Drug Metabolism and Bioanalysis Letters - Volume 17, Issue 3, 2024

Nicotine addiction remains a significant public health challenge, driving the need for effective treatment strategies. While various pharmacological approaches have been explored, targeting neurotransmitter and neuromodulator systems offers a promising avenue. These systems, particularly those involving dopamine, play a pivotal part in interceding the rewarding effects of nicotine and the development of dependence. Serotonin, a pivotal neuromodulator, exerts a profound influence on dopamine pathways. By interacting with these pathways, serotonin can significantly impact the substantiating effects of nicotine. Understanding the intricate interplay between serotonin and dopamine systems is pivotal for developing new remedial interventions that effectively address the intricacies of nicotine dependence.

The purpose of this research study was to examine the potential roles played by serotonin and its receptors in nicotine addiction by examining the involvement of serotonin modulators in the development of conditioned location preference in mice after exposure to nicotine.

Mice were subjected to conditioned place preference (CPP) training with nicotine. After induction of CPP, the extinction session was given for the disappearance of CPP. There were a total of five groups, each having six animals that participated in the experiments, including group 1 (controls; normal saline), group 2 (nicotine A; 0.25 mg/kg), group 3 (nicotine B; 0.5 mg/kg), group 4 (nicotine C; 0.75 mg/kg), and group 5 (standard drug; fluoxetine). All drugs were given through the subcutaneous route. The treatment of serotonin modulators, i.e., fluoxetine (100 mg/kg), a selective serotonin reuptake inhibitor (SSRI), was given before the priming dose of nicotine, and the effect of the serotonin modulator was observed.

On day 17^th, the CPP values were 390.16 s, 235.66 s, and 219.16 s, respectively, for nicotine A, nicotine B, and nicotine C in the black compartment groups; however, in the white compartment groups, the CPP values were 347.16 s, 588 s, and 549.66 s, respectively, for nicotine A, nicotine B, and nicotine C.

Using the conditioned place preference (CPP) paradigm, we administered both drugs in a context in which their rewarding properties could be measured. Fluoxetine produced a significant but less robust CPP than nicotine. A single injection of fluoxetine was found to reduce nicotine-induced CPP. Moreover, the rewarding properties of nicotine were completely abolished in response to repeated fluoxetine injections. Long-term fluoxetine users may benefit more from the drug than those who have only used it occasionally or in small doses, according to the study.

The study aimed to develop and optimize a sustained-release matrix tablet of diclofenac sodium (50 mg) using carboxymethylated chitosan (CMCS) as the matrix-forming polymer, in combination with hydroxypropyl methylcellulose (HPMC). The research investigated the impact of CMCS (50-200 mg) and HPMC (150-300 mg) composition on the critical quality attributes of the sustained-release matrix tablets.

A 2-factor mixture design investigated the impact of HPMC and CMCS proportions on critical quality attributes. Tablets (650 mg) were prepared by wet granulation and characterized for flow properties, hardness, and drug release kinetics. The in vitro drug release studies were carried out at 37 ± 0.5°C in a phosphate buffer of pH 6.8 using a USP type II dissolution apparatus operated at 50 rpm. The in vitro dissolution profile of the optimized formulation was compared with a marketed product, Reactin^® SR, using ANOVA and model-independent methods (f1 and f2 values).

Granule properties showed good flow characteristics with Carr's index (14.25-18.36) and Hausner ratio (1.05-1.25). FTIR and DSC studies confirmed no drug-excipient interactions, with the drug's characteristic peaks maintained at 766 cm⁻¹, 1454 cm⁻¹, 1017 cm⁻¹, and 2915 cm⁻¹, and a melting endotherm at 54°C. The optimized formulation (F3) with 150 mg HPMC and 200 mg CMCS demonstrated 90.57% drug release in 8 hours following super case II transport (n = 1.11). The release kinetics best fitted the Korsmeyer-Peppas with the F0 model (R² = 0.9959). The response parameters hardness (4.2 ± 0.126 kg/cm²), t25 (115 ± 11.60 min), t50 (290 ± 21.42 min), and t90 (630 ± 31.51 min) were best fitted to the quartic model. The similarity factor (f2 = 67.63) and difference factor (f1 = 13.85) indicated the equivalency of the dissolution profile with that of the marketed formulation.

The study successfully developed a sustained-release matrix tablet of diclofenac sodium using CMCS as the primary matrix material. The optimized formulation demonstrated a dissolution profile comparable to the marketed product (>90% release in 8 hours), with f2 > 50 and f1 < 15, suggesting its potential as a generically equivalent alternative. Moreover, the findings indicate that CMCS is an effective carrier for sustained-release formulations and can potentially be applied to other drugs requiring controlled release.

Rheumatoid arthritis (RA) is a chronic autoimmune disease which leads to pain and disability that may trigger anxiety and sleep disturbances. Naproxen and St. John’s Wort concomitant administration in RA and anxiety raises the question of safety due to a potential drug interaction.

Albino Wistar rats were treated with naproxen and St. John’s Wort for 30 days. The study involved the evaluation of safety of naproxen when combined with St. John’s Wort by estimation of biochemical markers such as SGOT, SGPT, TG’s, Creatinine, BUN, the extent of gastromucosal damage and estimation of AUC, t1/2 and Clearance using blood serum analysis with HPLC after 30 days of treatment. Histopathological studies were also conducted to determine the tissue architecture.

Elevated levels of hepatic markers SGOT, SGPT, TG, and gastro-mucosal damage with enhanced ulcer index were found in naproxen-St. John’s Wort treated rats as compared to only naproxen treated rats. HPLC analysis displayed increased AUC and t1/2 of naproxen with decreased clearance in naproxen-St. John’s Wort treated rats. Histopathological findings revealed tissue rupture and mucosal damage supporting the naproxen toxicity.

Consulting a healthcare professional before combining St. John's Wort with naproxen is essential to assess potential risks, manage drug interactions, and ensure safety. Personalized advice helps optimize treatment outcomes for both rheumatoid arthritis and mental health.

Microbial biotransformation of steroids is a valuable method for producing active pharmaceuticals or potentially active steroids, and fungi serve as powerful biocatalysts in this process. On the other hand, in silico analyses are preliminary yet influential studies for the evaluation of compounds in the drug development process.

This study aimed to examine the ability of Mucor hiemalis to biotransform hydrocortisone, predict the potential binding ability of the products to the 11β-hydroxysteroid dehydrogenase enzyme (as a target for the control of diabetes mellitus type 2), and assess the products’ pharmacokinetic properties.

The incubation of M. hiemalis with hydrocortisone for nine days resulted in the production of a main product in the culture medium. The metabolite was subsequently isolated using chromatographic procedures and its identity was determined by spectroscopic analysis. Computational binding studies and pharmacokinetic profile prediction of the metabolite were conducted using AutoDock Vina and SwissADME, respectively.

The biotransformation of hydrocortisone by M. hiemalis produced 11β,17α,20β,21-tetrahydroxypregn-4-en-3-one as the major metabolite. Molecular docking studies demonstrated that the metabolite can interact with functional residues located at the catalytic site of the enzyme in different ways. Furthermore, the results indicated a favorable pharmacokinetic profile of the produced metabolite.

The current study showed that M. hiemalis may be considered an effective tool for the biotransformation of steroids and the production of potentially bioactive compounds.