ABSTRACT
Molnupiravir, a broad-spectrum antiviral is an isopropyl ester prodrug of beta-D-N4-hydroxycytidine. Molnupiravir targets RNA-dependent RNA-polymerase enzyme of the viruses. A new stability-indicating HPLC-method was developed to determine related substances and assay of molnupiravir. Separation was achieved by using Shim-pack GWS C18 column. The method was validated according to current ICH requirements. The calibration plot gave a linear relationship for all known analytes over the concentration range from LOQ to 200%. LOD and LOQ for all known analytes were found in 0.05-0.08 microg mL-1 and 0.12-0.20 microg mL-1, respectively, the mean recovery was found to be 97.79-102.44 %. Study showed that the method, results of robustness, solution stability studies are precise and within the acceptable limits. Molnupiravir was found to degrade in acid, alkali, and oxidative conditions, and was stable in thermal, moisture, and photolytic degradation condition. The method is simple, accurate, precise, and reproducible for routine purity analysis of drug-samples.Copyright © 2022 Indian Drug Manufacturers' Association. All rights reserved.
ABSTRACT
The worldwide epidemic of Coronavirus disease 2019 (COVID-19), caused by a new virus known as severe acute respiratory syndrome (SARS) coronavirus 2, has posed a growing threat to public health (SARS-CoV-2). The only antiviral drug authorized by the FDA for treating adult and pediatric patients hospitalized with a severe disease is remdesivir, which is given intravenously (IV). Although only a few methods for estimating remdesivir in pharmaceutical formulations using high-pressure liquid chromatography (HPLC) have been described, its determination still requires an accurate, precise, quick, and easy analytical methodology. The main goal of this study was to develop and validate a reliable and accurate HPLC method for quantitative estimation of remdesivir in its intravenous dosage formulation. The separation was performed on a C18 (4.6 mm x 150 mm, 5.0 microm) column with a flow rate of 0.7 mL/min and a total run duration of 6 minutes using a simple isocratic mobile phase of acetonitrile and 0.1 percent formic acid. The method was validated for the system suitability, linearity, precision, accuracy, robustness, and others as per the International Council for Harmonization (ICH) Q2 (R1) guideline. The results show that the method for measuring remdesivir using HPLC is simple, quick, sensitive, accurate, precise and robust. The described approach was successfully used to quantify remdesivir in a commercially available pharmaceutical formulation.Copyright All © 2023 are reserved by International Journal of Pharmaceutical Sciences and Research.
ABSTRACT
Effective drug delivery to the brain is critical for the treatment of glioblastoma (GBM), an aggressive and invasive primary brain tumor that has a dismal prognosis. Radiation therapy, the mainstay of brain tumor treatment, works by inducing DNA damage. Therefore, inhibiting DNA damage response (DDR) pathways can sensitize tumor cells to radiation and enhance cytotoxicity. AZD1390 is an inhibitor of ataxia-telangiectasia mutated kinase, a critical regulator of DDR. Our in vivo studies in the mouse indicate that delivery of AZD1390 to the central nervous system (CNS) is restricted due to active efflux by P-glycoprotein (P-gp). The free fraction of AZD1390 in brain and spinal cord were found to be low, thereby reducing the partitioning of free drug to these organs. Coadministration of an efflux inhibitor significantly increased CNS exposure of AZD1390. No differences were observed in distribution of AZD1390 within different anatomic regions of CNS, and the functional activity of P-gp and breast cancer resistance protein also remained the same across brain regions. In an intracranial GBM patient-derived xenograft model, AZD1390 accumulation was higher in the tumor core and rim compared with surrounding brain. Despite this heterogenous delivery within tumor-bearing brain, AZD1390 concentrations in normal brain, tumor rim, and tumor core were above in vitro effective radiosensitizing concentrations. These results indicate that despite being a substrate of efflux in the mouse brain, sufficient AZD1390 exposure is anticipated even in regions of normal brain. SIGNIFICANCE STATEMENT Given the invasive nature of glioblastoma (GBM), tumor cells are often protected by an intact blood-brain barrier, requiring the development of brain-penetrant molecules for effective treatment. We show that efflux mediated by P-glycoprotein (P-gp) limits central nervous system (CNS) distribution of AZD1390 and that there are no distributional differences within anatomical regions of CNS. Despite efflux by P-gp, concentrations effective for potent radiosensitization are achieved in GBM tumor-bearing mouse brains, indicating that AZD1390 is an attractive molecule for clinical development of brain tumors.Copyright © 2022 American Society for Pharmacology and Experimental Therapy. All rights reserved.
ABSTRACT
This study was aimed to detect trace amounts of drugs in littoral crustaceans of ancient Lake Baikal. For the first step, these drugs were presented by ibuprofen and azithromycin. Ibuprofen is widely used to reduce fever and pain. Azithromycin is an antimalarial drug, that was recently reported to be active against acute respiratory coronavirus syndrome. Endemic crustaceans related to species Eulimnogammarus verrucosus were collected near village B. Goloustnoe. Animals were homogenized with acetonitrile and shaken intensively. Then precipitation of proteins was performed with a solution of TCA, and centrifuged. The supernatant was removed and filtered in chromatographic vials. The analysis was performed using an HPLC Agilent 1290 Infinity coupled with Agilent 6470 Triple Quadrupole. Mobile phase A consisted of 0.1% formic acid in the water, and mobile phase B was presented by 100% acetonitrile. The registration of ions was performed in different modes, such as: Full scan, MRM, Product Ion. For reliable identification of drug contaminants, we used the pharmaceutical substances of azithromycin and ibuprofen. Thus, here we first time reliably detected drugs in the amphipods of Lake Baikal and demonstrated the contamination of the Baikal ecosystem by azithromycin and ibuprofen. It indicates the ability to accumulate the drug substances from wastewater by amphipods, and increasing anthropogenic load on the ancient lake.
ABSTRACT
Objective: Methanol poisoning may result in significant morbidity and mortality, particularly during poisoning outbreaks in lowand- middle-income countries (LMIC) [1]. Although not readily available to the public in South Africa, methanol may be used as a substitute for ethanol in alcoholic beverages or to fortify illicit spirits. Following the announcement of the global COVID-19 pandemic, the South African government declared a State of Emergency in March 2020 which amongst other things prohibited the consumption, sale and transportation of alcohol [2]. We aim to describe the clinical presentation, diagnosis, treatment and outcome of a series of cases presenting to a Cape Town hospital after reportedly drinking illicit alcohol. Case series: We performed a retrospective case record review using the available records for 19 of 24 patients presenting to False Bay Hospital during June 2020 with presumed methanol poisoning. Almost all the patients were male (n=18), with a mean age of 35.1 years (SD =7.3). At least half of the patients had central nervous system effects (n=12;headache, ataxia, confusion, weakness), as well as gastrointestinal symptoms (n=10;abdominal pain, nausea, vomiting), and 5 patients reported visual loss. Time from exposure to presentation varied from 12 hours to 8 days, with 47.4% (n=9) presenting within the first 24 hours. On admission, venous blood gas samples from the patients showed the following mean values: pH of 7.14 (SD =0.23);serum bicarbonate 17.4 (SD =8.5) mmol/L;base deficit of -7.8 (SD =11.6) mmol/L, and lactate concentration of 4.1 (SD =4.0) mmol/ L. Assays to measure methanol or formate concentrations were not performed as these are not routinely available. Ten patients (52.6%) received both ethanol via nasogastric tube and intravenous sodium bicarbonate. Haemodialysis was considered for one patient but never started due to intensive care unit (ICU) resource constraints with COVID-I9 admissions. The mortality rate was 26.3% (n=5) and one patient had ongoing visual loss. Conclusion: To the authors' knowledge, this is the first published data concerning a methanol poisoning outbreak in South Africa. As described in other LMICs, the mortality rate was high, diagnosis was difficult, and access to ethanol antidote and supportive care was challenging, particularly during the COVID-19 pandemic. (Table Presented).
ABSTRACT
In this study, type-I bovine collagen solved in diluted acidic solutions (acidic acid and formic acid) and fed into the centrifugal spinning device to obtain nanofiber formation. The centrifugal spinning device is providing submicron fibers thanks to its rotational movement during the solution feeding. Different feeding ratios and rotational speeds are studied to optimize the process. Obtained na nofiber webs were observed via scanning electron microscopy (SEM). Structural characterization of samples was investigated via FTIR. Fabricated collagen-based nanofibers filtration performance was evaluated in terms of filtration efficiency and air permeability tests. Tests results are pointed that fabricated gelatin nanofibers can be an efficient alternative biomaterial design against Covid-19.
ABSTRACT
Background: Outbreaks of methanol poisoning were observed during the COVID-19 pandemic. Acute methanol poisoning is a global crisis. Methanol can cause acute and fatal toxicity through metabolic acidosis. In the present study, we evaluated demographic, clinical, and paraclinical characteristics of patients who died in the recent outbreak of methanol poisoning in Tehran from March to April 2020. Methods: This cross-sectional study was accomplished at the Loghman-Hakim Hospital in Tehran on 80 patients who died of methanol toxicity. Demographic, clinical, and laboratory data were collected retrospectively from the patient's files and analyzed with appropriate statistical tests. Results: Men were significantly more involved than women (%85 vs. %15). There were no significant differences between other characteristics of male and female patients, including the time between consumption to arrive hospital, dialysis sessions, pulse rate, respiratory rate, loss of consciousness, seizure, acute kidney injury, brain CT, and Intracerebral Hemorrhage ( ICH). Blood sugar, serum potassium, and liver function tests were higher than average in most of the patients. Conclusion: Our study showed that this outbreak of methanol poisoning was due to the use of alcoholic drinks that contain methanol. Men were primarily affected that could be because of the cultural and social status of our country. The greater seizure probability in females could be because of enhancing the NMDA receptor by estrogen. Abnormalities in Alanine aminotransferase (ALT), Aspartate Aminotransferase (AST), and Prothrombin Time (PT) were seen in most patients, indicating liver damage. Misbeliefs about the protective effects of alcohol consumption against COVID-19 may lead many to consume poorly made alcohols that contain methanol and outbreaks of methanol intoxication.
ABSTRACT
Remdesivir (RDV) is a phosphoramidate prodrug designed to have activity against a broad spectrum of viruses. Following IV administration, RDV is rapidly distributed into cells and tissues and simultaneously metabolized into GS-441524 and GS-704277 in plasma. LC-MS/MS methods were validated for determination of the 3 analytes in human plasma that involved two key aspects to guarantee their precision, accuracy and robustness. First, instability issues of the analytes were overcome by diluted formic acid (FA) treatment of the plasma samples. Secondly, a separate injection for each analyte was performed with different ESI modes and organic gradients to achieve sensitivity and minimize carryover. Chromatographic separation was achieved on an Acquity UPLC HSS T3 column (2.1 × 50 mm, 1.8 µm) with a run time of 3.4 min. The calibration ranges were 4-4000, 2-2000, and 2-2000 ng/mL, respectively for RDV, GS-441524 and GS-704277. The intraday and interday precision (%CV) across validation runs at 3 QC levels for all 3 analytes was less than 6.6%, and the accuracy was within ±11.5%. The long-term storage stability in FA-treated plasma was established to be 392, 392 and 257 days at -70 °C, respectively for RDV, GS-441524 and GS-704277. The validated method was successfully applied in COVID-19 related clinical studies.