Current management of metabolic acidosis in patients with chronic kidney disease (CKD) relies on dietary intervention to reduce daily endogenous acid production or neutralization of retained acid with oral alkali (sodium bicarbonate, sodium citrate). Veverimer is being developed as a novel oral treatment for metabolic acidosis through removal of intestinal acid, resulting in an increase in serum bicarbonate. Veverimer is a free-amine polymer that combines high capacity and selectivity to bind and remove hydrochloric acid (HCl) from the gastrointestinal (GI) tract. In vitro studies demonstrated that veverimer had a binding capacity of 10.7 ± 0.4 mmol HCl per gram of polymer with significant binding capacity (> 5 mmol/g) across the range of pH values found in the human GI tract (1.5 to 7). Upon protonation, veverimer bound chloride with high specificity, but showed little or no binding of phosphate, citrate or taurocholate (< 1.5 mmol/g), all anions commonly found in the human GI tract. Administration of veverimer to rats with adenine-induced CKD and metabolic acidosis resulted in a significant increase in fecal chloride excretion and a dose-dependent increase in serum bicarbonate to within the normal range, compared to untreated controls. Absorption, distribution, metabolism and excretion studies in rats and dogs dosed with 14 C-labeled veverimer showed that the polymer was not absorbed from the GI tract and was quantitatively eliminated in the feces. Acid removal by veverimer, an orally administered, non-absorbed polymer, may provide a potential new treatment for metabolic acidosis in patients with CKD.

Zingiber officinale (Linn.) has been used in traditional medicine for the treatment of diabetes. The aim of the study was to evaluate the antidiabetic effect of ethanolic extract of Zingiber officinale (EthZO) by concomitantly administering with synthetic oral hypoglycaemic agents (OHA) in diabetic mice. (EthZO)150 mg-metformin (250 mg/kg) were administered orally alone as well as concomitantly in alloxan-induced diabetic mice. After acute and chronic treatment the serum glucose level was determined. Administration of EthZO (150 mg) + metformin (200 mg) with optimized dose was studied concomitantly at the interval of 15 min. Decreased blood glucose level (BGL) was compared with standard dose of metformin and was found to be lower than normoglycemia. Hence, it can be concluded that concomitant administration of EthZO and metformin causes synergistic significant effect than metformin alone. It can be investigated as the novel drug therapy in the treatment of diabetes mellitus.

Word Count: 243 Introduction Word Count: 539 Discussion Word Count: 1269 Abbreviations: AE, adverse event; ASA, acetylsalicylic acid; AUC 0-t , area under the concentration-time curve from time 0 to the last observed non-zero concentration; AUC 0-inf , area under the concentration-time curve from time 0 extrapolated to infinity; BLQ, below the limit of quantitation; CKD, chronic kidney disease; CI, confidence interval; C max = maximum observed plasma concentration; CRU, clinical research unit; Da, dalton; DDI, drug-drug interaction; GI, gastrointestinal; GLSM, geometric least squares mean; GLSMR, geometric least squares mean ratio; HCl, hydrochloric acid; HPLC, high-performance liquid chromatography; INR, international normalized ratio; INR AUC 0-168 = area under the INR versus time curve from hour 0 to hour 168 post dosing; INR max = maximum observed INR measurement; LC-MS/MS, liquid chromatography with tandem mass spectrometric detection; LSM, least squares mean; MW, This article has not been copyedited and formatted. The final version may differ from this version.

The present investigation was carried out to evaluate neuroprotective efficacy of swarna bhasma on cognitive impairment induced by sleep deprivation in rats. Radial arm maze and elevated plus maze methods were used for behavioural testing in rats. The male albino rats were divided into five experimental groups as normal, sleep deprived control, galantamine and two test groups of swarna bhasma. All the animals except normal were kept on daily 8 to 9 hrs sleep restriction for the induction of cognitive impairment. The cognitive performances were checked on the 7th, 14th and 20th day. Treatment with Swarna bhasma reversed the performances by improved spatial memory, increased correct arm entries, decreased number of errors, time to complete task and decreased in transfer latency. Estimation of biochemical parameters in blood plasma of treated groups with Swarna bhasma showed to be more potent antioxidant and reverts the sleep deprived induced cognitive deficits in rats.

Background and Aims Veverimer is an investigational drug being developed as an orally administered hydrochloric acid binder for the treatment of metabolic acidosis associated with chronic kidney disease (CKD). In clinical studies, treatment with veverimer safely and effectively increased serum bicarbonate and improved objective and subjective measures of physical functioning1-3. Veverimer, a free-amine polymer, is not systemically absorbed; therefore, its potential for drug-drug interactions (DDIs) is limited to those that occur in the gastrointestinal (GI) tract (i.e., direct binding or indirect effects resulting from transient increases in gastric pH). We assessed the potential for DDIs with veverimer both in vitro and in vivo in healthy subjects. Methods In vitro binding to veverimer was evaluated with 16 drugs of varying molecular weight and charge. In a separate study, the effect of veverimer on gastric pH was measured continuously in vivo in healthy subjects using a microelectrode pH probe placed in the gastric compartment. Human DDI studies were conducted with 4 orally administered drugs, including those that demonstrated the most in vitro binding to veverimer and those with pH-dependent solubility (furosemide, aspirin, warfarin, dabigatran). Results Veverimer did not bind to any of the positively charged, neutral or zwitterionic drugs tested in vitro. It bound to 3 small (MW &lt;332 Da), negatively charged drugs (aspirin, ethacrynic acid, furosemide); these interactions were reduced or eliminated in the presence of physiologically relevant concentrations of chloride. Neither furosemide nor aspirin showed clinically meaningful changes in pharmacokinetic parameters when coadministered with veverimer in human DDI studies (Figure 1). Veverimer increased gastric pH by ∼3.0 and 1.5 pH units in fasted and fed subjects, respectively. The increase in gastric pH was short-lived, with a peak within 1 hour after dosing and a return to baseline after ∼1.5 hours and ∼3 hours under fasting and fed conditions, respectively. The effect of veverimer on gastric pH was similar in the presence and absence of omeprazole. No clinically meaningful changes in systemic exposure, as indicated by Cmax and AUC, were observed when 3 drugs with pH-dependent solubility were coadministered with veverimer in human DDI studies (Figure 1). Conclusions In human DDI studies, we observed: a) no effect of veverimer on the bioavailability of drugs with physicochemical characteristics most susceptible to direct binding to the polymer; b) small, short-lived effects of veverimer on gastric pH; and c) no effect of veverimer on the bioavailability of drugs with pH-sensitive solubility. Therefore, it is concluded that there is a negligible risk of veverimer involvement in clinically significant DDIs.