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Fulltext Frequency, types and predictors of drug therapy problems among non-dialysis chronic kidney disease patients at a tertiary care hospital in Pakistan

Hayat M, Ahmad N, Mohkumuddin S, Ali Khan SL, Khan AH, Haq NU, et al.

PLoS One, 2023;18(4):e0284439.
PMID: 37058504 DOI: 10.1371/journal.pone.0284439

BACKGROUND: Drug therapy problems (DTPs) are common among patients suffering from chronic kidney disease (CKD). However, there is a lack of information about DTPs and its predictors among CKD patients from Pakistan.
OBJECTIVES: To evaluate the frequency, type and predictors of various types of DTPs among CKD patients at a tertiary-care hospital in Pakistan.
METHODOLOGY: This was a cross-sectional study carried out at Sandeman Provincial Hospital, Quetta between 1-11-2020 and 31-1-2021. It included 303 non-dialysis ambulatory patients of CKD-stage 3 and above. Cipolle et al., criterion was used for classifying the DTPs and a clinician at the study site checked the identified DTPs for accuracy. Data were analyzed by SPSS 23. Multivariate analysis was conducted to find the predictors of individual types of DTPs. A p-value <0.05 was considered statistically significant.
RESULTS: The patients received a total of 2265 drugs with a median of eight drugs per patient (range: 3-15 drugs). A total of 576 DTPs were identified among 86.1% patients with a median of two DTPs (interquartile range 1-3) per patient. Dosage too high (53.5%) was the most common DTP followed by adverse drug reactions (ADRs) (50.5%) and need of additional drug therapy (37.6%). In multivariate analysis, patients' age of >40 years emerged as a predictor of unnecessary drug therapy and dosage too high. The odds of needing a different drug product was significantly high in patients with cardiovascular diseases (CVD) and diabetes mellitus (DM). The dosage too low had significant association with CVD. The risk of ADRs was significantly high in elderly patients (>60 years) and those with CVD. The presence of hypertension, DM and CKD stage-5 emerged as predictors of dosage too high.
CONCLUSION: This study revealed a high prevalence of DTPs among CKD patients. Targeted interventions in high risk patients may reduce the frequency of DTPs at the study site.
Fulltext Virtual Screening, Synthesis, and Biological Evaluation of Some Carbohydrazide Derivatives as Potential DPP-IV Inhibitors

Jadhav PB, Jadhav SB, Zehravi M, Mubarak MS, Islam F, Jeandet P, et al.

Molecules, 2022 Dec 24;28(1).
PMID: 36615348 DOI: 10.3390/molecules28010149

Dipeptidyl peptidase-4 (DPP-IV) inhibitors are known as safe and well-tolerated antidiabetic medicine. Therefore, the aim of the present work was to synthesize some carbohydrazide derivatives (1a-5d) as DPP-IV inhibitors. In addition, this work involves simulations using molecular docking, ADMET analysis, and Lipinski and Veber's guidelines. Wet-lab synthesis was used to make derivatives that met all requirements, and then FTIR, NMR, and mass spectrometry were used to confirm the structures and perform biological assays. In this context, in vitro enzymatic and in vivo antidiabetic activity evaluations were carried out. None of the molecules had broken the majority of the drug-likeness rules. Furthermore, these molecules were put through additional screening using molecular docking. In molecular docking experiments (PDB ID: 2P8S), many molecules displayed more potent interactions than native ligands, exhibiting more hydrogen bonds, especially those with chloro- or fluoro substitutions. Our findings indicated that compounds 5b and 4c have IC50 values of 28.13 and 34.94 µM, respectively, under in vitro enzymatic assays. On the 21st day of administration to animals, compound 5b exhibited a significant reduction in serum blood glucose level (157.33 ± 5.75 mg/dL) compared with the diabetic control (Sitagliptin), which showed 280.00 ± 13.29 mg/dL. The antihyperglycemic activity showed that the synthesized compounds have good hypoglycemic potential in fasting blood glucose in the type 2 diabetes animal model (T2DM). Taken all together, our findings indicate that the synthesized compounds exhibit excellent hypoglycemic potential and could be used as leads in developing novel antidiabetic agents.
Fulltext Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay

Vawhal PK, Jadhav SB, Kaushik S, Panigrahi KC, Nayak C, Urmee H, et al.

Molecules, 2023 Jan 19;28(3).
PMID: 36770672 DOI: 10.3390/molecules28031004

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.
An overview of polymer surface coated synthetic quantum dots as therapeutics and sensors applications

Babu AK, Raja MKMM, Zehravi M, Mohammad BD, Anees MI, Prasad C, et al.

Prog Biophys Mol Biol, 2023 Nov;184:1-12.
PMID: 37652186 DOI: 10.1016/j.pbiomolbio.2023.08.004

Quantum dots (QDs) are a class of remarkable materials that have garnered significant attention since their initial discovery. It is noteworthy to mention that it took approximately a decade for these materials to be successfully implemented in practical applications. While QDs have demonstrated notable optical properties, it is important to note that these attributes alone have not rendered them a feasible substitute for traditional organic dyes. Furthermore, it is worth noting that the substance under investigation exhibited inherent toxicity and instability in its initial state, primarily due to the presence of a heavy metal core. In the initial stages of research, it was observed that the integration of nanocomposites had a positive impact on the properties of QDs. The discovery of these nanocomposites was motivated by the remarkable properties exhibited by biocomposites found in nature. Recent discoveries have shed light on the potential utilization of QDs as a viable strategy for drug delivery, offering a promising avenue to enhance the efficacy of current pharmaceuticals and pave the way for the creation of innovative therapeutic approaches. The primary objective of this review was to elucidate the distinctive characteristics that render QDs highly suitable for utilization as nanocarriers. In this study, we will delve into the multifaceted applications of QDs as sensing nanoprobes and their utilization in diverse drug delivery systems. The focus of our investigation was directed toward the utilization of QD/polymer composites in sensing applications, with particular emphasis on their potential as chemical sensors, biosensors, and physical sensors.
Fulltext Natural polymers as potential P-glycoprotein inhibitors: Pre-ADMET profile and computational analysis as a proof of concept to fight multidrug resistance in cancer

Gandla K, Islam F, Zehravi M, Karunakaran A, Sharma I, Haque MA, et al.

Heliyon, 2023 Sep;9(9):e19454.
PMID: 37662819 DOI: 10.1016/j.heliyon.2023.e19454

P-glycoprotein (P-gp) is known as the "multidrug resistance protein" because it contributes to tumor resistance to several different classes of anticancer drugs. The effectiveness of such polymers in treating cancer and delivering drugs has been shown in a wide range of in vitro and in vivo experiments. The primary objective of the present study was to investigate the inhibitory effects of several naturally occurring polymers on P-gp efflux, as it is known that P-gp inhibition can impede the elimination of medications. The objective of our study is to identify polymers that possess the potential to inhibit P-gp, a protein involved in drug resistance, with the aim of enhancing the effectiveness of anticancer drug formulations. The ADMET profile of all the selected polymers (Agarose, Alginate, Carrageenan, Cyclodextrin, Dextran, Hyaluronic acid, and Polysialic acid) has been studied, and binding affinities were investigated through a computational approach using the recently released crystal structure of P-gp with PDB ID: 7O9W. The advanced computational study was also done with the help of molecular dynamics simulation. The aim of the present study is to overcome MDR resulting from the activity of P-gp by using such polymers that can inhibit P-gp when used in formulations. The docking scores of native ligand, Agarose, Alginate, Carrageenan, Chitosan, Cyclodextrin, Dextran, Hyaluronic acid, and Polysialic acid were found to be -10.7, -8.5, -6.6, -8.7, -8.6, -24.5, -6.7, -8.3, and -7.9, respectively. It was observed that, Cyclodextrin possess multiple properties in drug delivery science and here also demonstrated excellent binding affinity. We propose that drug efflux-related MDR may be prevented by the use of Agarose, Carregeenan, Chitosan, Cyclodextrin, Hyaluronic acid, and/or Polysialic acid in the administration of anticancer drugs.