Molecular Consequences of Depression Treatment: A Potential In Vitro Mechanism for Antidepressants-Induced Reprotoxic Side Effects

The incidence of depression among humans is growing worldwide, and so is the use of antidepressants. However, our fundamental understanding regarding the mechanisms by which these drugs function and their off-target effects against human sexuality remains poorly defined. The present study aimed to determine their differential toxicity on mouse spermatogenic cells and provide mechanistic data of cell-specific response to antidepressant and neuroleptic drug treatment. To directly test reprotoxicity, the spermatogenic cells (GC-1 spg and GC-2 spd cells) were incubated for 48 and 96 h with amitriptyline (hydrochloride) (AMI), escitalopram (ESC), fluoxetine (hydrochloride) (FLU), imipramine (hydrochloride) (IMI), mirtazapine (MIR), olanzapine (OLZ), reboxetine (mesylate) (REB), and venlafaxine (hydrochloride) (VEN), and several cellular and biochemical features were assessed. Obtained results reveal that all investigated substances showed considerable reprotoxic potency leading to micronuclei formation, which, in turn, resulted in upregulation of telomeric binding factor (TRF1/TRF2) protein expression. The TRF-based response was strictly dependent on p53/p21 signaling and was followed by irreversible G2/M cell cycle arrest and finally initiation of apoptotic cell death. In conclusion, our findings suggest that antidepressants promote a telomere-focused DNA damage response in germ cell lines, which broadens the established view of antidepressants’ and neuroleptic drugs’ toxicity and points to the need for further research in this topic with the use of in vivo models and human samples.

Venlafaxine Hydrochloride Controlled Release Bilayer Tablets: Optimization of Formulation Variable by Using Dyspnea on Exertion

The current research work was to develop bilayer tablet of venlafaxine hydrochloride to increase drug efficacy for efficient treatment of depression. The satisfactory result of treatment can be achieved upon the maintenance of drug concentration within an effective level in the body, so a uniform and constant drug supply are desirable. An immediate layer of venlafaxine HCl was formulated using super disintegrants, i.e., croscarmellose sodium (CCS) and sodium starch glycolate (SSG); tablet compact by direct compression. HPMC K100M and ethylcellulose (EC) were utilized as release retarding polymers in sustained release layer by wet granulation technique with the help of PVP K30 in IPA solution (10%) as a granulating agent. Full 32 factorial designs were used to find out the optimum quantity of release retardant polymers. Bilayer tablet was evaluated for various parameters, i.e. hardness, friability, weight variation, % drug content, disintegration time (IR layer), and % drug release study. Statically, an analysis was carried out using factor X1 (HPMC K100M) and X2 (EC) for dependent variable % drug release at 8, 12, and 20 hours. A formulation was optimized and a formulation containing 305.36 mg of HPMC K100M and 54.03 mg of ethyl cellulose. Optimized formulation show 47.12 ± 2.1, 59.89 ± 2.2, and 89.06 ± 2.3 drug release at 8, 12, and 20 hours, respectively, which is almost similar to theoretical dose calculation with similarity factor f2 97, 99, and 98%, respectively. Bilayer tablet formulation was observed to be stable and fulfilled all compendia specifications.