Banxia Baizhu Tianma Decoction for Essential Hypertension: A Systematic Review of Randomized Controlled Trials

Objectives. To assess the current clinical evidence of Banxia Baizhu Tianma Decoction (BBTD) for essential hypertension (EH). Search Strategy. Electronic databases were searched until July 2012. Inclusion Criteria. We included randomized clinical trials testing BBTD against placebo, antihypertensive drugs, or combined with antihypertensive drugs against antihypertensive drugs. Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to Cochrane standards. Results. 16 randomized trials were included. Methodological quality of the included trials was evaluated as generally low. 2 trials compared prescriptions based on BBTD using alone with antihypertensive drugs. Meta-analysis showed no significant effect of modified BBTD compared with captopril in systolic blood pressure (MD: −0.75 (−5.77, 4.27); P=0.77) and diastolic blood pressure (MD: −0.75 (−2.89, 1.39); P=0.49). 14 trials compared the combination of BBTD or modified BBTD plus antihypertensive drugs with antihypertensive drugs. Meta-analysis showed there are significant beneficial effect on systolic blood pressure in the combination group compare to the antihypertensive drugs (MD: −4.33 (−8.44, −0.22); P=0.04). The safety of BBTD is uncertain. Conclusions. There is encouraging evidence of BBTD for lowering SBP, but evidence remains weak. Rigorously designed trials are warranted to confirm these results

Effect of Canagliflozin on Renal Threshold for Glucose, Glycemia, and Body Weight in Normal and Diabetic Animal Models

Background: Canagliflozin is a sodium glucose co-transporter (SGLT) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus (T2DM). Methods: 14 C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human, rat, or mouse SGLT2 or SGLT1; 3 H-2-deoxy-D-glucose uptake in L6 myoblasts; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed. Graded glucose infusions were performed to determine rate of urinary glucose excretion (UGE) at different blood glucose (BG) concentrations and the renal threshold for glucose excretion (RTG) in vehicle or canagliflozin-treated Zucker diabetic fatty (ZDF) rats. This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity. Results: Treatment with canagliflozin 1 mg/kg lowered RT G from 415612 mg/dl to 94610 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RTG. Canagliflozin dose-dependently decreased BG concentrations in db/db mice treated acutely. In ZDF rats treated for 4 weeks, canagliflozin decreased glycated hemoglobin (HbA1c) and improved measures of insulin secretion. In obese animal models, canagliflozin increased UGE and decreased BG, body weight gain, epididymal fat, liver weight, and the respiratory exchange ratio

Antithrombotic Effects of the Novel Small-Molecule Factor XIa Inhibitor Milvexian in a Rabbit Arteriovenous Shunt Model of Venous Thrombosis

Abstract Background Factor XIa (FXIa) is an emerging therapeutic target, and FXIa inhibition is a promising mechanism to improve therapeutic index over current anticoagulants. Milvexian (BMS-986177/JNJ-70033093) is an oral small-molecule FXIa inhibitor. Objective Milvexian's antithrombotic efficacy was characterized in a rabbit arteriovenous (AV) shunt model of venous thrombosis and compared with the factor Xa inhibitor apixaban and the direct thrombin inhibitor dabigatran. Methods The AV shunt model of thrombosis was conducted in anesthetized rabbits. Vehicle or drugs were administered as intravenous bolus plus a continuous infusion. Thrombus weight was the primary efficacy endpoint. Ex vivo activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) were measured as the pharmacodynamic responses. Results Milvexian dose dependently reduced thrombus weights by 34.3 ± 7.9, 51.6 ± 6.8 (p < 0.01; n = 5), and 66.9 ± 4.8% (p < 0.001; n = 6) versus vehicle at 0.25 + 0.17, 1.0 + 0.67, and 4.0 ± 2.68 mg/kg bolus + mg/kg/h infusion, respectively. Ex vivo clotting data supported a dose-dependent prolongation of aPTT (with 1.54-, 2.23-, and 3.12-fold increases from baseline upon the AV shunt start), but no changes in PT and TT. Dose-dependent inhibition in thrombus weight and clotting assays was also demonstrated for both apixaban and dabigatran as the references for the model validation. Conclusion Results demonstrate that milvexian is an effective anticoagulant for prevention of venous thrombosis in the rabbit model, which supports the utility of milvexian in venous thrombosis, as seen in the phase 2 clinical study

A slowly inactivating sodium current (INa2) in the plateau range in canine cardiac purkinje single cells.

The action potential of Purkinje fibres is markedly shortened by tetrodotoxin, suggesting the possibility that a slowly inactivating sodium current might flow during the plateau. The aim of the present experiments was to investigate, in canine cardiac Purkinje single cells by means of a whole cell patch clamp technique, whether a sodium current slowly inactivates at less negative potentials and (if so) some of its distinctive characteristics. The results showed that a 500 ms depolarizing step from a holding potential of −90 mV to −50 mV induced the fast inward current INa (labelled here INa1).With steps to−40 mV or less negative values, a slowly decaying component (tentatively labelled here INa2) appeared, which peaked at −30 to −20 mV and decayed slowly and incompletely during the 500 ms steps. The INa2 was present also during steps to −10 mV, but then the transient outward current (Ito) appeared.When the holding potential (Vh) was decreased to−60 to−50 mV, INa2 disappeared even if a small INa1 might still be present. Tetrodotoxin (30 μM), lignocaine (100 μM) and cadmium (0.2mM; but not manganese, 1mM) blocked INa2. During fast depolarizing ramps, the rapid inactivation of INa1 was followed by a negative slope region. During repolarizing ramps, a region of positive slope was present,whereas INa1 was absent. At less negative values of Vh, the amplitude of the negative and positive slopes became gradually smaller.Gradually faster ramps increased the magnitude of the negative slope, and tetrodotoxin (30 μM) reduced or abolished it. Thus, Purkinje cells have a slowly decaying inward current owing to Na+ entry (INa2) that is different in several ways from the fast INa1 and that appears important for the duration of the plateau

Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes

We have discovered a novel series of tetrahydrobenzimidazoles <b>3</b> as TGR5 agonists. Initial structure–activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC₅₀ values for mTGR5. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGR5 (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13–22% reduction in the area under the blood glucose curve (AUC)_0–120 min in oral glucose tolerance tests (OGTT)

Effects of canagliflozin on SGLT1-, SGLT2-, and facilitative glucose transporter-mediated glucose transport, and on SGLT3-induced currents.

<p>CHOK cells over-expressed with human, rat, or mouse SGLT1 or SGLT2 and rat L6 myoblast cells were used. AMG or 2-DG uptake was determined and IC₅₀ values were calculated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030555#s2" target="_blank">Methods</a> section. Data of human SGLT1 and SGLT2 were presented the summary of 5 studies. Other data presented the mean value of 2 experiments. Oocytes expressed with human SGLT3 were used to determine canagliflozin effect on DNJ-induced current.</p><p>2-DG, 2-deoxy-d-glucose; AMG, alpha-methylglucoside; CHOK, Chinese hamster ovary-K; IC₅₀, concentration required to inhibit 50% of activity; SGLT, sodium glucose co-transporter; DNJ, imino sugars 1-deoxynojirimycin.</p