Linagliptin in Combination With Metformin Ameliorates Diabetic Osteoporosis Through Modulating BMP-2 and Sclerostin in the High-Fat Diet Fed C57BL/6 Mice

BackgroundDiabetic osteoporosis is a poorly managed serious skeletal complication, characterized by high fracture risk, increased bone resorption, reduced bone formation, and disrupted bone architecture. There is a need to investigate drugs that can improve bone health along with managing glycemic control. DPP-4 inhibitors and metformin have proven benefits in improving bone health. Here, we investigated the effects of linagliptin, a DPP inhibitor, and metformin alone and in combination to treat diabetic osteoporosis in high-fat-fed mice.MethodsC57BL/6 mice were kept on the high-fat diet (HFD) for 22 weeks to induce diabetic osteoporosis. Linagliptin (10mg/Kg), metformin (150mg/Kg), and their combination were orally administered to the diabetic mice from the 18th-22nd week. Femur and tibial bone microarchitecture together with bone mineral density (BMD) were evaluated using µCT and histopathological changes were assessed. Further, bone turnover biomarkers namely bone morphogenetic protein-2 (BMP-2), sclerostin, tartrate-resistant acid phosphatase (TRAP), osteocalcin, alkaline phosphatase (ALP), calcium, and pro-inflammatory cytokines were assessed. Additionally, metabolic parameters including body weight, fasting blood glucose (FBG), glucose & insulin tolerance, lipids profile, and leptin were measured.ResultsHFD feeding resulted in impaired bone microarchitecture, reduced BMD, distorted bone histology, and altered bone turnover biomarkers as indicated by the significant reduction in bone ALP, BMP-2, osteocalcin, and an increase in sclerostin, TRAP, and serum calcium. Interestingly, treatment with linagliptin and its combination with metformin significantly reverted the impaired bone architecture, BMD, and positively modulated bone turnover biomarkers, while metformin alone did not exhibit any significant improvement. Further, HFD induced diabetes and metabolic abnormalities (including an increase in body weight, FBG, impaired glucose and insulin tolerance, leptin, triglycerides, cholesterol), and pro-inflammatory cytokines (TNF-alpha and IL-1β) were successfully reversed by treatment with linagliptin, metformin, and their combination.ConclusionLinagliptin and its combination with metformin successfully ameliorated diabetic osteoporosis in HFD-fed mice possibly through modulation of BMP-2 and sclerostin. The study provides the first evidence for the possible use of linagliptin and metformin combination for managing diabetic osteoporosis

PHARMACOKINETIC STUDY OF OLOPATADINE 10 MG EXTENDED RELEASE TABLET IN COMPARISON WITH OLOPATADINE 5 MG IMMEDIATE RELEASE TABLET IN INDIAN POPULATION

Objective: This study was designed to assess the pharmacokinetics of single dose of olopatadine hydrochloride 10 mg extended release (ER) tablet of Ranbaxy laboratories limited (two test formulations) with two doses of Allelock® 5 mg immediate release (IR) tablets of Kyowa Hakko Kogyo Co. Ltd. (reference formulation R), in healthy, adult, Indian male subjects under fed condition. Methods: Fifteen healthy male volunteers, 26.07±6.62 y in age and 57.17±6.68 kg in body weight, were divided into three groups and received either olopatadine hydrochloride 10 mg ER tablet or two doses of Allelock® 5 mg tablets in each period. Blood samples were taken at predetermined time points and plasma concentrations of olopatadine were monitored by liquid chromatography mass spectrometric (LCMS/MS). Pharmacokinetic (PK) parameters AUC0-t, AUC0-24, AUC0-∞, and Cmax were calculated for olopatadine using WinNonlin. A statistical analysis was performed on PK data using SAS system. Results: The ER formulations showed a similar AUC as compared to the IR formulation and there was no statistically significant difference in AUC of test formulation A and B and reference R. The ratios of AUC0-t, AUC0-24 and AUC0-∞ for A/R were 91.08, 94.90 and 91.32 and for B/R were 89.63, 93.95 and 89.63 respectively. The ER formulations reported a higher Cmax value as compared to IR formulation. The ratios of Cmax for A/R and B/R were 151.09 and 167.96 respectively. But these higher Cmax values did not pose any safety issue as there were no serious adverse events reported during the study. Conclusion: In conclusion, we can say that though the study drugs did not meet the bioequivalence criteria set by regulatory agencies, but this study gave an insight about PK properties of olopatadine extended release formulation and given an idea about effect of smoking on the PK profile of olopatadine which can be studied in future

COMPARATIVE EFFECT OF BETA BLOCKERS AND ANGIOTENSIVE RECEPTOR BLOCKERS ON BLOOD GLUCOSE LEVEL IN HYPERTENSIVE PATIENTS IN UNIVERSITY HOSPITAL

Objective: There is highly co-incidence between hypertension and insulin resistance which is the important causative factor to develop diabetes mellitus (DM). There is paucity of data to establish the effect of beta-blockers and ARB on blood glucose level in Indian population. Therefore the present study was planned to search so that confederation among Indian population in a teaching hospital. Methods: The research study was carried out in 85 hypertensive patients without diabetes visiting the OPD of University teaching hospital (Majeedia hospital) New Delhi. Blood glucose levels and drug history of hypertensive patients were observed during four month of study. Results: The gender distribution of hypertensive patients reveals a higher percentage of incidences in males (53%) as compared to females (47%). Hypertensive patient without diabetes mellitus (DM) on beta blockers shows higher incidence of impaired glucose tolerance (IGT) (13.3%) and DM (5%) as compared to patient receiving ARBs as antihypertensive therapy. There was proportionate increase in incidence as the duration of therapy. None of the patients who were on angiotensin receptor blockers (ARBs) reported any incidence of IGT or DM. Conclusion: Beta blockers  may be the risk factor to develop diabetes mellitus type 2 on long term use as an antihypertensive therapy. There were no any incidence of impaired glucose tolerance or diabetes mellitus found in case of patients taking ARBs as an antihypertensive therapy so it can be safely prescribe in hypertensive patients associated with diabetes mellitus type 2. Key Words: Hypertension, Diabetes mellitus, Impaired glucose tolerance, Beta blockers and ARBs

Data of aromatase inhibitors alone and in combination with raloxifene on microarchitecture of lumbar vertebrae and strength test in femoral diaphysis of VCD treated ovotoxic mice

Currently, the third generation aromatase inhibitors are the drugs of choice for treatment of early and advanced breast cancer in postmenopausal women. The negative impact of these drugs on bone health is the significant limiting factor during this therapy. Here we report the effect of two aromatase inhibitors viz. letrozole and exemestane alone and in combination with raloxifene on lumbar vertebrae and femoral diaphysis after one month of treatment but no discernible effects were observed on bone when tested by micro CT and strength test except in trabecular number which was reduced in lumbar vertebrae following letrozole and exemestane. Further studies with letrozole and exemestane should be done at higher doses for longer duration of time to check whether effects are observed in other parameters as well. The data is an extension of our published work in Mol. Cell Endocrinology (A. Kalam, S. Talegaonkar, D. Vohora, 2017) [1] describing letrozole-induced bone loss on femoral epiphysis and its reversal by raloxifene

Serotonin reuptake inhibitors and bone health: A review of clinical studies and plausible mechanisms

Selective serotonin reuptake inhibitors (SSRIs) are currently the treatment of choice in depression and constitute major portion of prescription in depressive patients. The role of serotonin receptors in bone is emerging, raising certain questions regarding the effect of blockade of serotonin reuptake in the bone metabolism. Clinical studies have reported an association of SSRI antidepressants which with increase in fracture and decrease in bone mineral density. This review focus on recent evidence that evaluate the association of SSRIs with the risk of fracture and bone mineral density and also the probable mechanisms that might be involved in such effects

Antiepileptic drugs prescription utilization behavior and direct costs of treatment in a national hospital of India

Background and Objectives: The present study evaluated the direct costs of active epilepsy and looked at the pattern of drug prescription and utilization in epileptic patients visiting the neuroscience centre of a national hospital of India. Materials and Methods: A total of 134 epileptic patients were studied over a period of 4 months. Patients demography, commonly prescribed antiepileptic drugs (AEDs), socioeconomic status, direct costs, response ratio (RR) for newer drugs, and quality of life (QOLIE-10) was evaluated. Results and Discussion: We found a higher percentage of male patients (67.9%) as compared with females. Most of the patients were in the age group 11-30 years and majority of them (39.6%) belonged to lower middle group. A higher percentage (68.7) of drugs was prescribed as polytherapy. Higher monthly cost was observed for some of the newer AEDs including the lamotrigine, levetiracetam, and lacosamide as compared with older drugs. Among the newer drugs, clobazam had the lowest cost. RR was calculated for 12 patients out of which 8 had a RR < −0.50. The QOL domains, following conventional or newer drugs, were not much affected. Conclusion: The study indicates an increasing trend toward clinical usage of newer AEDs, increasing trend of poly-therapy with significant escalations in the cost of therapy

Prevalence of osteoporosis and osteopenia in an apparently healthy Indian population - a cross-sectional retrospective study

Objectives: An understanding of bone mineral density (BMD) pattern in a population is crucial for prevention and diagnosis of osteoporosis and management of its complications in later life. This study aimed to screen the bone health status and factors associated with osteoporosis in an apparently healthy Indian population. Methods: A retrospective review of medical records was done in a tertiary-care hospital for the subjects who had undergone preventive health-check-ups that included BMD measurements at femur-neck, total-femur, and lumbar-spine. Results: We evaluated 524 subjects (age, 50.0 ± 12.4 years) including 41.2% female and 58.8% male subjects. Osteoporosis was present in 6.9% subjects (female, 11.1%; male, 4.2%) and osteopenia in 34% subjects (female, 40.3%; male, 29.9%). Absolute BMD was higher in male subjects (P  0.05) at any site. Conclusions: Further data on absolute BMD, T scores, and prevalence rates of osteoporosis/osteopenia on multiple bone sites have been presented in this article. Keywords: Osteoporosis, Bone mineral density, Prevalence, T-scores, Osteopeni