Drug Research最新文献

Canagliflozin is a synthetic sodium glucose transporter inhibitor (SGLT2i). It is the latest approved class of medicine used in the treatment of type 2 diabetes mellitus. As diabetes is emerging as the most common metabolic disorder, SGLT2i has lightened up the path of treatment with additional benefits. SGLT2 is located in the proximal convoluted tubules of the nephron and is responsible for glucose reabsorption. Thus, inhibiting the SGLT2 leads to a decline in glucose concentration in the plasma. The secondary effects of canagliflozin, such as cardiac protection, renoprotective, and decreased obesity, have made it more putative in the treatment of diabetes mellitus. There are some side effects of canagliflozin, such as volume depletion, genital and urinary tract infection, and lower limb amputation, which could be a matter of concern for patients. Being an anti-diabetic drug, canagliflozin also possesses anti-inflammatory and anti-cancer properties. Several studies have been conducted to determine the efficacy of canagliflozin as an anti-cancer agent. Its pharmacokinetics indicate rapid absorption, reaching peak plasma concentrations within 1-2 hours. With a half-life of approximately 12 hours, it undergoes minimal hepatic metabolism and is primarily excreted unchanged via urine. Common adverse drug reactions (ADRs) include urinary tract infections and dehydration. Clinical trials on canagliflozin, both alone and in combination with other diabetes complications, have been conducted, with some completed and others in various phases. This review article contains information about the pharmacokinetics, drug safety, and efficacy profile of canagliflozin, along with details regarding toxicological studies of canagliflozin.

Chronic use of morphine may induce tolerance to its different pharmacological effects. Vitamin B6 has a central role, as a cofactor, in the biosynthesis of neurotransmitters that are involve in morphine's effects. Moreover, this vitamin affects on morphine's reward and analgesic properties. Therefore, the current research aimed to evaluate the effects of vitamin B6 on the expression and acquisition of tolerance to morphine locomotor-stimulating effects.Twenty groups of mice (n=8) were selected randomly. Acute effects of different doses of morphine (1-30 mg/kg) or vitamin B6 (25-75 mg/kg) on locomotor activity were evaluated using an activity meter. Induction of tolerance was conducted using morphine (30 mg/kg)×2 times a day×3 days plus a single dose of morphine (30 mg/kg) on fourth day. In expression experiment, vitamin B6 (25-75 mg/kg) or saline was injected one hour before the last dose morphine, after tolerance induction. In the acquisition test, one hour before each dose of morphine (in the first three days of tolerance induction) saline or vitamin B6 (25-75 mg/kg) was administered to mice.Although vitamin B6 had no effect on locomotion, administration of morphine had a biphasic effect on mice's locomotor activity; it decreased locomotion at a low dose (5 mg/kg) and increased it at a high dose (30 mg/kg). Furthermore, administration of vitamin B6 before morphine could inhibit the expression and the acquisition of tolerance to morphine-stimulating effects on locomotor activity.Vitamin B6 may be considered as a nutritional supplement in reducing morphine tolerance.

Mesalamine (mesalazine, 5-aminosalicylic acid, 5-ASA) is an essential anti-inflammatory agent both used for therapy and as a remission control in patients with inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). Tricyclic antidepressants (TCAs) are used to alleviate remaining symptoms in patients already receiving IBD therapy or with quiescent inflammation. The cytochrome P4502D6 enzyme is involved in the metabolism of TCAs. Hence, it is crucial to investigate the role of CYP2D6 in 5-ASA metabolism. Initially, in silico analysis involving the docking of 5-ASA to CYP2D6 and molecular dynamics simulations was conducted. Next, the rate of O-demethylation of a nonfluorescent probe 3-[2-(N,N-diethyl-N-methylammonium)-ethyl]-7-methoxy-4-methylcoumarin (AMMC) into a fluorescent metabolite AMHC (3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-hydroxy-4-methylcoumarin) was optimized with baculosomes co-expressing human CYP2D6 and human P450 oxidoreductase (hCPR) to monitor CYP2D6 activity in a microtiter plate assay. The apparent Km and Vmax were found to be 1.30 μM and 32.68 pmol/min/mg of protein for the O-demethylation of AMMC to AMHC, and the reaction was linear for 40 min. Then, nonselective inhibition of CYP2D6 activity with various concentrations of 5-ASA was detected. Finally, the conversion of AMMC to metabolites was analyzed by HPLC-ESI-MS/MS spectrometry, and none were identified. Thus, this study suggests that concurrent use of mesalamine with TCA may lead to adverse effects, and CYP2D6 genotyping should be routinely performed on these patients to eliminate possible threats.

To determine the potential benefit of adding Saccharomyces boulardii (S. boulardii) probiotic supplementation to conventional treatments in asthmatic patients.In this randomized, double-blinded, and placebo-controlled trial 50 asthmatic patients were enrolled. The eligible subjects received either S. boulardii (N=25) or placebo (N=25) added to conventional treatments for three months. Spirometry parameters (FEV1, FVC, FEV1/FVC, and FEF 25-75%) and blood test parameters (CBC, eosinophil percentage, IgE, IL-5, ESR and CRP) were measured and compared at baseline and after treatment completion.The mean age was 39.22±12.55 years. As compared to baseline values, a significant improvement was noted in FEV1 in patients who received S. boulardii (p=0.026). Although the changes in FEV1, FVC, FEV1/FVC, and FEF 25-75% were comparable between the study groups, the differences were not statistically significant (p ˃ 0.05). In addition, patients who received probiotic showed lower levels of IL-5 and IgE in comparison with patients who received placebo.Our findings showed that the addition of S. boulardii to conventional treatments partially improved the pulmonary function and was associated with reductions in IgE and IL-5 levels.

Sotagliflozin, a dual SGLT1/2 inhibitor, enhances glucagon like peptide-1 (GLP-1) levels and GLP-1 receptor agonists are used to manage non-alcoholic fatty liver disease (NAFLD). Study investigates the effects of sotagliflozin on NAFLD, alone and combined with linagliptin, comparing outcomes in normoglycemic and hyperglycemic animal models.Obese fatty liver disease (FLD) model was induced by high-fat diet (HFD) feeding, while a diabetic non-alcoholic steatohepatitis (NASH) model was developed by administering a single dose of streptozotocin to neonatal mice, followed by HFD feeding post-weaning. At termination of the study, parameters including biochemical markers, inflammatory cytokines, hepatic lipid content, and histopathology were assessed.In NASH mice, sotagliflozin and linagliptin reduced hepatic triglycerides by 60% and 44%, respectively, and cholesterol by 46% and 49%. Their combination further decreased triglycerides by 68.5% and cholesterol by 83.9%. In FLD mice, sotagliflozin and linagliptin reduced triglycerides by 33% and 17%, respectively, and cholesterol by 46% and 21%. Combination treatment offered no benefit, reducing triglycerides by 38% and cholesterol by 27%. Both the treatments improved plasma fibroblast growth factor 21, hepatic interlukin-6, glucose tolerance, steatosis and mitigated fat pad weight, but their combination did not show additional benefit. However, combination treatment demonstrated added benefit in modulating NAFLD activity score, liver enzymes, glycogenated hepatic nuclei, plasma glucose and active GLP-1 levels.Study underscores sotagliflozin's potential to mitigate NAFLD and highlights the benefit of combining it with linagliptin in hyperglycemic NASH model, which showed limited efficacy in normoglycemic FLD mice.

Cyclophosphamide (CP) is a potent anticancer drug, but nephrotoxicity is one of the vital organ toxicities that it causes as a side effect. We tried to evaluate the nephroprotective effect of levocabastine (LEV) in CP-induced nephrotoxicity in Swiss albino mice. Mice were given CP 200 mg/kg, i.p., once on the 7^th day. LEV (0.05 and 0.1 mg/kg, i.p.) and fenofibrate (FF) (80 mg/kg, p.o.) were given daily for 14 days. On the 15^th day, animals were sacrificed and kidneys were removed for examination. The docking study showed significant binding of LEV and FF against TGF-β1, which is a prime target molecule involved in nephrotoxicity. CP 200 group showed nephrotoxicity in terms of oxidative stress, apoptosis, inflammation, and fibrosis as manifested by decreased levels of SOD, catalase, GSH, blood urea nitrogen/creatinine (BUN/Cr) ratio, and increased TBARS, nitrite, TNF-α, IL-6, TGF-β1, IL-1β, urea, uric acid, creatinine, and BUN. A decrease in body weight (BW) and an increase in kidney weight (KW) with an increased KW/BW ratio was also observed. Cleaved caspase-3 and NF-κB expression was also increased. Histopathological aberrations, like renal corpuscle damage, Bowman's space widening, glomerulus, mesangium cell disintegration, atrophic podocytes, vacuolation, and fibrotic changes were also seen. LEV 0.1 and FF 80 significantly reversed these changes toward normal and showed nephroprotective potential. Thus, seeing the protective effect of LEV on CP-intoxicated mice, we conclude that LEV may be used as an adjuvant with CP in cancer, however, it needs more studies with the direct cancer model to confirm the claim.

Diabetic retinopathy, the most common microvascular complication of diabetes mellitus, is the leading cause of vision impairment worldwide. Flavonoids with antioxidant properties have been shown to slow its progression. Myricetin, a flavonoid polyphenolic compound, possesses antioxidant properties, but its clinical use in ocular delivery is limited by poor aqueous solubility, stability, and bioavailability. Recently, in situ gels have gained interest as ocular drug delivery vehicles due to their ease of installation and sustained drug release. This study aimed to develop a myricetin-loaded thermoresponsive in situ nanoemulgel to enhance its efficacy in treating diabetic retinopathy. Nanoemulsions were developed via aqueous phase titration using Sefsol 218 as the oil phase, Kolliphore RH40 as the surfactant, and PEG 400 as the co-surfactant. Physicochemical evaluations identified formulation batch ISG17, consisting of 10% oil phase, 30% S_mix (1:2), and 60% distilled water, as the optimal formulation. The developed in situ nanoemulgel showed significant enhancement in corneal permeation and retention, which was further confirmed by fluorescence microscopy. Ocular tolerability was demonstrated through corneal hydration tests and histopathology investigations. The antioxidant potential of the myricetin-loaded nanoemulgel was assessed using the DPPH assay. Myricetin was found to be an efficient antioxidant, as indicated by its IC₅₀ values compared to ascorbic acid. The MTT cell viability assay results showed that the developed formulation effectively inhibits the proliferation of Y79 retinoblastoma cells, demonstrating comparable efficacy to the standard marketed preparation Avastin (Bevacizumab injection). In conclusion, the nanoemulsion formulation containing a thermoresponsive polymer for in situ gelling presents a promising drug delivery system, offering superior therapeutic efficacy and better patient compliance for the treatment of diabetic retinopathy.

To investigate the effect of 1α,25(OH)₂D₃ on hepatic stellate cells and the mechanism of the TGF-β1/Smad signaling pathway.LX2 cells were treated with TGF-β1 and different concentrations of 1α,25(OH)₂D₃. Cell proliferation was assessed using the CCK8 assay to determine the optimal concentration of 1α,25(OH)₂D₃ activity. The cell cycle and apoptotic rates were evaluated using flow cytometry. The expressions of Samd2, Samd3, Samd4, and Samd7 was assessed by western blotting, whereas the expression of MMP1, MMP13, and TIMP-1 was detected by qPCR.Compared with the control group, the 1α,25(OH)₂D₃ group had a higher apoptotic rate of LX2 cells, the cell cycle was blocked from the G1 stage to the S stage, the expressions of Samd2, Samd7, MMP1, and MMP13 increased, while the expressions of Samd3, Samd4, and TIMP-1 decreased.1α,25(OH)₂D₃ inhibits hepatic stellate cell activation and exerts anti-hepatic fibrosis effects by downregulating the expression of Samd3, Samd4, TIMP-1 and upregulating the expression of Samd2, Samd4, MMP1, and MMP13.

Fragment based novel drug identification and its validation through use of molecular dynamics and simulations.Comparing primary microcephaly genes with glioblastoma expression profiles reveals potential oncogenes, with proteins that support growth and survival in neural stem/progenitor cells likely retaining critical roles in glioblastoma. Identifying such proteins in familial and congenital microcephalic disorders offers promising targets for brain tumor therapy. Among these, KIF11, a kinesin motor protein (KSP), stands out as a significant oncogene. Expression analyses across various cancer types, including glioblastoma, demonstrate its overexpression in brain tumor patients. Using a targeted fragment-based drug discovery approach, we explored alternative small molecule inhibitors for KIF11. Existing drugs, such as ispinesib, are limited by side effects and multidrug resistance. Through molecular docking and simulations, we identified three candidate drug fragments. Further analysis confirmed that Mol-121026 exhibits a more stable interaction with KIF11 compared to ispinesib. Detailed analyses indicate that Mol-121026 binds to the same active site as the reference drug, effectively inhibiting KIF11's mechano-chemical activity. Importantly, Mol-121026, a derivative of 3-phenyl-1H-pyrazol-5-carboxylic acid, offers a promising alternative due to its lower molecular complexity, ability to target allosteric sites, and potential for optimization into a potent and effective drug candidate. Our findings identified Mol-121026 as a top candidate with a docking score of -10.2 kcal/mol and MM/GBSA binding energy of -19.10 kcal/mol. Molecular dynamics simulations revealed stable interactions with key residues GLU116 and GLU118, supporting its potential as a promising KIF11 inhibitor.

Conjugated single-walled carbon nanotubes (SWNT) have been shown to be promising in cancer-targeted accumulation and is biocompatible, easily excreted, and possesses little toxicity. The present study aims at reviewing the recent advancements in carbon nanotubes especially SWNT for improving the treatment of breast cancer. Nanotube drug delivery system is a potential high efficacy therapy with minimum side effects for future tumor therapy with low doses of drug.