The Role of Diazepam in Epigenetics: From the Molecular Level to Clinical Implications.

There is growing evidence linking epigenetic mutations to neurologic disorders such as epilepsy. The effect of the medications primarily used to treat neurologic disorders has recently been studied, including research on epilepsy and the epigenetic process. The impact of the widely used medication diazepam on epigenomics, microRNA levels, the ensuing genetic exposure and potential clinical effects was reviewed. The action of diazepam, particularly in altering the synthesis of enzyme 5' adenosine monophosphate activated protein kinase (AMPK) was found to affect many enzymes, which changes or modifies the epigenetics. Epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) are mainly activated by AMPKs, including the phosphorylate substrates, which often lead to their inhibition, although HAT1 activity may be improved. It has been reported that diazepam can reduce histone methyltransferase expression exposure, may increase class III histone deacetylases activity and may decrease the effect of DNA methyltransferases inhibitors. Diazepam has been found to contribute to mutations of the epigenome and genetic expression, and may protect against neurologic disorders, aging, dementia and several brain diseases. It has also been found that microRNA expression can be influenced by diazepam treatment and may have neurologic effects. Although the reported effects of diazepam on epigenetic enzymes of are equally effective in both amplifying and reducing acetylation of histone, histone and DNA methylation and gene expression, the effect of diazepam on the epigenome, genetic expression, and subsequent effects in all healthy diazepam users is unclear.

A contemporary biological pathway of islet amyloid polypeptide for the management of diabetic dementia.

Major challenges of dealing elder patients with diabetes mellitus (DM) are the individualization of consideration in persons with various comorbid types of conditions. In spite of the fact that microvascular and macrovascular problems associated with DM are well documented, there is only a few numbers of reports viewing different conditions, for example, cognitive dysfunction. Cognitive dysfunction is of specific significance due to its effect on self-care and quality of life. All in all, the etiology of cognitive dysfunction in the maturing populace is probably going to be the grouping of ischemic and degenerative pathology. It is likewise trusted that Hyperglycemia is engaged with the system of DM-related cognitive dysfunction. At present, it isn't certain in the case of enhancing glycemic control or utilizing therapeutic agents can enhance the risk of cognitive decay. Amylin was later characterized as an amyloidogenic peptide, confined from a beta cell tumor and called islet amyloid polypeptide (IAPP), and after that, amylin. Conversely, we investigate the beneficial role and hypothesizing the mechanism of amylin related expanding the level and activation of CGRP receptor to enhance the cognition declination amid diabetic dementia.

Granulated colloidal silicon dioxide-based self-microemulsifying tablets, as a versatile approach in enhancement of solubility and therapeutic potential of anti-diabetic agent: formulation design and in vitro/in vivo evaluation.

The current research work was executed with an aim to explore and promote the potential of self-microemusifying drug delivery systems (SMEDDS) in the form of tablets, in order to enhance solubility and oral bioavailability of poorly aqueous soluble drug Repaglinide (RPG). RPG-loaded liquid SMEDDS were developed consisting Labrafil M 1944CS, Kolliphor EL and Propylene glycol, which were then characterized on various parameters. After characterization and optimization, liquid SMEDDS were converted into solid form by adsorbing on Aeroperl® 300 pharma and polyplasdoneTM XL. Further, selection of suitable excipients was done and mixed with prepared solidified SMEDDS powder followed by the preparation of self-microemulsifying tablets (SMET's) wet granulation-compression method. SMET's were subjected to differential scanning calorimetry (DSC) and particle X-ray diffraction (RXRD) studies, results of which indicated transformation of crystalline structure of RPG because of dispersion of RPG at molecular level in liquid SMEDDS. This was further assured by micrographs obtained from scanning electron microscope. SMET's shown more than 85% (30 min) of in vitro drug release in contrast to conventional marketed tablets (13.2%) and pure RPG drug (3.2%). Results of in vivo studies furnished that SMET's had shown marked decrease in the blood glucose level and prolonged duration of action (up to 8 h) in comparison with conventional marketed tablets and pure RPG drug. In conclusion, SMET's serves as a promising tool for successful oral delivery of poorly aqueous soluble drug(s) such as RPG.

Investigation of in vitro absorption, distribution, metabolism, and excretion and in vivo pharmacokinetics of paromomycin: Influence on oral bioavailability.

OBJECTIVE: The objective of this study is to investigate in vitro Caco2 permeability, metabolism and in vivo pharmacokinetic (PK) properties of paromomycin to develop an efficient dosage form with improved oral bioavailability. MATERIALS AND METHODS: For the purpose, Caco2 permeability assay, mouse microsomal stability assay and in vivo PKs in male BALB/c mice were performed. RESULTS: In Caco-2 permeability assay, paromomycin showed negligible permeability in the apical to basolateral (A-to-B) direction and vice versa (B-to-A). Marginal increase in permeability with the use of P-glycoprotein (P-gp) inhibitor, namely, verapamil suggesting paromomycin could be a P-gp substrate. Paromomycin was unstable in liver microsomes of mouse. Paromomycin showed good PK properties after intravenous dose in male BALB/c mice which included low plasma clearance, i.e., <10% of hepatic blood flow in mice, high volume of distribution (Vd), and half-life (T½) of 2.6 h. Following per oral dose, it exhibits low oral bioavailability (0.3%) with carboxymethyl cellulose formulation. Oral plasma exposure increased in mice by 10% and 15% after pretreatment with P-gp inhibitor verapamil and CYP inhibitor 1-Aminobenztriazole, respectively. CONCLUSION: Comparatively significant increase in oral plasma exposure of paromomycin was observed with an alternative oral formulation approach, use of P-gp and CYP inhibitors resulting in improved oral bioavailability up to 16%.

A clinical perspective on mucoadhesive buccal drug delivery systems.

Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for extended periods of time by the help of interfacial forces. Among the various transmucosal routes, buccal mucosa has excellent accessibility and relatively immobile mucosa, hence suitable for administration of retentive dosage form. The objective of this paper is to review the works done so far in the field of mucoadhesive buccal drug delivery systems (MBDDS), with a clinical perspective. Starting with a brief introduction of the mucoadhesive drug delivery systems, oral mucosa, and the theories of mucoadhesion, this article then proceeds to cover the works done so far in the field of MBDDS, categorizing them on the basis of ailments they are meant to cure. Additionally, we focus on the various patents, recent advancements, and challenges as well as the future prospects for mucoadhesive buccal drug delivery systems.