Implications of Pharmacokinetic Potentials of Pioglitazone Enantiomers in Rat Plasma Mediated through Glucose Uptake Assay.

Pioglitazone, a PPAR-gamma activator used to diagnose hyperglycemia, was studied for its stereoselective deposition and active enantiomers in female albino Wistar rats. In accordance with USFDA recommendations, a bioanalytical technique was employed to assess the segregation of pioglitazone enantiomers in rat plasma with glimepiride as an internal standard. A Phenomenox i-Amylose-3 column (150 mm × 4.6 mm) of 5 µm was used for high-performance liquid chromatography (HPLC) with a mobile phase of 10 mM ammonium acetate buffer in Millipore water and acetonitrile in 60:40 (v/v) admixture with column temperature 35 °C, wavelength 265 nm, and flow rate 0.6 mL/min, respectively. Pioglitazone-S, Pioglitazone-R, and the internal standard had retention times of 3.1, 7.4, and 1.7 min, respectively. The study found that within-run and between-run precision ranged from 0.1606-0.9889% for Pioglitazone-R and from 0.2080-0.7919% for Pioglitazone-S, while the accuracy ranged from 99.86 to 100.36% for Pioglitazone-R and 99.84 to 99.94% for Pioglitazone-S. In addition, a non-radioactive glucose uptake assay was employed to examine the enantiomers in 3T3-L1 cell lines by flow cytometry. Significant differences were demonstrated in Cmax, AUClast (h*µg/mL), AUCINF obs (h*µg/mL), and AUC%Extrap obs (%) of Pioglitazone-R and S in female albino Wistar rats, suggesting enantioselectivity of pioglitazone.

Bioanalytical chiral chromatographic technique and docking studies for enantioselective separation of meclizine hydrochloride: Application to pharmacokinetic study in rabbits.

Enantiomeric resolution and molecular docking studies of meclizine hydrochloride on polysaccharide-based chiral stationary phase comprising cellulose tris(4-methylbenzoate) chiral selector (150 × 4.6 mm, 3.0 µm) were presented. The mobile phase used was acetonitrile:10mM ammonium bicarbonate (95:05, v/v). The developed technique was used to perform the enantioselective assay of meclizine hydrochloride in its marketed formulation. The elution order of meclizine hydrochloride enantiomers was determined by docking studies. Target compound was extracted from rabbit plasma using protein precipitation technique, followed by development of bioanalytical chiral separation method using the same matrix. Application of the method to determine pharmacokinetic parameters of meclizine hydrochloride enantiomers was performed using Phoenix WinNonlin 8.1 software. The results demonstrated stereoselective disposition of meclizine hydrochloride enantiomers in rabbits.

Pharmacokinetics and Pharmacodynamics of a Nanostructured Lipid Carrier Co-Encapsulating Artemether and miRNA for Mitigating Cerebral Malaria.

Cerebral malaria (CM), a severe neurological pathology caused by Plasmodium falciparum infection, poses a significant global health threat and has a high mortality rate. Conventional therapeutics cannot cross the blood-brain barrier (BBB) efficiently. Therefore, finding effective treatments remains challenging. The novelty of the treatment proposed in this study lies in the feasibility of intranasal (IN) delivery of the nanostructured lipid carrier system (NLC) combining microRNA (miRNA) and artemether (ARM) to enhance bioavailability and brain targeting. The rational use of NLCs and RNA-targeted therapeutics could revolutionize the treatment strategies for CM management. This study can potentially address the challenges in treating CM, allowing drugs to pass through the BBB. The NLC formulation was developed by a hot-melt homogenization process utilizing 3% (w/w) precirol and 1.5% (w/v) labrasol, resulting in particles with a size of 94.39 nm. This indicates an effective delivery to the brain via IN administration. The results further suggest the effective intracellular delivery of encapsulated miRNAs in the NLCs. Investigations with an experimental cerebral malaria mouse model showed a reduction in parasitaemia, preservation of BBB integrity, and reduced cerebral haemorrhages with the ARM+ miRNA-NLC treatment. Additionally, molecular discoveries revealed that nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) and Interleukin-6 (IL-6) levels were reduced in the treated groups in comparison to the CM group. These results support the use of nanocarriers for IN administration, offering a viable method for mitigating CM through the increased bioavailability of therapeutics. Our findings have far-reaching implications for future research and personalized therapy.

Nitrosamines crisis in pharmaceuticals - Insights on toxicological implications, root causes and risk assessment: A systematic review.

The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates their toxicity in active pharmaceutical ingredients (APIs), drug products, and pharmaceutical excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, and regulatory guidelines for nitrosamines. This review emphasizes the molecular toxicity of N-nitroso compounds, focusing on genotoxic, mutagenic, carcinogenic, and other physiological effects. Additionally, it addresses the ongoing nitrosamine crisis, the development of nitrosamine-free products, and the importance of sensitive detection methods and precise risk evaluation. This comprehensive overview will aid molecular biologists, analytical scientists, formulation scientists in research and development sector, and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.

In vitro study and pharmacokinetic evaluation of sitagliptin phosphate enantiomers in rat plasma.

Background: A chiral HPLC technique was developed to determine sitagliptin phosphate enantiomers in rat plasma in compliance with US FDA regulations. Methods & results: The technique used a Phenomenex column with a mobile phase consisting of a 60:35:5 (v/v/v) blend of pH4, 10-mM ammonium acetate buffer, methanol and 0.1% formic acid in Millipore water. The precision for both (R) and (S) sitagliptin phosphate varied between 0.246 and 1.246%, while the accuracy was 99.6-100.1%. A glucose uptake assay was used to assess enantiomers in 3T3-L1 cell lines through flow cytometry. Conclusion: Investigation of the pharmacokinetic impacts of sitagliptin phosphate racemic enantiomers in rat plasma revealed notable contrasts in R and S enantiomers in female albino Wistar rats, suggesting enantioselectivity for sitagliptin phosphate.

An Overview of CDK Enzyme Inhibitors in Cancer Therapy.

The ability to address the cell cycle in cancer therapy brings up new medication development possibilities. Cyclin-dependent kinases are a group of proteins that control the progression of the cell cycle. The CDK/cyclin complexes are activated when specific CDK sites are phosphorylated. Because of their non-selectivity and severe toxicity, most first-generation CDK inhibitors (also known as pan-CDK inhibitors) have not been authorized for clinical usage. Despite this, significant progress has been made in allowing pan-CDK inhibitors to be employed in clinical settings. Pan-CDK inhibitors' toxicity and side effects have been lowered in recent years because of the introduction of combination therapy techniques. As a result of this, pan-CDK inhibitors have regained a lot of clinical potential as a combination therapy approach. The CDK family members have been introduced in this overview, and their important roles in cell cycle control have been discussed. Then, we have described the current state of CDK inhibitor research, with a focus on inhibitors other than CDK4/6. We have mentioned first-generation pan-CDKIs, flavopiridol and roscovitine, as well as second-generation CDKIs, dinaciclib, P276-00, AT7519, TG02, roniciclib, and RGB-286638, based on their research phases, clinical trials, and cancer targeting. CDKIs are CDK4/6, CDK7, CDK9, and CDK12 inhibitors. Finally, we have looked into the efficacy of CDK inhibitors and PD1/PDL1 antibodies when used together, which could lead to the development of a viable cancer treatment strategy.

A response surface modeling and optimization of photocatalytic degradation of 2,4-dichlorophenol in water using hierarchical nano-assemblages of CuBi2O4 particles.

Photocatalytic degradation, as an advanced oxidation process (AOPs), offers a great advantage to target persistent organic pollutants (POPs) in water. RSM in the present study which is statistical means for optimizing processes like photocatalysis with minimum laboratory experimentation. RSM has a history of being a potent design experiment tool for creating new processes, modifying their designs, and optimizing their performances. Herein, a highly sought-after, easily preparable, visible-light active, copper bismuth oxide (CuBi2O4) is applied against a toxic emerging contaminant, 2,4-dichlorophenol (2,4-DCP) under an LED light source (viible light λ > 420 nm). A simple coprecipitation method was adopted to synthesize CuBi2O4 and later analyzed with FESEM, EDX, XRD, FTIR, and spectroscopy to determine its intrinsic properties. Principally, the photocatalytic degradation investigations were based on response surface methodology (RSM), which is a commanding tool in the optimization of the processes. The 2,4-DCP concentration (pollutant loading), CuBi2O4 dosage (catalyst dosge), contact time, and pH were the chosen as dependent factors, that were optimized. However, under optimal conditions, the CuBi2O4 nanoparticle showed a remarkable photocatalytic performance of 91.6% at pH = 11.0 with a pollutant concentration of 0.5 mg/L and a catalyst dose of 5 mg/L within 8 h. The obtained RSM model showed a satisfactory correlation between experimental and predicted values of 2,4-DCP removal, with an agreeable probability value (p) of 0.0069 and coefficient of regression (R2) of 0.990. It is therefore anticipated that the study may open up new possibilities for formulating a plan to specifically target these organic pollutants. In addition, CuBi2O4 possessed fair reusability for three-consequent cycles. Hence, the as-synthesized nanoparticles applied for photocatalysis foster a fit-for-purpose and reliable system in the decontamination of 2,4 DCP in environmental samples, and also the study highlights the efficient use of RSM for environmental remediation, particularly in AOP implementation.

Enantiomeric separation of oxomemazine in rabbit plasma by ultra-fast LC and application in a stereoselective pharmacokinetic study.

Aim: Ultra-fast LC was used to establish a new bioanalytical method for enantiomeric separation of oxomemazine. Methods: The proposed study was carried out using the ultra-fast LC technique with an amylose chiral column. The bioanalytical approach was used in rabbit plasma following US FDA regulations and then extended to oxomemazine enantiomeric separation using metronidazole as the internal standard. Results: The retention times of (R)-oxomemazine, (S)-oxomemazine and the internal standard were found to be 9.511, 10.712 and 6.503 min, respectively. Within-run and between-run precision (percent relative standard deviation) was found to be in the range of 0.018-0.102% for (R)-oxomemazine and 0.028-0.675% for (S)-oxomemazine, whereas accuracy (%) was found to be in the range of 95.971-99.720% for (R)-oxomemazine and 97.199-103.921% for (S)-oxomemazine. Conclusion: The findings revealed that stereospecific distribution of oxomemazine enantiomers does not change significantly.

Coprecipitation aided synthesis of bimetallic silver tungstate: a response surface simulation of sunlight-driven photocatalytic removal of 2,4-dichlorophenol.

In the present study, the response surface methodology (RSM) model was used to investigate the photocatalytic performance of silver tungstate (Ag2WO4) in the removal of 2,4-dichlorophenol (2,4-DCP) under natural sunlight. The Ag2WO4 which has nanoflower-like structure was synthesized by a coprecipitation method. The synthesized photocatalyst was characterized for FESEM, TEM, EDX, XRD, FTIR, and UV-Vis spectroscopy. RSM was employed to scrutinize the suitable model to yield a profound pollutant removal rate. The four independent factors such as pollutant concentration, catalyst dosage, pH, and contact time are simulated using RSM. A total of 91% of 2,4-DCP degradation was achieved at a higher catalyst dosage and lower pollutant concentration with a contact duration of 8 h in an alkaline pH condition. The coefficient of regression (R2) and probability value (P) were 0.98 and 0.0472, respectively, which confirmed the ideality of RSM modeling. The study discusses on the possible photocatalytic degradation mechanisms of 2,4-DCP. The results showed a significant dependence of the photocatalytic removal of 2,4-DCP on the functional parameters.

Degradation of doxycycline antibiotics using lanthanum copper oxide microspheres under simulated sunlight.

In this study, lanthanum copper oxide was synthesized under hydrothermal techniques and characterized for doxycycline degradation. The catalyst exhibited enhanced photocatalytic doxycycline degradation under visible light owing to its compatible bandgap energy (1.7 eV). The XRD data revealed high crystallinity of the material with no noticeable impurities. Three-dimensional microspheres of varying sizes (average diameter of 2.52 µm) were observed from SEM. EDX confirms the successful synthesis of La2CuO4. The effect of DC concentration, catalyst dosage, and initial pH on the degradation rate of DC was studied methodically. Interestingly, about 85% of doxycycline (10 mg/L) was degraded within 120 min of light-emitting diode irradiation at pH 10. Oxygen vacancies and surface defects were determined through photoluminescence spectra. The recyclability experiments suggested that the catalyst is capable of degrading DC for three consecutive runs. Radical trapping trials suggested that holes (h+), superoxide radicals (●O2-), and hydroxyl radicals (●OH) are involved in the photodegradation of DC. Herein, the novel approach of La2CuO4 synthesis and the efficient visible-light harvesting capability of as-prepared catalyst reveal the potentiality for DC degradation thereby opening a new horizon of research employing La2CuO4 used for various environmental applications.

Sonochemical synthesis of graphitic carbon nitride-manganese oxide interfaces for enhanced photocatalytic degradation of tetracycline hydrochloride.

The present study focuses on the sonochemical synthesis of graphitic carbon nitride-manganese oxide (GCN/MnO2) nanocomposite for photocatalytic degradation of an environmentally hazardous pharmaceutical compound, tetracycline hydrochloride (TcH). The sonochemical synthesis aided in tailoring the morphology of GCN/MnO2. The characterization results of SEM/FESEM, XRD, FTIR, UV-Vis spectra, EIS, CV, etc., revealed on the morphology, composition, crystallinity, and other photo-electro-intrinsic properties of the materials. The synergy of GCN and MnO2 results in rapid electron transfer, efficient visible-light absorption, and slower electron-hole pair recombination through its photo-responsive traits against TcH. It was noted that ~ 93% TcH (20 mg L-1) degradation was achieved for 30-mg catalyst dose under light-emitting diode (LED) irradiation (9 W, 220 V) in 135-min duration. The TcH mineralization results were well fit to pseudo-first-order kinetics with a rate constant of 0.02 min-1 (R2 = 0.994). In addition, the composite possessed fair reusability for consequent cycles. Hence, the as-synthesized composite applied for photocatalysis and photoelectrocatalysis fosters a fit-for-purpose and reliable system in the decontamination of TcH in environmental samples. Graphical Abstract.

Recent Advances in Chiral Separation of Antihistamine Drugs: Analytical and Bioanalytical Methods.

Chirality is now a key area in the field of research. Researchers are well versed with analytical separations but at the same time, they are unaware of the growth in the field of chiral separation. According to the United States Food and Drug Administration (US FDA) guidelines, it is mandatory to separate chiral drugs before they are marketed. Chiral separation has gained importance in the last 10 years due to the differential biological responses of the enantiomers in chiral environment. Identical physical and chemical properties of the enantiomers pose a major challenge for the separation of chiral compounds. Further, bioanalytical method development is also necessary to throw light on the fate of separated enantiomers in biological environment. High Performance Liquid Chromatography (HPLC) and Capillary Electrophoresis (CE) are the most widely used techniques for such separation. Antihistamines are a class of drugs that are represented by a wide number of chiral compounds. Hence this review focuses on enantioseparation of chiral antihistamine drugs. It begins with a brief discussion about antihistamine drugs, chiral separation and its need for study, followed by a brief overview of the analytical and bio-analytical work carried out on different chiral antihistamine drugs. The analytical and bio-analytical techniques that are used include HPLC, CE and some new techniques.

Current Perspectives on Novel Drug Carrier Systems and Therapies for Management of Pancreatic Cancer: An Updated Inclusive Review.

Pancreatic cancer (PC) is one of the most fatal solid tumors, resulting in more than 250,000 deaths per year globally. It is the eighth leading cause of death from cancer in men and women throughout the world and is now third leading cause of cancer-related deaths in the United States. In addition, the worldwide occurrence of PC ranges from 1 to 10 cases per 100,000 people, indicating a higher incidence in developed countries. Most patients with locally advanced or metastatic disease are not candidates for curative resection due to enormously poor prognosis. Substantial efforts have been taken during the past decade to distinguish better treatments in the absence of efficient screening methods. Regardless of wide-ranging efforts, various systems and therapies have shown insufficient efficacy for PC patients. Therefore, the development of novel drug delivery systems, strategies, and diverse therapeutic approaches to improve the range of active molecules for the treatment of PC is critical. Currently, cancer research focuses on improving the treatment of PC via diverse novel drug delivery systems of chemotherapeutic agents. These novel drug delivery systems consist of nanoparticles and liposomes. Strategies or therapeutic approaches intended for PC include radiation therapy, ablation therapy, and gene therapy. These systems and approaches can carry the drug molecules to targeted cancer cells to enhance the effectiveness of tumor penetration. The present review encloses existing novel drug carrier systems and approaches for PC management.

Enantioselective UFLC Determination of Hydroxyzine Enantiomers and Application to a Pharmacokinetic Study in Rabbits.

Hydroxyzine is the first generation H1 receptor antagonist drug that is now marketed as a racemic mixture. The paper describes a validated enantioselective liquid chromatography method for the resolution of hydroxyzine enantiomers and cyclizine (internal standard) from 200 µL of rabbit plasma by liquid-liquid extraction technique using n-hexane and isopropanol. Hydroxyzine enantiomers were resolved at 10.2 and 11.1 min with good baseline resolution (Rs = 1.9) on a Lux amylose-2 chiral column (250 mm × 4.0 mm, 5 microns) at ambient room temperature. The mobile phase consisted of n-hexane-ethanol-diethylamine (90:10:0.1 v/v/v) pumped at 0.9 mL/min. The eluted enantiomers were detected at 254 nm. The linear calibration curve was constructed in the range 20-1000 ng/mL for both the (S)- and (R)-enantiomers. The intra- and inter-day precision were 0.16-2.6% and 0.2-1.92% for (S)-hydroxyzine and (R)-hydroxyzine, respectively. The method was successfully applied to determine the kinetic parameters of (S)- and (R)-hydroxyzine enantiomers in rabbits. The results illustrate that the disposition of hydroxyzine enantiomers is not stereoselective in rabbits.

Optimized and Validated RP-UPLC Method for the Determination of Losartan Potassium and Chlorthalidone in Pharmaceutical Formulations.

PURPOSE: A validated ultra performance liquid chromatography (UPLC) method has been developed and validated for the simultaneous determination of losartan potassium and chlorthalidone in pharmaceutical preparations. METHODS: Waters-Acquity UPLC system equipped with Auto Sampler, PDA detector and operated with Empower-2 software was used for the present study. Detection was done at wavelength of 230 nm, HSS C18, 100 mm x 2.1x 1.8 µm column with a reverse phase elution and mobile phase composed of A and B mixed in the ratio 56:44 v/v (Where mobile phase A consists of potassium dihydrogen phosphate buffer of pH 3.0 and Mobile phase B consists of acetonitrile and methanol mixed in the ratio of 90:10 v/v) used at a flow rate of 0.4ml per minute. RESULTS: The retention times for losartan potassium and chlorthalidone were observed at 0.72 and 1.89 minutes. The developed method was validated as per ICH guidelines. Linearity ranges were found to be 12.5-125 µg/ml and 3.125-31.25 µg/ml for losartan potassium and chlorthalidone, respectively. CONCLUSION: This method is fast, accurate, precise and sensitive hence it can be employed for routine quality control of tablets containing both drugs in industries.