Terms Of Pharmacokinetic Profile Research Articles

Computational Analysis of ZINC Analogues for Antidiabetic Phytochemical with Inhibitory Activity against Aldose Reductase Enzyme

The pathognomonic role of sorbitol pathway in the development of microvascular complications cannot go underappreciated; while it may not be a sole independent initiator, it remains a key contributor to the initiation and progression of diabetic microangiopathies, particularly retinopathy, neuropathy, and nephropathy. The sorbitol pathway is a two-step reaction process initiated by the rate-limiting enzyme aldose reductase. This study aimed to screen ZINC databases for chemical compounds similar to Ellagic acid, Kaempferol, and Mangiferin and analyze their pharmacokinetic, toxicological and docking profile using computational methods. These phytochemicals were chosen based on literature review of ethnobotanical studies and validated via SwissTargetPrediction. An in-silico study design was employed using computational algorithms. Molecular structures of analogues were obtained from ZINC database and prepared using Avogadro software. Docking analysis was carried out using AutoDock Vina embedded in Chimera. Visualization of ligand-enzyme interactions was done using Discovery studio. SWISSADME and Protox-II were used to profile pharmacokinetic and toxicity of the analogs. A total of 44 analogs were analyzed. Sulindac and parent phytochemicals were used as comparators. Kaempferol had strongest binding affinity (-8.7) followed by Ellagic acid and Mangiferin tying at -8.4. Kaempferol analogs had highest binding affinity compared to analogues of Ellagic acid and Mangiferin. In terms of Pharmacokinetic profile, analogues of Ellagic acid demonstrated a favorable profile with no Lipinski rule violations, high GI absorption, and inhibition limited to CYP1A2, which plays a minor role in drug metabolism compared to other enzymes. Toxicology predictions indicated that Kaempferol exhibited a higher safety profile compared to Ellagic acid and Mangiferin, with LD50 values of 3919 mg/kg, 2991 mg/kg, and 2 mg/kg, respectively. Ellagic acid analogues demonstrated chemical safety, absence of mutagenicity, hepatotoxicity, cytotoxicity, and activation of various pathways. Among the Kaempferol analogues, a subset was potentially carcinogenic and mutagenic, while all exhibited potential pathway activation. Mangiferin analogues, except for a few compounds, did not activate specific pathways, nor did they demonstrate hepatotoxicity or cytotoxicity. However, some analogues exhibited potential immunogenicity and mutagenicity. Kaempferol and some of its ZINC analogues had strongest binding affinity compared to Ellagic acid, Mangiferin and their analogues. This can be attributed to the simpler structure of Kaempferol, allowing it to fit snugly into the hydrophobic pocket of aldose reductase. Ellagic acid, with its planar and rigid structure, interacted primarily with the outer surface of the hydrophobic pocket. Similarly, due to its complex and large structure, Mangiferin demonstrated a relatively lower affinity. Analogues ZINC000005004393, ZINC000003872446, and ZINC000031156069 for Kaempferol, Ellagic acid, and Mangiferin respectively depicted the best optimal characteristics required for further development. We recommend an in vitro study be conducted to assess and validate the claims arrived at in this study

Design and evaluation of oral formulation for apixaban

Non-valvular atrial fibrillation (NVAF) is a common form of cardiac arrhythmia that affects 1–1.5% of adults and roughly 10% of elderly adults with dysphagia. Apixaban is an anticoagulant referred to as a factor Xa inhibitor, which has been shown to reduce the risk of stroke and systemic embolism in cases of NVAF. Our objective in the current study was to formulate an orally disintegrating film to facilitate the administration of apixaban to elderly patients who have difficulty swallowing. Researchers have used a wide variety of cellulose-based or non-cellulose-based polymers in a variety of combinations to achieve specific characteristics related to film formation, disintegration performance, drug content, in vitro drug release, and stability. One of the two formulations in this study was specify that bioequivalence criteria met with respect to Cmax of the reference drug (ELIQUIS®) in terms of pharmacokinetic profile. Further research will be required to assess the applicability of orodispersible films created using colloidal polymers of high and low molecular weights to other drugs with poor solubility in water.

Discovery of pyrimidine-bridged CA-4 CBSIs for the treatment of cervical cancer in combination with cisplatin with significantly reduced nephrotoxicity

A series of pyrimidine-bridged CA-4 derivatives (9a-u) targeting colchicine site were designed, synthesized and evaluated. Among them, the most potent compound 9j showed favorable anti-proliferative activities against a panel of cervical cancer cells (IC50 = 0.09–0.15 μM) and tubulin polymerization inhibitory activity (IC50 = 4.6 μM). Meanwhile, compound 9j exhibited superior anti-proliferative activity against cisplatin-resistant HeLa/DDP and SiHa/DDP cells than CA-4 and cisplatin. Particularly, the combination of 30 mg/kg 9j with 3 mg/kg cisplatin resulted in a 73% tumor suppression rate in HeLa xenograft model and reduced the renal dysfunction and injuries caused by high doses of cisplatin. Moreover, 9j was highly selective over the normal human proximal tubular cells (HK-2 cells, IC50 = 188 μM). Mechanism studies revealed that 9j could disrupt tubulin polymerization and vasculature, arrest the cell cycle at the G2/M phase, induce apoptosis, and suppress clonogenesis and migration in HeLa cells. Further druggability characterization in terms of pharmacokinetic profile, acute toxicity, and hERG inhibition confirmed 9j could serve as a promising and safe combination agent for cervical cancer therapy.

In Vitro Dissolution and In Vivo Bioequivalence Evaluation of Two Metformin Extended‐Release Tablets

The objective of the present study was to evaluate the bioequivalence between generic and branded metformin extended-release (ER) tablets in Chinese subjects. We tested bioequivalence in vitro and in vivo using a comparative dissolution study and a comparative pharmacokinetic trial. Safety assessments were conducted throughout the entire trial period. The dissolution profiles of the generic formulation expressed obvious extended-release properties, similar to those of the branded formulation (f2 > 60.0%). Consistent with the result of the in vitro study, no remarkable differences were found in terms of pharmacokinetic profiles between generic and branded formulations. The 90% confidence intervals of Ln AUC0-36h , Ln AUC0-∞ , and Ln Cmax from generic formulation versus branded formulation were 91.4% to 105.0%, 91.3% to 104.7%, and 101.2% to 119.4%, respectively. During the entire trial period, 4 subjects experienced 11 adverse events. All these were mild and spontaneously resolved. The results obtained from the present study suggest that the generic and branded metformin ER tablets were bioequivalent in Chinese subjects.

Recombinant Filgrastim (BK0023) Pharmacodynamics and Pharmacokinetics After Single and Multiple Escalating Doses in an Equivalence Study in Healthy Men

The new filgrastim formulation, BK0023, whose synthesis method is patented, was tested in a phase I clinical study that was aimed at investigating the pharmacodynamic and pharmacokinetic equivalence and the safety of BK0023 in healthy male subjects. Single and multiple escalating doses were administered to healthy male volunteers according to a double-blind, randomised, two-way crossover design. Thirty-two subjects received subcutaneous filgrastim 2.5µg/kg/day for 7 consecutive days in each period, 36 subjects received 5µg/kg/day for 7days in each period, and 22 subjects received 10µg/kg/day for 5days. Absolute neutrophil count (ANC) and CD34+ cell count were measured in whole blood as primary and secondary pharmacodynamic parameters. Filgrastim concentrations were measured in serum to calculate the primary pharmacokinetic parameters. The maximum ANC and the area under the curve of the ANC after the first dose and to the end of treatment satisfied the equivalence criterion (95% confidence intervals within 85-115 or 85-117% in case of log-transformation). At all three dose regimens, BK0023 was also bioequivalent to the reference product in terms of pharmacokinetic profile of serum filgrastim. The frequency of the treatment-emergent adverse events did not differ significantly between treatments, with the most frequent untoward effects being back and bone pain. Equivalence could be established using both the baseline-adjusted values and the original unadjusted values. The tested formulation at all three dose regimens was also bioequivalent to the reference product in terms of pharmacokinetic profile.