or pathological features were evident from PML associated with HIV Clade B. Clinical suspicion of PML was entertained in only half of the patients. Hence, a high index of suspicion is essential for diagnosis. There are no significant differences between clinical, radiological, and pathological picture of PML between Indian and Western countries.

Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus,™ simulations to predict absorption.

Dogs are one of the most commonly used non-rodent species in toxicology studies and are known to have basal stomach pH ranging from 2 to 7 in the fasted state. Thus absorption and resulting plasma exposure of weakly basic compounds administered as crystalline suspensions to dogs are often variable. LY2157299 is a potent and selective transforming growth factor (TGF)-beta receptor type 1 kinase (TGF-ßRI) inhibitor that displayed variable absorption in early dog studies. This molecule is a weakly basic Biopharmaceutics Classification System (BCS)Class II compound, and depends on the rate and extent of dissolution to drive oral absorption. An artificial stomach and duodenum (ASD) dissolution model was utilized to evaluate potential effect of gastric pH on the absorption of suspension and buffered solution formulations. GastroPlus™ was also employed to predict the magnitude of gastric pH changes on LY2157299 absorption. The ASD experiments demonstrated that administration of a buffered acidic solution could improve the potential for absorption by normalizing gastric pH and enabling supersaturation in the duodenum. GastroPlus™ modeling suggested that direct modulation of gastric pH could lead to marked changes in bioavailability. Pharmacokinetic experiments were conducted in dogs to evaluate the effect of gastric pH modification on plasma exposure. The data were qualitatively consistent with the predictions.

Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor.

Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for the treatment of inflammatory pain and other nervous system disorders. Herein, we report the discovery and characterization of a highly efficacious and selective FAAH inhibitor PF-04457845 (23). Compound 23 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (k(inact)/K(i) and IC(50) values of 40300 M(-1) s(-1) and 7.2 nM, respectively, for human FAAH). Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. Oral administration of 23 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Compound 23 is being evaluated in human clinical trials.

Weak bases and formation of a less soluble lauryl sulfate salt/complex in sodium lauryl sulfate (SLS) containing media.

This work reports on the solubility of two weakly basic model compounds in media containing sodium lauryl sulfate (SLS). Results clearly show that the presence of SLS in the media (e.g. simulated gastric fluid or dissolution media) can result in an underestimation of solubility of some weak bases. We systematically study this phenomenon and provide evidence (chromatography and pXRD) for the first time that the decrease in solubility is likely due to formation of a less soluble salt/complex between the protonated form of the weak base and lauryl sulfate anion.

Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain.

The endogenous cannabinoid (endocannabinoid) anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH). Pharmacological blockade of FAAH has emerged as a potentially attractive strategy for augmenting endocannabinoid signaling and retaining the beneficial effects of cannabinoid receptor activation, while avoiding the undesirable side effects, such as weight gain and impairments in cognition and motor control, observed with direct cannabinoid receptor 1 agonists. Here, we report the detailed mechanistic and pharmacological characterization of N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidine-1-carboxamide (PF-04457845), a highly efficacious and selective FAAH inhibitor. Mechanistic studies confirm that PF-04457845 is a time-dependent, covalent FAAH inhibitor that carbamylates FAAH's catalytic serine nucleophile. PF-04457845 inhibits human FAAH with high potency (k(inact)/K(i) = 40,300 M(-1)s(-1); IC(50) = 7.2 nM) and is exquisitely selective in vivo as determined by activity-based protein profiling. Oral administration of PF-04457845 produced potent antinociceptive effects in both inflammatory [complete Freund's adjuvant (CFA)] and noninflammatory (monosodium iodoacetate) pain models in rats, with a minimum effective dose of 0.1 mg/kg (CFA model). PF-04457845 displayed a long duration of action as a single oral administration at 1 mg/kg showed in vivo efficacy for 24 h with a concomitant near-complete inhibition of FAAH activity and maximal sustained elevation of anandamide in brain. Significantly, PF-04457845-treated mice at 10 mg/kg elicited no effect in motility, catalepsy, and body temperature. Based on its exceptional selectivity and in vivo efficacy, combined with long duration of action and optimal pharmacokinetic properties, PF-04457845 is a clinical candidate for the treatment of pain and other nervous system disorders.

Outcomes after carotid angioplasty and stenting in symptomatic octogenarians.

OBJECTIVE: Octogenarians were excluded from participation in many carotid endarterectomy trials due to the high complication rates observed in past studies. However, stroke resulting from carotid stenosis is expected to increase with the aging population. Moreover, advances in Carotid Angioplasty and Stenting (CAS) techniques have resulted in perceived improved safety of this procedure. We sought to review our experience with carotid stenting in symptomatic octogenarians with an emphasis on short-term outcomes and complications. METHODS: This is a retrospective longitudinal cohort study of all symptomatic patients who underwent CAS in our center between 1997 and 2007. Thirty-day stroke and death rates, and length of hospitalization were compared between the symptomatic octogenarians and non-octogenarians. RESULTS: A total of 214 procedures were performed on 211 symptomatic patients (56 females). Fifty-nine patients (14 females) were octogenarians. The median (interquartile range) age on procedure date for the octogenarian cohort was 83 (4) years. Periprocedural death occurred in two (3.4%) octogenarians and five (3.3%) non-octogenarians (p = 0.97). At 30 days from the procedure, stroke occurred in four (6.8%) octogenarians and seven (4.6%) non-octogenarians (p= 0.52). The mean hospital stay (4.8 days) was not different between the two cohorts. Age was not a predictor of the 30-day risk of composite stroke or death. CONCLUSION: The complications rate observed in octogenarians was not significantly higher than non-octogenarians. Our findings suggest that octogenarians should be included in randomized trials examining CAS to better define the risk-benefit profile of this procedure in the elderly.

Carotid stenting in asymptomatic carotid stenosis: the Calgary experience.

BACKGROUND: Although carotid endarterectomy is considered the 'gold standard' for standard risk symptomatic patients, the treatment of choice for asymptomatic patients remains controversial. Carotid stenting has demonstrated real-world outcomes consistent with established guidelines for carotid endarterectomy in asymptomatic high-surgical risk patients in recent prospective multicenter trials. We describe our experience with asymptomatic patients who underwent carotid stenting at our center in a routine clinical setting. METHODS: This is a retrospective, longitudinal cohort study of patients who underwent carotid angioplasty and stenting at the Foothills Medical Center, Calgary, Canada between 1997 and 2007. The qualifying events were categorized as symptomatic and asymptomatic. The procedures were performed by four experienced neurointerventionists. The primary outcome was stroke or death at 30-day follow- up. RESULTS: 243 patients underwent 255 carotid stenting procedures. Their ages ranged from 50 to 83 years; the mean age was 72.0 ± 9.3 years; 67(26.3%) were women. Forty one patients (16.1%) were asymptomatic; 214 patients (83.9%) were symptomatic. The patients in the asymptomatic group were significantly younger - 66.0 ± 8.8 years compared to patients in the symptomatic group 73.2 ± 8.9 years (p < 0.0001). Intraprocedurally one minor stroke (2.4%) occurred in the asymptomatic group. At 30-day follow-up, no deaths or further strokes were noted in the asymptomatic group; while eight deaths, six major and seven minor strokes occurred in the symptomatic group (p = 0.22). CONCLUSION: Carotid stenting appears to be a safe procedure in asymptomatic patients with severe carotid stenosis in routine clinical settings as witnessed in this single center study.

Differences in stroke outcome based on sex.

OBJECTIVE: Stroke thrombolysis may have a differential effect by sex. We sought to examine the relationship between sex and outcome after thrombolysis. METHODS: This is a retrospective cohort study of stroke patients from the Registry of Canadian Stroke Network phase 1 (June 2001-February 2002) and phase 2 (June 2002-December 2002). Variables including demographics, history, clinical data, process measures, and outcome were analyzed. The primary outcomes were the Stroke Impact Scale-16 score (SIS-16) and mortality at 6 months. We compared the outcomes of the thrombolyzed and nonthrombolyzed cohorts and examined the data for a tissue plasminogen activator (tPA)-by-sex interaction on the 2 primary outcomes. RESULTS: The overall proportion of patients who achieved an excellent outcome (SIS-16 >75) was not different by gender. However, the proportion of patients achieving an excellent outcome in the non-tPA cohort was much greater in males, with an absolute risk difference of 11.8%. A multiplicative treatment by sex interaction was evident (p = 0.054). This interaction was not present for stroke case fatality. CONCLUSIONS: Women fared poorly compared to men in the placebo groups, but this negative prognostic sex effect was neutralized by thrombolysis.