Indian Journal of Pharmacology最新文献

Background: Azathioprine (AZA) is a widely used immunosuppressant drug. Leukopenia is a serious adverse effect of the drug which often necessitates dose reduction or drug withdrawal. Predictors of leukopenia include genetic and nongenetic factors. Genetic polymorphism of AZA-metabolizing enzyme, thiopurine S-methyltransferase (TPMT) is well established. There is inconclusive evidence about the role of Nudix hydrolase (NUDT15) gene polymorphism. This case-control study assessed the association of genetic polymorphisms of NUDT15 and TPMT with leukopenia induced by AZA.

Materials and methods: Cases were patients on AZA who developed leukopenia (white blood cell count <4000/μl) within 1 year of treatment initiation that necessitated dose reduction or drug withdrawal. Age and gender-matched patients without leukopenia within 1 year of treatment with AZA served as controls. TPMT (3 loci: c238G to C, c460G to A, c719A to G) and NUDT15 (c 415C to T, rs116855232) genotyping were done using TPMT strip assay and polymerase chain reaction-restriction fragment length polymorphism, respectively. Genotype frequencies were noted, and the odds ratio was calculated to determine the association between genotypes and leukopenia.

Results: Twenty-nine subjects (15 cases and 14 controls) were enrolled. Statistically significant differences were not observed in the TPMT genotype (*1/*1 and *1/*3C) (P = 0.23) between cases and controls. NUDT15 genotypes (*1/*1 and *1/*3) (P = 0.65) also showed no statistically significant difference between cases and controls.

Conclusion: The above genotypes do not appear to be associated with AZA-induced leukopenia in an eastern Indian population.

Objectives: Drug-drug interactions (DDIs) are a common problem in pharmacotherapy, particularly in situations where multiple disorders must be treated at the same time. We conducted a drug use survey in the general medicine outpatient department of a tertiary care hospital with the objective of assessing the potential for DDI in individual prescriptions for adult patients.

Materials and methods: Drugs prescribed in the current physician-patient encounter were considered in conjunction with medicines already being received by the patient as well as those discontinued in the past 1 month. Free online DDI checkers (available at https://www.drugs.com/drug_interactions.html and https://reference.medscape.com/) were used to identify potential DDI and categorize them into mild, moderate, and severe categories. We did not consider food, alcohol, or smoking-related interactions.

Results: A total of 153 prescriptions, having two or more drugs, were collected, and they accounted for 1052 prescribed drugs. Among them, 613 (58.27%) were prescribed in index visits, and the rest 438 (41.63%) were preexisting medication. The number of drugs prescribed in index visits ranged from 1 to 9 (mean ± standard deviation [SD] 4.0 ± 1.86; median 4). Potential DDIs were identified in 103 (67.32%) instances. The total number of interactions identified was 412. Of these, 19.66% had minor, 77.67% moderate, and 7.19% major clinical implications. Potential DDI count in each prescription was found from 0 to 13 in number (mean ± SD 2.7 ± 3.12; median 2.0). This number correlated strongly with the number of drugs being received by individual subjects (Rho 0.744; P < 0.001).

Conclusions: Potential DDIs are a reality in day to day prescribing practice. Substantial proportion of these DDIs may have significant clinical implications. Prescribers need to be sensitized to this issue. Combining human expertise with technological solutions such as automated drug interaction alerts can help rectify the situation. Similar surveys are needed on a periodic basis to improve medication safety for patients.

Background: Topical corticosteroids treat cutaneous inflammation but have side effects. In earlier studies, bilirubin exhibited anti-inflammatory effect, but its hydrophobicity and poor absorption limit its potential.

Aim: Synthesis of bilirubin nanoparticles (BNP) and bilirubin nanoparticles gels (BNP gel) to study the anti-inflammatory effect of topical BNP gel against carrageenan-induced rat paw edema in Wistar rats.

Materials and methods: BNP were synthesized, and BNP gels were prepared by mixing BNP of different concentrations with pluronic F-127 (PF-127). A different group for each formulation was assigned with five rats in each group. After 1 h of carrageenan (1% [w/v]) injection in each group, different gels were applied topically to their respective groups. Paw edema size, percent inflammation, percent edema inhibition, and inhibition time50 were evaluated. Interleukin-10 (IL-10) levels and neutrophil infiltration in rat paw tissue were evaluated by enzyme-linked immunosorbent assay and hematoxylin and eosin, respectively.

Results: Synthesized spherical-shaped BNP had negative zeta potential. BNP gels markedly reduced paw edema size and % inflammation as compared to carrageenan and bulk bilirubin gel (Bulk B gel) treated group and significantly increased IL-10 levels and inhibited neutrophil infiltration.

Conclusion: BNP gels exhibited a better anti-inflammatory effect than bulk B gel and comparable anti-inflammatory potential with clobetasol.

Objective: In the present study, the effect of sildenafil on the pharmacokinetics of metformin was studied in experimental rats, and we also postulated the molecular mechanism by performing molecular docking studies.

Materials and methods: Analysis of metformin and sildenafil (SIL) from rat plasma was done by high performance liquid chromatography. Optimum chromatographic separation and quantification of MET, SIL and Cetirizine was achieved on Phenomenex EVO C18 column with triethyl amine (0.3%): Methanol: Acetonitrile (70:05:25 v/v) as mobile phase maintaining flow rate of 1 ml/min, the detector was tuned at 224 nm. The extraction of MET and sildenafil from rat plasma was achieved by solid-phase extraction using Strata-X cartridges. The method was validated as per the ICH guidelines. For docking studies, the crystal structure of organic cation transporter 1 (OCT1) protein and multidrug and toxin extrusion (MATE) protein (5XJJ) were downloaded from the PubChem database. The docking study was performed by PyRx virtual screening software, and the results were analyzed by BIOVIA Discovery Studio.

Results: The validation of HPLC method was done, intraday and interday precision study of HPLC method demonstrated %RSD values less than 5%, the extraction recovery for MET and SIL were near to 80 % for low, medium and high QC samples. The plasma stability of MET and SIL showed % RSD values <10% for low, medium, and high QC samples. A sensitivity study for MET and SIL in rat plasma suggested a lower limit of quantification values of 8 and 10 ng/mL, respectively. The pharmacokinetic parameters were recorded, Cmax of experimental and control rats was 611.2 and 913.2 ng/mL; t1/2 1.66 and 1.98, AUC (0-t) 1637.5 and 2727.24, AUC (0-∞) 1832.38 and 2995.24 for MET. The results suggested that the Cmax of MET in experimental rats (MET + SIL) was 33.07% lower than the control (MET only) and also the t1/2 was 0.32 h shorter. Docking analysis suggested a higher binding affinity of sildenafil with MATE protein (5XJJ) compared to OCT1, suggesting possible involvement of MATE family proteins for pharmacokinetic alterations of MET.

Conclusions: The HPLC and solid-phase extraction method were developed and applied successfully for the pharmacokinetics of MET and SIL. Intake of SIL altered the pharmacokinetics of MET in rats. Molecular docking studies suggested the involvement of MATE family proteins for alterations of MET pharmacokinetics.

Objectives: Single-nucleotide polymorphism (SNP) codes for multiple amino acids, impacting protein functions and disease prognosis. Runt-related transcription factor-2 (RUNX2), a transcription factor linked to osteoblast differentiation, regulates cell proliferation in endothelium and osteoblastic cells. Understanding Runx2's role in nonosseous tissues is rapidly advancing. This study aims to identify harmful SNPs of the RUNX2 gene that may alter disease susceptibility using computational techniques.

Methods: The study uses various in silico methods to identify nonsynonymous SNPs (nsSNPs) of the RUNX2 gene, which could potentially alter protein structure and functions, with further analyses by I-Mutant, ConSurf, Netsurf 3.0, GeneMANIA, and Have (y)Our Protein Explained.

Results: Six missense nsSNPs were identified as potentially harmful, disease-causing, and damaging. Four were found to be unstable, while five were conserved. All six nsSNPs had a coiled secondary structure. Five nsSNPs were found to be destabilized.

Conclusion: The RUNX2 gene's deleterious missense nsSNPs were identified by this study, and they may be exploited in future experimental studies. These high-risk nsSNPs might be considered target molecules in therapeutic and diagnostic therapies in teeth and bone development.

Background: Chlorpyrifos belongs to a broad-spectrum organophosphate insecticide that has high toxicity, is metabolized in the liver by the oxidation reaction, and can inhibit acetylcholinesterase activity. Acetylcholinesterase inhibition generates the reactive oxygen species and induces oxidative stress, which ultimately results in cellular damage like in the kidney. Examining blood urea nitrogen (BUN) levels, creatinine, and kidney histopathology is an appropriate indicator to assess the toxicity of chlorpyrifos to the degree of damage to cells and kidney tissue.

Materials and methods: This research used to determine the effect of duration of exposure to chlorpyrifos and dose-response relationships is important for early detection of the effects of chlorpyrifos toxicity on health. The research study was a true experimental (completely randomized design) consisting of 30 subjects divided into 5 groups. Controlled Group (K1) given 1 mg/kg BW Tween 20 and NaCl 0, 9% until the 56th day. The chlorpyrifos exposed group (P1, P2, P3, and P4) was given chlorpyrifos 5 mg/kg BW for 7, 14, 28, and 56 days. After the treatment, BUN and creatinine levels were measured, and microscopic changes in the kidney were analyzed. The results of BUN, creatinine, and kidney histopathologic were analyzed using the analysis of variance statistical test.

Results: The data result showed that compared to the control group, there were significant increases of BUN and creatinine (P = 0.013 and P = 0.003). Histopathological examinations of kidney glomerulus diameter were also smaller compared to the control group (P = 0.00). All the data measurement indicates significant differences compared to the control group.

Conclusions: We concluded that sub-chronic oral exposure to chlorpyrifos at low doses can damage the kidneys and cause kidney failure.