PHARMACOKINETIC DRUG INTERACTIONS OF GLICLAZIDE AND ITOPRIDE IN NORMAL AND DIABETIC RATS

Objective: The present study was aimed to investigate the safety, reliability of Gliclazide and possible drug interaction with Itopride when they were administered as combination treatment.Methods: Studies were conducted in normal and streptozotocin induced diabetic rats with oral administration of selected doses of gliclazide, itopride and their combination. Blood samples were collected from rats by retro orbital/marginal ear vein puncture at regular intervals of time. All the blood samples were analyzed for pharmacokinetic parameters by HPLC method.Results: There was no significant difference in pharmacokinetic parameters of both Gliclazide alone and combination with itopride in healthy and diabetic rats on day 1 and day 8.Conclusion: Based on the results it can be concluded that the concurrent administration of these two drugs have potential benefit without any drug interactions in the effective management of diabetes and gastroparesis.Â

A New Class of Monoamine Oxidase Inhibitors

Newly synthesized compounds have been found to inhibit mitochondrial monoamine oxidase (MAO) in mouse brain and rat liver. A series of 2-acylamino-3- tert -aminopropiophenones acted preferentially against MAO type B (2-phenylethylamine as substrate), apparently irreversibly. 2-Decanoylamino-3-morpholinopropiophenone acted similarly in vivo toward the cerebral MAO, producing a dose-related inhibition. At high dose levels, MAO type A was also severely inhibited. The effects were produced rapidly and restoration of enzyme activity also appeared rapidly. The half-life for MAO type A could be estimated from the rate of enzyme reappearance to be 13 h. It is suggested that the amino ketones undergo a Β-elimination reaction at the enzyme's active site, forming a reactive species (an Α,Β-unsaturated ketone), which reacts covalently with a nucleophilic group of the enzyme by a Michael addition. Some other related compounds, derivatives of phenylpropane, also showed inhibitory activity against MAO, particularly against type A (serotonin as substrate). The morpholino compound might have promise as a quickly effective, short-acting inhibitor of MAO type B.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66333/1/j.1471-4159.1980.tb06611.x.pd

Pharmacokinetic interactions between concomitantly administered Metformin and Itopride in rats

Gastroparesis is a syndrome characterized by delayed gastric emptying, in the absence of mechanical obstruction of the stomach. Diabetes mellitus (DM) is responsible for almost one third of cases of gastroparesis. Gastroparesis typically develops after at least 10 years of evolution of DM, and often is associated with other complications. The present study aimed to investigate the safety, reliability of Metformin and possible drug interaction with Itopride when they were administered as combination treatment. The study was conducted on healthy Wistar and streptozotocin induced diabetic rats.  A simple and sensitive high performance liquid chromatographic method was developed for the simultaneous estimation of Metformin and Itopride in rat plasma and also to estimate possible pharmacokinetic parameters of these drugs after oral administration. There was no significant difference in the Metformin alone and combination with Itopride and Itopride alone and combination with Metformin on day 1 and day 8 respectively. There is no significant change in tmax, cmax, AUC (0 – t) and AUC (o-inf), t½, Cl/f and V/f on day 1 and day 8 respectively in both diabetic and healthy rats. From the above results it can be concluded that the concurrent administration of these two drugs have potential benefit in the treatment of Diabetes and Gastroparesis. In addition, due to their insignificant pharmacokinetic interaction the combinational therapy can be safe and highly advantageous in Gastro paresis patients with diabetes. 

All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers

Alzheimer’s disease (AD) is the most common type of senile dementia in aging populations. Amyloid β (Aβ)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Aβ-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Aβ binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Aβ effects even in the absence of receptor–peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Aβ isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn2+, a known blocker of l-Aβ isomer channels. MD simulations further verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca2+ leaking, unregulated channels in AD, and suggest that Aβ toxicity is mediated through a receptor-independent, nonstereoselective mechanism