DESIGN AND EVALUATION OF BUCCOADHESIVE CONTROLLED RELEASE FORMULATIONS OF PROCHLORPERAZINE MALEATE

Objective: The Purpose of this work was to design mucoadhesive tablets of prochlorperazine maleate to release the drug in buccal cavity for an extended period of time in order to avoid the first-pass metabolism.Methods: Six formulations were prepared using different polymer like Xanthan gum, Locust bean gum, Carbopol 974P NF, HPMC K100MCR, Polyox-WSR301 and Gantrez AN139 as a mucoadhesive and controlled release agents. The formulations were tested for content uniformity, thickness, weight variation, friability, in vitro drug release, in-vitro bio-adhesion, swelling index and residence time.Results: Drug excipient compatibility studies performed using DSC. The DSC studies revealed endothermic peak at 200o–205oC for Prochlorperazine maleate. Similarly endothermic peaks were obtained for separate excipient when heated in the range of 50-300 °C indicating their melting points. There was no separate peak observed when the drug was mixed with the different polymers like Xanthan gum, locust bean gum, Carbopol 974 P, HPMC K100 MCR, Gantrez AN139 and Polyox-WSR301 in ratio (1:1) indicating that no interaction took place between drug and polymers used in the study. Dissolution studies of the tablets of the optimized batch (BDS-6) containing Carbopol 974P (CP) and HPMC K100 MCR showed extended release 90.65% up to 24 hr. The bioadhesive force of optimized formulation is 12.18±.011 gm and the maximum swelling index was observed in 3.87±.0057 h.Conclusion: From the study it can be concluded that formulation BDS-6 containing Carbopol and HPMC K100 MCR give a promising result for sustained release action of PrM. Â

PULSATILE RELEASE OF KETOPROFEN FROM COMPRESSION COATED TABLETS USING EUDRAGIT® POLYMERS

Objective: The objective of the present research work is to develop compression coated tablet of ketoprofen as a pulsatile release system for treatment of rheumatoid arthritis.Methods: Core tablets of ketoprofen were prepared using the wet granulation method and evaluated for appearance, hardness, friability, weight variation, thickness, disintegration time and % drug release. Core tablets were coated with Eudragit S100 and Eudragit L100 by compression coating method to achieve desired lag time. The blends of core and coating materials were evaluated for bulk density, tapped density, Hausner's ratio, % Compressibility index and angle of repose. Compression coated tablets were evaluated for appearance, hardness, friability, weight variation, thickness and % drug release.Results: Core tablets, as well as compression coated tablets, showed acceptable Pharmaco technical properties. Optimized core tablets were disintegrated within 15s due to the effectiveness of super disintegrant, sodium starch glycolate. Dissolution studies of compression coated tablets in media with different pH (1.2, 6.8, and 7.4) showed that drug release could be modulated by changing the concentration of EudragitL100 and Eudragit S100. The optimized batch exhibited 80% drug release up to 6 h with a 4 h lag time. Stability study of the optimized formulation indicated no significant change in appearance, physical parameters, drug content and drug release profile at accelerated conditions for two months.Conclusion: compression coated tablet of ketoprofen was successfully developed to achieve burst drug release after specific lag time.Keywords: Chronomodulated drug delivery, Pulsatile release, Compression coated tablets, Lag tim

Recognition of fold- and function-specific sites in the ligand-binding domain of the thyroid hormone receptor-like family

Background: The thyroid hormone receptor-like (THR-like) family is the largest transcription factors family belonging to the nuclear receptor superfamily, which directly binds to DNA and regulates the gene expression and thereby controls various metabolic processes in a ligand-dependent manner. The THR-like family contains receptors THRs, RARs, VDR, PPARs, RORs, Rev-erbs, CAR, PXR, LXRs, and others. THR-like receptors are involved in many aspects of human health, including development, metabolism and homeostasis. Therefore, it is considered an important therapeutic target for various diseases such as osteoporosis, rickets, diabetes, etc. Methods: In this study, we have performed an extensive sequence and structure analysis of the ligand-binding domain (LBD) of the THR-like family spanning multiple taxa. We have use different computational tools (information-theoretic measures; relative entropy) to predict the key residues responsible for fold and functional specificity in the LBD of the THR-like family. The MSA of THR-like LBDs was further used as input in conservation studies and phylogenetic clustering studies. Results: Phylogenetic analysis of the LBD domain of THR-like proteins resulted in the clustering of eight subfamilies based on their sequence homology. The conservation analysis by relative entropy (RE) revealed that structurally important residues are conserved throughout the LBDs in the THR-like family. The multi-harmony conservation analysis further predicted specificity in determining residues in LBDs of THR-like subfamilies. Finally, fold and functional specificity determining residues (residues critical for ligand, DBD and coregulators binding) were mapped on the three-dimensional structure of thyroid hormone receptor protein. We then compiled a list of natural mutations in THR-like LBDs and mapped them along with fold and function-specific mutations. Some of the mutations were found to have a link with severe diseases like hypothyroidism, rickets, obesity, lipodystrophy, epilepsy, etc. Conclusion: Our study identifies fold and function-specific residues in THR-like LBDs. We believe that this study will be useful in exploring the role of these residues in the binding of different drugs, ligands, and protein-protein interaction among partner proteins. So this study might be helpful in the rational design of either ligands or receptors

Impact of different grades of anaemia severity during pregnancy on maternal and neonatal outcomes: a prospective study

Background: Anaemia in pregnancy is a universal health problem that may cause a number of obstetrical and neonatal complications. This prospective observational study aims to evaluate and compare maternal and neonatal outcomes in different grades of anaemia severity.Methods: A total of 400 pregnant women with anaemia in third trimester were classified into three groups according to haemoglobin (Hb) levels-group I with Hb:10-10.9 g/dl, group II with Hb:7-9.9g/dl and group III with Hb<7 g/dl. Maternal and neonatal outcomes of women with different severity of anaemia were analyzed and compared. Two groups means were compared by Student’s t-independent test and more than two groups means by one way analysis of variance test followed by post-hoc pairwise comparison using Bonferroni test.Results: The prevalence of anaemia in the study population was 35.2%. Mild, moderate and severe anaemia were found in 58% (n=232), 29.0% (n=116) and 13% (n=52) women respectively. A statistically significant difference in maternal outcomes such as Preterm labor (p=0.001), Prelabor premature rupture of membranes (p=0.044), Intrauterine growth restriction (p=0.002) and postpartum hemorrhage (p=0.001) was observed amongst the three groups. Cardiac failure occurred in 26.9% (n=14) and mortality in 13.4% (n=7) women with severe anaemia. Amongst the neonatal morbidities, the rate of low birth weight, preterm birth, respiratory distress syndrome, septicaemia, pneumonitis and jaundice revealed an increasing trend with rising severity of anaemia which was statistically significant.Conclusions: Targeted interventions addressing early detection and appropriate treatment in early pregnancy can prevent and avoid dismal maternal and neonatal consequences

Development and validation of dissolution method for carvedilol compression-coated tablets

The present study describes the development and validation of a dissolution method for carvedilol compression-coated tablets. Dissolution test was performed using a TDT-06T dissolution apparatus. Based on the physiological conditions of the body, 0.1N hydrochloric acid was used as dissolution medium and release was monitored for 2 hours to verify the immediate release pattern of the drug in acidic pH, followed by pH 6.8 in citric-phosphate buffer for 22 hours, to simulate a sustained release pattern in the intestine. Influences of rotation speed and surfactant concentration in medium were evaluated. Samples were analysed by validated UV visible spectrophotometric method at 286 nm. 1% sodium lauryl sulphate (SLS) was found to be optimum for improving carvedilol solubility in pH 6.8 citric-phosphate buffer. Analysis of variance showed no significant difference between the results obtained at 50 and 100 rpm. The discriminating dissolution method was successfully developed for carvedilol compression-coated tablets. The conditions that allowed dissolution determination were USP type I apparatus at 100 rpm, containing 1000 ml of 0.1N HCl for 2 hours, followed by pH 6.8 citric-phosphate buffer with 1% SLS for 22 hours at 37.0 ± 0.5 ºC. Samples were analysed by UV spectrophotometric method and validated as per ICH guidelines.O presente estudo descreve o desenvolvimento e a validação de método de dissolução para comprimidos revestidos de carvedilol. O teste de dissolução foi efetuado utilizando-se o aparelho para dissolução TDT-06T. Com base nas condições fisiológicas do organismo, utilizou-se ácido clorídrico 0,1 N como meio de dissolução e a liberação foi monitorada por 2 horas para se verificar o padrão de liberação imediata do fármaco em condições de pH baixo, seguidas por pH 6,8 em tampão cítrico-fosfato por 22 horas, para simular o padrão de liberação controlada no intestino. Avaliou-se a influência da velocidade de rotação e a concentração de tensoativo no meio. As amostras foram analisadas por método espectrofotométrico UV-visível validado, em 286 nm. O laurilsulfato sódico a 1% (SLS) mostrou-se ótimo para aumentar a solubilidade do carvedilol em pH 6,8 em tampão cítrico-fosfato. A análise da variância não mostrou diferença significativa entre os resultados obtidos a 50 e a 100 rpm. O método da dissolução discriminante foi desenvolvido com sucesso para os comprimidos revestidos de carvedilol. As condições que permitiram a determinação da dissolução foram: aparelho USP tipo I a 100 rpm, contendo 1000 mL de HCL 0,1 N por 2 horas, seguido de pH 6,8 com tampão cítrico-fosfato, com 1% de SLS por 22 horas a 37,0 ± 0,5 ºC. Amostras foram analisadas por método espectrofotométrico e validadas pelas normas ICH

Experimental investigation of tensile properties and microstructure of TIG welded dissimilar joints of Al6061/Al5083 Aluminium alloy

262-270The welding of aluminium alloys especially in dissimilar combination is challenging owing to numerous problems. The present study focuses to optimize processes parameters for dissimilar welding of 6 mm thick dissimilar Al-6061 and Al-5083, using Tungsten Inert Gas welding as well as to investigate the influence of the process parameters on tensile properties and microstructure of developed welds. A single V-butt joint configuration (bevel angle 60 ̊ and root gap 2 mm) of plates was used for welding. Three levels of input parameters viz. voltage, current and welding speed were selected for performing experiments as per L9 orthogonal array. The hardness and tensile strength were taken as output parameters or performance characteristic in the study. The optimum parameter settings for highest heat affected zone hardness and ultimate tensile strength of dissimilar welds have been suggested by using S/N ratio. The result predicted by optimization has an error of 2-3%. Finally, the effects of voltage, current and welding speed on m icro structure, hardness and tensile strength of welds have been investigated. Welding speed and current were the most influencing process parameter for controlling the hardness of HAZ and tensile strength of the welds

Engineering nucleotide specificity of succinyl-CoA synthetase in blastocystis: the emerging role of gatekeeper residues

Charged, solvent-exposed residues at the entrance to the substrate binding site (gatekeeper residues) produce electrostatic dipole interactions with approaching substrates, and control their access by a novel mechanism called "electrostatic gatekeeper effect". This proof-of-concept study demonstrates that the nucleotide specificity can be engineered by altering the electrostatic properties of the gatekeeper residues outside the binding site. Using Blastocystis succinyl-CoA synthetase (SCS, EC 6.2.1.5), we demonstrated that the gatekeeper mutant (ED) resulted in ATP-specific SCS to show high GTP specificity. Moreover, nucleotide binding site mutant (LF) had no effect on GTP specificity and remained ATP-specific. However, via combination of the gatekeeper mutant with the nucleotide binding site mutant (ED+LF), a complete reversal of nucleotide specificity was obtained with GTP, but no detectable activity was obtained with ATP. This striking result of the combined mutant (ED+LF) was due to two changes; negatively charged gatekeeper residues (ED) favored GTP access, and nucleotide binding site residues (LF) altered ATP binding, which was consistent with the hypothesis of the "electrostatic gatekeeper effect". These results were further supported by molecular modeling and simulation studies. Hence, it is imperative to extend the strategy of the gatekeeper effect in a different range of crucial enzymes (synthetases, kinases, and transferases) to engineer substrate specificity for various industrial applications and substrate-based drug design

Social cohesion among healthcare workers during COVID-19: qualitative research in Indonesia, Nepal, and Vietnam

Existing literature has portrayed numerous challenges that healthcare workers (HCWs) faced during the COVID-19 pandemic, such as heightened risks of transmission against the scarcity of protective equipment, burgeoning workload, and emotional distress, to name a few. However, most studies explored HCWs' experiences at the individual level rather than examining the collective responses. Exploring these experiences could reveal the social-cultural locality of the pandemic while identifying the system constraints in public health emergencies. As part of a mixed-method study on COVID-19 pandemic impacts, we analysed qualitative interview data with 129 HCWs and health-related staff to explore their experiences during the pandemic between 2020 and 2021 in Vietnam, Indonesia, and Nepal. Using Bahers' sociological framework, Community of Fate, we describe five themes reflecting the formation of a community of HCWs and the social cohesion underlying their efforts to survive hardship. The first three themes characterise the HCW community of fate, including (1) Recognition of extreme work-related danger, (2) physical and figurative closures where HCWs restrict themselves from the outside world, (3) chronic ordeals with overwhelming workload and responsibilities, encompassing recurrent mental health challenges. Against such extreme hardship, cohesive bonding and social resilience are reflected through two additional themes: (4) a mutual sense of moral and professional duty to protect communities, (5) the vertical and horizontal convergence among HCWs across levels and among government departments. We discuss these HCWs’ challenges in relation to systemic vulnerabilities while advocating for increasing investment in public health and collaboration across government sectors to prepare for emergency situation

The N137 and P140 amino acids in the p51 and the P95 amino acid in the p66 subunit of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase are instrumental to maintain catalytic activity and to design new classes of anti-HIV-1 drugs

Amino acids N137 and P140 in the p51 subunit of HIV-1 reverse transcriptase (RT) are part of the beta 7-beta 8-loop that contributes to the formation of the base of the non-nucleoside RT inhibitor (NNRTI)-binding pocket and makes up a substantial part of the dimerization interface. Amino acid P95 in p66 also markedly contributes to the dimerization binding energy. Nine RT mutants at amino acid 137 were constructed bearing the mutations Y, K, T, D, A, Q, S, H or E. The prolines at amino acid positions 95 and 140 were replaced by alanine in separate enzymes. We found that all mutant RT enzymes showed a dramatically decreased RNA-dependent DNA polymerase activity. None of the mutant RT enzymes showed marked resistance against any of the clinically used NNRTIs but they surprisingly lost significant sensitivity for NRTIs such as ddGTP. The denaturation analyses of the mutant RTs by urea are suggestive for a relevant role of N137 in the stability of the RT heterodimer and support the view that the beta 7-beta 8 loop in p51 is a hot spot for RT dimerization and instrumental for efficient polymerase catalytic activity. Consequently, N137 and P140 in p51 and P95 in p66 should be attractive targets in the design of new structural classes of RT inhibitors aimed at compromising the optimal interaction of the beta 7-beta 8 loop in p51 at the p66/p51 dimerization interface. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved