DEVELOPMENT AND VALIDATION OF UV-VISIBLE SPECTROSCOPIC METHOD FOR ESTIMATION OF CARBAMAZEPINE IN BULK AND TABLET DOSAGE FORM

Objective: To develop and validate simple, accurate, rapid, precise, reproducible and cost effective spectrophotometric method for the quantitative estimation of carbamazepine in a pharmaceutical formulation.Methods: The developed UV spectrophotometric method for the quantitative estimation of carbamazepine is based on measurement of absorption at maximum wavelength 284 nm using methanol as a solvent. The stock solution of carbamazepine was prepared, and subsequent suitable dilution was prepared in distilled water to obtained standard curve. The standard solution of carbamazepine shows absorption maxima at 284 nm.Results: The drug obeyed beer lambert's law in the concentration range of 2-14 µg/ml with regression 0.9997 at 284 nm. The overall % recovery was found to be 99.99% which reflects that the method was free from the interference of the impurities and other excipients used in the formulation. The low value of % RSD was indicative of accuracy and reproducibility of the method. The % RSD for inter-day and intra-day precision was found to be 0.1568 and 0.1746 respectively which is<2% hence proved that method is precise.Conclusion: The results of analysis have been validated as per International Conference on Harmonization (ICH) guidelines. The developed method can be adopted in routine analysis of carbamazepine in tablet dosage form as well bulk dosage form.Keywords: Carbamazepine, UV Spectrophotometry, Method development, Validation, ICH guidelines, Methanol

Diverse small molecule inhibitors of human apurinic/apyrimidinic endonuclease APE1 identified from a screen of a large public collection.

The major human apurinic/apyrimidinic endonuclease APE1 plays a pivotal role in the repair of base damage via participation in the DNA base excision repair (BER) pathway. Increased activity of APE1, often observed in tumor cells, is thought to contribute to resistance to various anticancer drugs, whereas down-regulation of APE1 sensitizes cells to DNA damaging agents. Thus, inhibiting APE1 repair endonuclease function in cancer cells is considered a promising strategy to overcome therapeutic agent resistance. Despite ongoing efforts, inhibitors of APE1 with adequate drug-like properties have yet to be discovered. Using a kinetic fluorescence assay, we conducted a fully-automated high-throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR), as well as additional public collections, with each compound tested as a 7-concentration series in a 4 µL reaction volume. Actives identified from the screen were subjected to a panel of confirmatory and counterscreen tests. Several active molecules were identified that inhibited APE1 in two independent assay formats and exhibited potentiation of the genotoxic effect of methyl methanesulfonate with a concomitant increase in AP sites, a hallmark of intracellular APE1 inhibition; a number of these chemotypes could be good starting points for further medicinal chemistry optimization. To our knowledge, this represents the largest-scale HTS to identify inhibitors of APE1, and provides a key first step in the development of novel agents targeting BER for cancer treatment

Functional and radiological outcome of expert tibia nailing in proximal tibia fractures

Background: Previously treatment of choice for proximal tibia fracture was internal fixation by plate. Presently, expert tibia nail is widely used in treating proximal tibia fracture. Expert tibia nailing system has features like multi directional locking options in the distal and proximal part of the nail, in addition to the standard static and dynamic locking options present in IMIL Nail. Purpose of study is to evaluate the outcome of expert tibia nail in proximal tibia fracture.Methods: We retrospectively, reviewed thirty patients having proximal tibia fracture with age more than 18 years treated with expert tibia nail and were followed up averagely for 12 months between May2016 to May2018. All patients were compared in terms of intraoperative and postoperative parameters and functionally assessed using the Johner and Wruchs criteria at 3 weeks, 3 months, 6 months and 12 months.Results: Functional outcome was measured by Johner and Wruhs criteria of 30 patients showed 20 excellent, 8 good, 2 patients had fair results. Average time unprotected full weight bearing walking was 7.2 weeks. Average time taken for radiological union was 18.2 weeks.Conclusions: Expert tibial Interlocking Nail is good treatment option for proximal tibia fracture

End tidal CO2 level (PETCO2) during laparoscopic surgery: comparison between spinal anaesthesia and general anaesthesia

Background: Laparoscopy is a procedure which involves insufflations of the abdomen by a gas, so that endoscope can visualise intra abdominal content without being in direct contact with viscera or tissues. Its advantages are small incisions, less pain, less postoperative ileus, short hospital stay compared to traditional open method. Monitoring of end tidal carbon dioxide (PETCO2) and hemodynamics is very necessary during Laparoscopy surgery. This study is conducted to find out effects of CO2 insufflation on parameters like PETCO2, Mean arterial pulse pressure, SPO2 under spinal anaesthesia and general anaesthesia in ASA I and ASA II patients.Methods: The present study was conducted in the department of anaesthesiology from December 2014 to September 2015.This study was a prospective, randomized controlled, single blind. Each group consisted of 30 patients having Group A and Group B as patient undergoing laparoscopic surgery under Spinal anaesthesia and General anaesthesia respectively. Preoperatively patients in Group A (Spinal anaesthesia) given inj. Midazolam 0.3mg/kg IM 45 before surgery and Group B (General anaesthesia) inj. pentazocin 0.3mg/kg, inj. promethazine 0.5mg/kg, inj. Glycopyrrolate 0.004 mg/kg IM 45 before surgery. In operation theatre, intra operative pulseoximetre, ECG, SPO2, Heart rate (HR), Mean arterial pulse pressure and PETCO2 monitoring done. Amount of CO2 insufflated noted.Results: It was found from present study that in both group there was significant progressive rise in PETCO2 after CO2 insufflation, with peak at 30 min and thereafter plateau till the end of procedure (avg. duration 45-60 min). In group A i.e. laparoscopic surgery under spinal anaesthesia with (spontaneous respiration) the rise in PETCO2 was significant as compared to the group B i.e. laparoscopic surgery under general anaesthesia with controlled ventilation. The heart rate increased after CO2 insufflation in both the group, but it was significant in group A. The increase in SBP, DBP, MAP were less in group A as compared to group B. SPO2 showed no significant changes and it remained above 97% in all patients throughout surgery. All values come to baseline 15 min after insufflation.Conclusions: From the present study it can be concluded that balanced general anaesthesia using IPPV with moderate hyperventilation, as the preferred anaesthetic technique for laparoscopic surgery

Fragment-based discovery of a regulatory site in thioredoxin glutathione reductase acting as "doorstop" for NADPH entry

Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectivity inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases

A REVIEW ON DISINTEGRATION CONTROL MATRIX TABLETS

A number of sustained release formulations are available in the market which successfully sustained the drug release over a prolonged period of time by different mechanisms. The new approach for sustaining the drug release is disintegration control matrix tablet which sustained the drug release up to 24hrs by controlling the disintegration rate of tablet. Disintegration control matrix tablet (DCMT) mainly forms the granules containing drug and disintegrating agent such as low substituted hydroxyl propyl cellulose by various methods such as solid dispersion technique. The sustained release of drug is maintained by increasing the wax coating or decreasing the amount of disintegrants. The release of drug from tablet is uniform throughout till all the drug releases from tablet as it involves drug release by diffusion, dissolution and surface erosion mechanism. DCMT increases the solubility of drug and improves the bioavailability without disturbing gastrointestinal transit. BCS Class II, III, IV drugs are the best candidate for DCMT formulations. Keywords: Disintegration control matrix tablet (DCMT), Wax, Disintegrating agent, Solid dispersion

High-Throughput Screen Identifies Cyclic Nucleotide Analogs That Inhibit Prostatic Acid Phosphatase

The secretory and transmembrane isoforms of Prostatic acid phosphatase (PAP) can dephosphorylate extracellular adenosine 5′-monophosphate (AMP) to adenosine, classifying PAP as an ectonucleotidase. Currently, there are no compounds that inhibit PAP in living cells. To identify small molecule modulators of PAP, we used a 1,536-well based quantitative high-throughput fluorogenic assay to screen the Library of Pharmacologically Active Compounds (LOPAC1280) arrayed as eight-concentration dilution series. This fluorogenic assay used difluoro-4-methylumbelliferyl phosphate (DiFMUP) as substrate and collected data in kinetic mode. Candidate hits were subsequently tested in an orthogonal absorbance-based biochemical assay that used AMP as substrate. From these initial screens, three inhibitors of secretory human (h) and mouse (m)PAP were identified: 8-(4-chlorophenylthio) cAMP (pCPT-cAMP), calmidazolium chloride and nalidixic acid. These compounds did not inhibit recombinant alkaline phosphatase. Of these compounds, only pCPT-cAMP and a related cyclic nucleotide analog [8-(4-chlorophenylthio) cGMP; pCPT-cGMP] inhibited the ectonucleotidase activity of transmembrane PAP in a cell-based assay. These cyclic nucleotides are structurally similar to AMP but cannot be hydrolyzed by PAP. In summary, we identified two cyclic nucleotide analogs that inhibit secretory and transmembrane PAP in vitro and in live cells

Quantitative high-throughput phenotypic screening of pediatric cancer cell lines identifies multiple opportunities for drug repurposing

Drug repurposing approaches have the potential advantage of facilitating rapid and cost-effective development of new therapies. Particularly, the repurposing of drugs with known safety profiles in children could bypass or streamline toxicity studies. We employed a phenotypic screening paradigm on a panel of well-characterized cell lines derived from pediatric solid tumors against a collection of ∼3,800 compounds spanning approved drugs and investigational agents. Specifically, we employed titration-based screening where compounds were tested at multiple concentrations for their effect on cell viability. Molecular and cellular target enrichment analysis indicated that numerous agents across different therapeutic categories and modes of action had an antiproliferative effect, notably antiparasitic/protozoal drugs with non-classic antineoplastic activity. Focusing on active compounds with dosing and safety information in children according to the Children's Pharmacy Collaborative database, we identified compounds with therapeutic potential through further validation using 3D tumor spheroid models. Moreover, we show that antiparasitic agents induce cell death via apoptosis induction. This study demonstrates that our screening platform enables the identification of chemical agents with cytotoxic activity in pediatric cancer cell lines of which many have known safety/toxicity profiles in children. These agents constitute attractive candidates for efficacy studies in pre-clinical models of pediatric solid tumors

Disrupting malaria parasite AMA1-RON2 interaction with a small molecule prevents erythrocyte invasion

Plasmodium falciparumresistance to artemisinin derivatives, the first-line anti-malarial drug, drives the search for new classes of chemotherapeutic agents. Current discovery is primarily directed against the intracellular forms of the parasite. However, late schizont-infected red blood cells (RBCs) may still rupture and cause disease by sequestration; consequently targeting invasion may reduce disease severity. Merozoite invasion of RBCs requires interaction between two parasite proteins AMA1 and RON2. Here we identify the first inhibitor of this interaction that also blocks merozoite invasion in genetically distinct parasites by screening a library of over 21,000 compounds. We demonstrate that this inhibition is mediated by the small molecule binding to AMA1 and blocking the formation of AMA1-RON complex. Electron microscopy confirms that the inhibitor prevents junction formation, a critical step in invasion that results from AMA1-RON2 binding. This study uncovers a strategy that will allow for highly effective combination therapies alongside existing anti-malarial drugs