Effect of Bedaquiline and Delamanid Pharmacokinetics on Sputum Culture Conversion and Adverse Events in Drug-Resistant Tuberculosis.

BACKGROUND: Pharmacokinetic studies of bedaquiline and delamanid in patients with pre-extensively drug-resistant tuberculosis (pre-XDR TB) will help in the optimization of these drugs for both culture conversion and adverse events. METHODS: A prospective cohort of 165 adult patients (56% male with mean [SD] age 29 [9.7] years) with pre-XDR TB was treated with bedaquiline, delamanid, clofazimine, and linezolid for 24 weeks at 5 sites in India. Bedaquiline was administered at 400 mg daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks, whereas delamanid was administered at 100 mg twice daily. In 23 consenting participants at 8 and 16 weeks of treatment, blood was collected at 0, 2, 4, 5, 6, 8, 12, and 24 hours postdosing for an intense pharmacokinetic study. Pharmacokinetic parameters were correlated with sputum culture conversion and adverse events. RESULTS: The mean (SD) age and weight of patients were 30 (10) years and 54 kg, respectively. The median minimum concentration (C min ) and time-concentration curve (AUC) for bedaquiline, respectively, were 0.6 mcg/mL and 27 mcg/mL·h at week 8 and 0.8 mcg/mL and 36 mcg/mL·h at week 16, suggesting drug accumulation over time. The median C min and AUC of delamanid, respectively, were 0.17 mcg/mL and 5.1 mcg/mL·h at week 8 and 0.20 mcg/mL and 7.5 mcg/mL·h at week 16. Delay in sputum conversion was observed in patients with drug concentrations lower than the targeted concentration. At weeks 8 and 16, 13 adverse events were observed. Adverse events were resolved through symptomatic treatment. Body mass index was found to be significantly associated with drug-exposure parameters. CONCLUSIONS: Bedaquiline and delamanid when co-administered exhibit plasma drug levels within the targeted concentrations, showing an exposure-response relationship.

Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis.

BACKGROUND: Treatment success rates for multidrug-resistant tuberculosis (MDR-TB) remain low globally. Availability of newer drugs has given scope to develop regimens that can be patient-friendly, less toxic, with improved outcomes. We proposed to determine the effectiveness of an entirely oral, short-course regimen with Bedaquiline and Delamanid in treating MDR-TB with additional resistance to fluoroquinolones (MDR-TBFQ+) or second-line injectable (MDR-TBSLI+). METHODS: We prospectively determined the effectiveness and safety of combining two new drugs with two repurposed drugs - Bedaquiline, Delamanid, Linezolid, and Clofazimine for 24-36 weeks in adults with pulmonary MDR-TBFQ+ or/and MDR-TBSLI+. The primary outcome was a favorable response at end of treatment, defined as two consecutive negative cultures taken four weeks apart. The unfavorable outcomes included bacteriologic or clinical failure during treatment period. RESULTS: Of the 165 participants enrolled, 158 had MDR-TBFQ+. At the end of treatment, after excluding 12 patients due to baseline drug susceptibility and culture negatives, 139 of 153 patients (91%) had a favorable outcome. Fourteen patients (9%) had unfavorable outcomes: four deaths, seven treatment changes, two bacteriological failures, and one withdrawal. During treatment, 85 patients (52%) developed myelosuppression, 69 (42%) reported peripheral neuropathy, and none had QTc(F) prolongation >500msec. At 48 weeks of follow-up, 131 patients showed sustained treatment success with the resolution of adverse events in the majority. CONCLUSION: After 24-36 weeks of treatment, this regimen resulted in a satisfactory favorable outcome in pulmonary MDR-TB patients with additional drug resistance. Cardiotoxicity was minimal, and myelosuppression, while common, was detected early and treated successfully.

Effect of pantoprazole on I-R-induced myocardial injury in diabetic rats targeting inflammatory cytokine release and oxidative stress.

OBJECTIVES: To evaluate the pleiotropic potential and underlying mechanism of pantoprazole (PPZ) (common Proton Pump Inhibitors, PPIs) in type 2 diabetes mellitus (T2DM) -associated ischemia/reperfusion (I-R)-induced myocardial infarction which is still uncharted. Whereas some other PPIs have demonstrated their anti-diabetic, antioxidant, and anti-inflammatory potential. MATERIALS AND METHODS: We evaluated the potential of coinciding treatment of PPZ (4 mg/kg/po/day for 8 weeks) in Wistar albino rats against STZ (50 mg/kg/IP) induced T2DM model and I-R provoked cardiac infarction model in diabetic and non-diabetic condition. RESULTS: PPZ significantly inhibited the perturbed deviations in blood glucose concentration, HbA1c, C-peptide, plasma insulin, and ameliorated the lipid profile (dyslipidemia). PPZ protected myocardial tissue against lipid peroxidation by restoring the levels of serum TBARS and reduced NBT. The significant protective effects of PPZ were evident by ameliorating CKMB, LDH, cTnI, and myocardial oxidative stress in PPZ treated animals. Additionally, PPZ prominently reduced various proinflammatory cytokines release including TGF-ß1, TNF-α, and IL-6. PPZ upsurges the bioavailability of nitrite/nitrate concentration which may pacify the impact of myocardial infarction in diabetic I-R injury. CONCLUSION: The consequences indicate that PPZ possesses a potent protective effect against diabetic I-R-induced myocardial infarction via suppressing oxidative stress, inflammation, and dyslipidemia-associated tissue damage.

Dose and time-dependent toxicological impact of pantoprazole on vascular endothelium and renal tissue.

Proton pump inhibitors (PPIs) have wide pleiotropic action in addition to their therapeutic potential in gastroesophageal reflux diseases. Conversely, recent reports revealed a significant incidence of toxic events of PPIs including nephritis, osteoporosis, and cardiac damage. Thus, the study was designed to reconcile the deceptive contraindications. The present investigation targeted to reveal the toxic impact of sub-acute and sub-chronic administration of pantoprazole (PPZ) with different concentrations (low dose 4 mg/kg, medium-dose 8 mg/kg and high dose 16 mg/kg once a day) on normal vascular endothelium and renal tissue of rats. Vascular endothelial dysfunction (VED) was estimated by the contractility of an isolated aortic ring, nitrite/nitrate concentration, oxidative stress, and integrity of the endothelium layer. Moreover, the renal abnormalities were further confirmed by an increased level of serum creatinine, blood urea nitrogen (BUN), the incidence of microproteinuria, and structural alteration. Sub-acute administration of PPZ treatment did not produce any toxicological impact on endothelium and renal tissue. Whereas, sub-chronic administration of PPZ treatment causes moderate VED and renal dysfunction in a dose-dependent manner. Sub-chronic treatment of PPZ also influences the mitigation of NO and elevation of oxidative stress. Collecting all the evidence, it concludes that decreased nitric oxide availability and increased levels of oxidative stress may be a possible underlying mechanism of causing VED and renal abnormalities from high-dose PPZ treatment.

Insulin analogs: Glimpse on contemporary facts and future prospective.

Insulin remains a predominant life-saving medication for type 1 and type 2 Diabetes Mellites. Natural insulin secretion limits the fluctuation of the narrow and high surge of blood glucose levels. However, imitating the same by external insulin remains a challenge as a variety of insulin analogs (rapid acting, short acting, intermediate acting and long-acting) have different pharmacokinetic (PK) and pharmacodynamic (PD) properties. Inconsistent reduction in overall hyperglycemia level and nocturnal hypoglycemia due to variable absorption time and time action profile predominantly highlights the need of revisiting the PK/PD of insulin analogs as single analog is not yet sufficed to replace internal insulin exogenously. Combination therapy with basal and prandial insulins or intensification of hypoglycemic therapy with premixed insulins are of prime importance in managing diabetes effectively, imitating the natural insulin secretion. Therefore, the knowledge of PK/PD properties might help a practitioner to design, implement and manage insulin replacement therapy effectively and averting adverse events. Present study reports the comparative analysis of PK/PD profile of various insulin analogs based on the concurrent information about clinical aspects. Moreover, study interlinks the major concerns of therapeutic efficacy of insulin analogs with their respective onset of action and duration of effectiveness and reported adverse drug reaction which explore the scope of improvement.

Nano-medicine and Vascular Endothelial Dysfunction: Options and Delivery Strategies.

The endothelium is a thin innermost layer of flat cells which release various mediators including endothelin-1 (ET-1), prostanoids, von Willebrand factor (vWF) and endothelium-derived relaxing factor (EDRF; nitric oxide) to regulate vascular tone. Endothelial nitric oxide synthase (eNOS) is a key enzyme that generates nitric oxide (NO). NO maintains vascular homeostasis and cardiac functions by influencing major vascular protective properties such as anti-platelet, anti-proliferative, anti-migratory, antioxidant and anti-inflammatory action in vessels. Abnormal endothelial production and release of NO lead to vascular endothelial dysfunction (VED) and further leads to pathogenesis in myocardial and other tissues. Numerous pharmacological agents such as angiotensin-converting enzyme inhibitors, statins, calcium channel blockers, ET-1 receptor antagonists, insulin sensitizers, antioxidants and supplements like tetrahydrobiopterin, arginine and folate have been implicated in the treatment of VED, but their therapeutic potency was restricted due to some unavoidable adverse effects. The new era with advances in nanotechnology and its ability to target a specific disease, nano-medicine explored an innovative gateway for advanced therapy for VED. The present commentary reveals the various available, pipeline nano-medicine, their interaction with endothelium and in other associated pathological conditions and their delivery strategies for target-specific treatment of VED.

Evaluation of oral pharmacokinetics, in vitro metabolism, blood partitioning and plasma protein binding of novel antidiabetic agent, S009-0629 in rats.

S009-0629 [methyl-8-(methylthio)-2-phenyl-6-p-tolyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate] is a novel antidiabetic agent with PTP1B inhibitory activity. In this study, we have investigated the in vitro metabolic stability, plasma protein binding, blood partitioning, and oral pharmacokinetic study of S009-0629 in rats. The plasma protein binding, blood partitioning, and metabolic stability were determined by HPLC method. The oral pharmacokinetic study was analyzed by liquid chromatography coupled mass spectrometry (LC-MS/MS) method. The plasma protein binding of S009-0629 using modified charcoal adsorption method at 5 and 10 µg/mL was 80.58 ± 1.04% and 81.95 ± 1.15%, respectively. The KRBC/PL of S009-0629 was independent of concentration and time. The in-vitro half-life of S009-0629 at 5 and 10 µM using rat liver microsomes was determined as 273 ± 24.46 and 281.67 ± 26.53 min, respectively. After oral administration, S009-0629 exhibited Cmax 55.51 ± 1.18 ng/mL was observed at 18 hr (tmax ). S009-0629 was found to have the large apparent volume of distribution (1,894.93 ± 363.67 L/kg). Oral in-vivo t1/2 of S009-0629 was found to be 41.23 ± 5.96 hr. A rapid and highly sensitive LC-MS/MS method was validated for S009-0629 in rat plasma. S009-0629 has high plasma protein binding and low hepatic extraction. S009-0629 has no affinity with human P-gp and BCRP in ATPase assay. After oral dosing, S009-0629 has slow absorption and elimination in rats.

Combined and individual strategy of exercise generated preconditioning and low dose copper nanoparticles serve as superlative approach to ameliorate ISO-induced myocardial infarction in rats.

BACKGROUND: Myocardial infarction (MI) is a solitary fatal condition with towering prevalence of mortality worldwide. Our previous study reports that low-dose copper nanoparticles (CuNP) can halt the progression of diabetes-induced cardiotoxicity as copper has anti-inflammatory, anti-proliferative and anti-oxidant potential. In addition, exercise training has also been considered a hallmark for cardiac health. METHOD: Cardioprotective potential of CuNP (1mg/kg/day, po, 4 weeks) and exercise (swimming, 90min, 5days/4 weeks) either alone or in combination was estimated by measuring the surge in serum nitrite/nitrate concentration and reduction in creatine kinase MB (CKMB), lactate dehydrogenase (LDH), cardiac troponin I (cTnI), lipid profile, oxidative stress, structural abnormalities against isproterenol (ISO)-induced MI. RESULTS: ISO significantly increased CKMB, LDH, cTnI, lipid alteration, oxidative stress, structural abnormalities and decrease nitrite/nitrate concentration in serum. Quantitative estimation of total and phosphorylated Akt(SER-473)/GSK-3b(SER-9) indicated the significant reduction in pAkt and pGSK-3b in ISO treated animal. Individual and combined treatment of CuNP and exercise significantly reduce ISO -induced CKMB, cTnI, LDH, and improve nitrite/nitrate concentration and lipid profile. Attenuation of myocardial oxidative stress and serum TBARS revealed the associated preconditioning effect of exercise and CuNP against oxidative stress. Exercise and CuNP also showed the protective potential against structural abnormalities. However, the cardioprotective effect of individual and combined strategy of exercise and CuNP was vanished by wortmannin and also avoid the downregulation of pGSK-3b. CONCLUSION: Low-dose CuNP and exercise training significantly prevents ISO-induced MI through preconditioning and GSK-3b inhibition. Ability to upsurge the NO level, lipid profile and reduced oxidative stress improve the potency of combined strategy.

Synthesis of substituted 2H-benzo[e]indazole-9-carboxylate as a potent antihyperglycemic agent that may act through IRS-1, Akt and GSK-3ß pathways.

Based on high throughput screening of our chemical library, we identified two 4,5-dihydro-2H-benzo[e]indazole derivatives (5d and 5g), which displayed a significant effect on glucose uptake in L6 skeletal muscle cells. Based on these lead molecules, a series of benzo[e]indazole derivatives were prepared. Among all the synthesized dihydro-2H-benzo[e]indazoles, 8-(methylthio)-2-phenyl-6-p-tolyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate (5e) showed significant glucose uptake stimulation in L6 skeletal muscle cells, even better than lead compounds. Additionally, 5e decreased glucagon-induced glucose release in HepG2 hepatoma cells. The 2H-benzo[e]indazole 5e exerted an antihyperglycemic effect in normal, sucrose challenged streptozotocin-induced diabetic rats and type 2 diabetic db/db mice. Treatment with 5e at a dose of 30 mg kg-1 in db/db mice caused a significant decrease in triglyceride and total cholesterol levels and increased the HDL-C level in a significant manner. The mechanistic studies revealed that the 2H-benzo[e]indazole 5e significantly stimulated insulin-induced signaling at the level of IRS-1, Akt and GSK-3ß in L6 skeletal muscle cells, possibly by inhibiting protein tyrosine phosphatase-1B. This new 2H-benzo[e]indazole derivative has potential for the treatment of diabetes with improved lipid profile.

Diversity-oriented general protocol for the synthesis of privileged oxygen scaffolds: pyrones, coumarins, benzocoumarins and naphthocoumarins.

A new general methodology for the synthesis of various functionalized privileged oxygen heterocyclic scaffolds, viz. pyrones, coumarins, and benzannulated coumarins, is developed. The synthesis proceeds through carbanion-induced ring transformation of lactones with various methylene carbonyl compounds followed by DDQ-mediated unprecedented oxidative cleavage of oxaylidenes intermediates. Studies of the mechanism of the conversions of oxaylidene intermediates into corresponding carbonyl compounds in the presence of DDQ revealed that the reactions took place via the formation of a Michael adduct instead of an intermolecular charge transfer complex. The methodology offers the fabrication of diverse privileged scaffolds with tolerance for many functional groups onto the oxygen heterocyclic molecular framework.

Fish oil blunted nicotine-induced vascular endothelial abnormalities possibly via activation of PPARγ-eNOS-NO signals.

Nicotine exposure is associated with an induction of vascular endothelial dysfunction (VED), a hallmark of various cardiovascular disorders. The present study investigated the effect of fish oil in nicotine-induced experimental VED. VED was assessed by employing isolated aortic ring preparation, estimating aortic and serum nitrite/nitrate, aortic superoxide anion generation, and serum TBARS, and carrying out electron microscopic and histological studies of thoracic aorta. Nicotine (2 mg/kg/day, i.p., 4 weeks) administration produced VED in rats by attenuating acetylcholine-induced endothelium-dependent relaxation in the isolated aortic ring preparation, decreasing aortic and serum nitrite/nitrate concentration, impairing endothelial integrity, and inducing vascular oxidative stress. Treatment with fish oil (2 mL/kg/day p.o., 4 weeks) markedly prevented nicotine-induced endothelial functional and structural abnormalities and oxidative stress. However, administration of GW9662, a selective inhibitor of PPARγ, to a significant degree attenuated fish oil-associated anti-oxidant action and vascular endothelial functional and structural improvements. Intriguingly, in vitro incubation of L-NAME (100 µM), an inhibitor of nitric oxide synthase (NOS), markedly attenuated fish oil-induced improvement in endothelium-dependent relaxation in the aorta of nicotine-administered rats. Nicotine administration altered the lipid profile by increasing serum total cholesterol, which was significantly prevented by fish oil treatment. The vascular protective potential of fish oil in preventing nicotine-induced VED may pertain to its additional properties (besides its lipid-lowering effect) such as activation of PPARγ and subsequent possible activation of endothelial NOS and generation of nitric oxide, and consequent reduction in oxidative stress.

Fish oil and vascular endothelial protection: bench to bedside.

Fish oil is recommended for the management of hypertriglyceridemia and to prevent secondary cardiovascular disorders. Fish oil is a major source of ω-3-polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Clinical studies suggest that fish oil not only prevents the incidence of detrimental cardiovascular events, but also lowers the cardiovascular mortality rate. In addition to a classic lipid-lowering action, ω-3-PUFAs in fish oil could regulate blood pressure and enhance vascular integrity and compliance. Additionally, ω-3-PUFAs have the ability to protect vascular endothelial cells by decreasing oxidative stress, halting atherosclerotic events, and preventing vascular inflammatory and adhesion cascades. Intriguingly, recent studies have demonstrated that ω-3-PUFAs improve the function of vascular endothelium by enhancing the generation and bioavailability of endothelium-derived relaxing factor (nitric oxide) through upregulation and activation of endothelial nitric oxide synthase (eNOS). This certainly opens up a new area of research identifying potential mechanisms influencing fish oil-mediated functional regulatory action on vascular endothelium. We address in this review the potential of fish oil to prevent vascular endothelial dysfunction and associated cardiovascular disorders. Moreover, the mechanisms pertaining to fish oil-mediated eNOS activation and nitric oxide generation in improving endothelial function are delineated. We finally suggest the importance of further studies to determine the dose adjustment of fish oil with an optimal ratio of EPA and DHA for achieving consistent cardiovascular protection.

Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins?

Statins are widely used in the treatment of dyslipidemia and associated cardiovascular abnormalities including atherosclerosis, hypertension and coronary heart disease. Needless to mention, statins have cholesterol-lowering effects by means of inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme of cholesterol biosynthesis. Besides cholesterol-lowering effects, statins possess pleiotropic anti-inflammatory, anti-oxidant, anti-platelet and anti-fibrotic properties, which may additionally play imperative roles in statins-mediated cardiovascular protection. However, the precise mechanisms involved in the cardiovascular defensive potential of statins have not completely been elucidated. Intriguingly, a considerable number of studies demonstrated the potential modulatory role of statins on endothelial nitric oxide synthase (eNOS), a key enzyme involved in the regulation of cardiovascular function by generating endothelium-derived relaxing factor (often represented 'nitric oxide'). Worthy of note is that vascular generation of nitric oxide has beneficial anti-inflammatory, anti-platelet and vasodilatory actions. The upregulation of eNOS by statins is mediated through inhibition of synthesis of isoprenoids and subsequent prevention of isoprenylation of small GTPase Rho, whereas statin-induced activation of eNOS is mediated through activation of phosphotidylinositol-3-kinase (PI3K)/protein kinase B (PKB/Akt) signals. Additionally, statins enhance eNOS activation by abrogating caveolin-1 expression in vascular endothelium. In light of this view-point, we suggest in this review that eNOS upregulation and activation, in part, could play a fundamental role in the cardiovascular defensive potential of statins. The eNOS modulatory role of statins may have an imperative influence on the functional regulation of cardiovascular system and may offer new perspectives for the better use of statins in ameliorating cardiovascular disorders.