Publications by authors named "Pramod Kumar"

405 Publications

Wheat Cultivar Growth, Biochemical, Physiological and Yield Attributes Response to Combined Exposure to Tropospheric Ozone, Particulate Matter Deposition and Ascorbic Acid Application.

Bull Environ Contam Toxicol 2021 Sep 14. Epub 2021 Sep 14.

School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India.

In the present study wheat (Triticum aestivum) cultivar HD 2967 was exposed to ambient and elevated levels of O and PM deposition, with and without exogenous application of ascorbic acid (AA). Cultivar HD 2967 exposed to eight treatments in free air O enrichment facility and the assessed results showed that wheat cultivar, growth, biochemical, physiological and yield attributes were variably but adversely affected by combined exposure to O and PM deposition. PM deposition clogged stomata and enhanced leaf temperature. However, plants exposed to O and PM deposition and treated with AA exhibited less reduction in yield as compared to plants exposed to O and PM deposition without AA treatment. The decline in grain yield of HD 2967 due to combined exposure of O and PM deposition were in the range of 4%-17%. AA spray partially mitigated ozone and PM deposition adverse impact and enhanced wheat yield by 16%.
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http://dx.doi.org/10.1007/s00128-021-03373-7DOI Listing
September 2021

Midodrine Improves the Tolerability of Diuretics in Patients with Acute-on-Chronic Liver Failure-A Pilot Study.

J Clin Exp Hepatol 2021 Sep-Oct;11(5):573-578. Epub 2020 Dec 17.

Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India.

Background: Acute-on-chronic liver failure (ACLF) is a syndrome of acute portal hypertension with high short-term mortality. ACLF patients have low mean arterial pressure (MAP), systemic vascular resistance, and high cardiac output. This, in turn, leads to an increased incidence of ascites, acute kidney injury, and hyponatremia. We evaluated the role of the early addition of midodrine, which has not been analyzed to date.

Methods: ACLF patients who were started on midodrine (Gr. A) in addition to standard of care (SOC) for ascites control were included and compared with those who received only SOC (Gr. B). The aim was to assess the hemodynamics, ascites control, diuretic-related complications, and mortality at 1 month.

Results: Forty-five ACLF patients (Gr. A-21; Gr. B-24) were included in the pilot study. At inclusion, the baseline characteristics were similar among the groups. The dose of midodrine was 22.5 (7.5-22.5) mg/day for 22.29 ± 8.75 days in Gr. A. Midodrine significantly improved the MAP and urinary sodium excretion. Only 33.34% of patients required paracentesis in Gr. A compared with 62.5% in Gr. B (p = 0.05). Gr. A patients tolerated a higher dose of diuretics than Gr. B. Diuretic-related complications developed in 54.2% of patients in Gr. B compared with only 23.8% in Gr. A (p = 0.03). Fourteen percent in Gr. A developed side effects to midodrine and required dose modification. Mortality at day 30 was similar in both groups.

Conclusion: Addition of midodrine improves the hemodynamics, tolerability of diuretics, and ascites control in ACLF patients.
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http://dx.doi.org/10.1016/j.jceh.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414320PMC
December 2020

Post-dental extraction bleeding: Emphasis on the diagnosis of rare coagulation disorders.

Clin Case Rep 2021 Sep 30;9(9):e04746. Epub 2021 Aug 30.

Division of Periodontology Department of Dental Surgery & Oral Health Sciences Armed Forces Medical College Pune India.

Disorders of the fibrin stabilizing and fibrinolytic pathway should be considered in patients with excessive postsurgical bleeding with normal screening tests of hemostasis. History, clinical assessment of the timing and severity of bleeding along with utilization of advanced tests such as global hemostasis assays and appropriate coagulation factor assays (especially FXIII) will aid in the diagnosis.
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http://dx.doi.org/10.1002/ccr3.4746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405522PMC
September 2021

Immunoinformatics driven construction of multi-epitope vaccine candidate against using its entire immunogenic epitopes.

Expert Rev Vaccines 2021 Sep 3:1-13. Epub 2021 Sep 3.

School of Basic Sciences, Indian Institute of Technology Mandi, Mandi, India.

Objective: infects 80 million people per year, causing malnutrition, stunted growth of children etc., but there is no vaccine available against it. We aimed to design a multimeric-subunit vaccine using comprehensive immunoinformatic approach.

Research Design And Methods: The T and B cell epitopes were shortlisted on antigenicity, allergenicity, and toxicity from proteome data and joined with appropriate linkers. The physical characteristics of vaccine candidate was calculated and docking/molecular dynamic simulation performed to validate its robustness. The multimeric protein was codon optimized and in-silico cloned in pET28b.

Results: From the 23,604 proteins of Ascaris, we filtered based on epitope prediction, localization, antigenicity, and allergenicity. Prepared a vaccine of 534 amino acid long, 56.31 kD weight and pI 4.52. Physiochemical features showed it is soluble, highly antigenic and non-allergenic. Its tertiary structure was forecasted, certified, and refined. The immunoinformatic simulation studies showed it to be potent T and B cell stimulator.

Conclusions: We identified highly antigenic peptides of Ascaris from its proteome with good potential to induce innate as well as humoral immune response. These peptides were used to design a chimeric vaccine against Ascariasis infection, which can be used for prophylactic purpose but needs experimental and clinical validation.
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http://dx.doi.org/10.1080/14760584.2021.1974298DOI Listing
September 2021

Isolation and characterization of thermal degradation impurity in brimonidine tartrate by HPLC, LC-MS/MS, and 2DNMR.

J Pharm Biomed Anal 2021 Aug 3;205:114297. Epub 2021 Aug 3.

Micro Labs Ltd, API R&D Centre, Plot No. 43-45, 4(th) Phase, KIADB, JB Link Road, Bengaluru, Karnataka, 560105, India.

One potential unknown impurity was detected during the analysis of stability batches of brimonidine tartrate (BMT) in the level ranging from 0.03 % to 0.06 % by high-performance liquid chromatography (HPLC). Based on the liquid chromatography-mass spectrophotometry (LC-MS) analysis, the unknown impurity structure was presumed as 3,6,11,13,16-pentaazatetracyclo [8.6.0.0²,⁷.0¹²,¹⁶] hexadeca-1,3,5,7,9,12-hexaene. The proposed structure was elucidated, after its isolation using preparative liquid chromatography from the impurity enriched reaction crude sample, using analytical applications such as 1D NMR (H, C and DEPT-135), 2D NMR (HMBC and COSY), high-resolution mass spectrometry (HRMS) and infrared spectroscopy (IR). The unknown impurity was prepared from brimonidine by following Ullman coupling reaction in the presence of CuBr in gram scale with optimum purity to use further in analytical developments. The identification, structural elucidation and synthesis of unknown degradation impurity such as BMT-cyclized impurity, and HPLC method validation were reported for the first time in this paper.
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http://dx.doi.org/10.1016/j.jpba.2021.114297DOI Listing
August 2021

Increasing adherence to plotting e-partograph: a quality improvement project in a rural maternity hospital in India.

BMJ Open Qual 2021 07;10(Suppl 1)

Obstetrics & Gynecology, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Maharashtra, India.

Abnormal prolonged labour and its effects are important contributors to maternal and perinatal mortality and morbidity worldwide. E-partograph is a modern tool for real-time computerised recording of labour data which improves maternal and neonatal outcome. The aim was to improve the rates of e-partograph plotting in all eligible women in the labour room from existing 30% to achieve 90% in 6 months through a quality improvement (QI) process.A team of nurses, obstetricians, postgraduates and a data entry operator did a root cause analysis to identify the possible reasons for the drop in e-partograph plotting to 30%. The team used process flow mapping and fish bone analysis. Various change ideas were tested through sequential Plan-Do-Study-Act (PDSA) cycles to address the issues identified.The interventions included training labour room staff, identification of eligible women and providing an additional computer and internet facility for plotting and assigning responsibility of plotting e-partographs. We implemented these interventions in five PDSA cycles and observed outcomes by using control charts. A set of process, output and outcome indicators were used to track if the changes made were leading to improvement.The rate of e-partograph plotting increased from 30% to 93% over the study period of 6 months from August 2018 to January 2019. The result has been sustained since the last PDSA cycle. The maternal outcome included a decrease in obstructed and prolonged labour with its associated complications from 6.2% to 2.4%. The neonatal outcomes included a decrease in admissions in the neonatal intensive care unit for birth asphyxia from 8% to 3.4%. It can thus be concluded that a QI approach can help in improving adherence to e-partography plotting resulting in improved maternal health services in a rural maternity hospital in India.
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http://dx.doi.org/10.1136/bmjoq-2021-001404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336132PMC
July 2021

Impact of COVID-19 on liver transplant recipients-A systematic review and meta-analysis.

EClinicalMedicine 2021 Aug 13;38:101025. Epub 2021 Jul 13.

Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India.

Background: Immunosuppression and comorbidities increase the risk of severe coronavirus disease-2019 (COVID-19) in solid organ transplant (SOT) recipients. The outcomes of COVID-19 in liver transplant (LT) recipients remain unclear. We aimed to analyse the outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients.

Methods: The electronic databases were searched for articles published from 1 December 2019 to 20 May 2021 with MeSH terms COVID-19, SARS-CoV-2, and liver transplantation. Studies reporting outcomes in more than 10 LT recipients were included for analysis. LT vs non-LT patients with COVID-19 infection were compared for all-cause mortality, which was the primary outcome studied. We also evaluated the relation between the timing of COVID-19 infection post-LT (< one year vs > one year) and mortality.

Findings: Eighteen articles reporting 1,522 COVID-19 infected LT recipients were included for the systematic review. The mean age (standard deviation [SD]) was 60·38 (5·24) years, and 68·5% were men. The mean time (SD) to COVID-19 infection was 5·72 (1·75) years. Based on 17 studies (I = 7·34) among 1,481 LT recipients, the cumulative incidence of mortality was 17·4% (95% confidence interval [CI], 15·4-19·6). Mortality was comparable between LT ( = 610) and non-LT ( = 239,704) patients, based on four studies (odds ratio [OR], 0·8 [0·6-1·08];  = 0·14). Additionally, there was no significant difference in mortality between those infected within one year vs after one year of LT (OR, 1·5 [0·63-3·56];  = 0·35). The cumulative incidence of graft dysfunction was 2·3% (1·3-4·1). Nearly 23% (20·71-25) of the LT patients developed severe COVID-19 infection. Before infection, 71% and 49% of patients were on tacrolimus and mycophenolate mofetil, respectively. Immunosuppression was modified in 55·9% (38·1-72·2) patients after COVID-19 infection.

Interpretation: LT and non-LT patients with COVID-19 have a similar risk of adverse outcomes.
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http://dx.doi.org/10.1016/j.eclinm.2021.101025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276632PMC
August 2021

Gut microbiota-derived metabolites in CRC progression and causation.

J Cancer Res Clin Oncol 2021 Jul 17. Epub 2021 Jul 17.

Gene Regulation Laboratory, National Institute of Immunology, New Delhi, 110067, India.

Background: Based on recent research reports, dysbiosis and improper concentrations of microbial metabolites in the gut may result into the carcinogenesis of colorectal cancer. Recent advancement also highlights the involvement of bacteria and their secreted metabolites in the cancer causation. Gut microbial metabolites are functional output of the host-microbiota interactions and produced by anaerobic fermentation of food components in the diet. They contribute to influence variety of biological mechanisms including inflammation, cell signaling, cell-cycle disruption which are majorly disrupted in carcinogenic activities.

Purpose: In this review, we intend to discuss recent updates and possible molecular mechanisms to provide the role of bacterial metabolites, gut bacteria and diet in the colorectal carcinogenesis. Recent evidences have proposed the role of bacteria, such as Fusobacterium nucleaturm, Streptococcus bovis, Helicobacter pylori, Bacteroides fragilis and Clostridium septicum, in the carcinogenesis of CRC. Metagenomic study confirmed that these bacteria are in increased abundance in CRC patient as compared to healthy individuals and can cause inflammation and DNA damage which can lead to development of cancer. These bacteria produce metabolites, such as secondary bile salts from primary bile salts, hydrogen sulfide, trimethylamine-N-oxide (TMAO), which are likely to promote inflammation and subsequently cancer development.

Conclusion: Recent studies suggest that gut microbiota-derived metabolites have a role in CRC progression and causation and hence, could be implicated in CRC diagnosis, prognosis and therapy.
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http://dx.doi.org/10.1007/s00432-021-03729-wDOI Listing
July 2021

Correlation Between Video-Otoendoscopy and Tympanograms of Patients with Acute Middle Ear Infections.

Indian J Otolaryngol Head Neck Surg 2021 Jun 30:1-8. Epub 2021 Jun 30.

Department of ENT and HNS, SRN Hospital, Prayagraj, Uttar Pradesh India.

The tympanic membrane (TM) undergoes a number of pathological changes in middle ear disease which can be detected by a video-otoendoscope. Middle ear disease is also accompanied by changes in middle ear pressure which can be assessed by tympanometry. The objectives of this study were to find the correlation between video-otoendoscopy and tympanometry in acute middle ear infections and to deduce which of the two is more efficient and reliable for early diagnosis. 75 patients with AOM or OME were included over 1 year where each patient was followed for 21 days. Detailed history and clinical examination with videootoendoscope and tympanometry was done on each visit. Each TM was graded using OMGRADE scale. Symptoms and clinical findings consistent with acute otitis media were given a clinical score (CO Score). The results were collected and correlation between video-otoendoscopy and tympanometry was determined and their individual sensitivity, specificity and diagnostic accuracy was calculated. The sensitivity, specificity and diagnostic accuracy for tympanometry and video-otoendoscopy was calculated individually for each of the 4 visits and positive correlation between the 2 was found. Our study showed that tympanometry had a higher overall sensitivity than video-otoendoscopy. While, video-otoendoscopy showed a higher specificity than Tympanometry. Otoendoscopy is good for ruling out AOM/OME but cannot rule out persisting Middle Ear Effusion and Tympanometry is a better tool for detecting MEE but cannot differentiate well between AOM and OME. We found that tympanometry plus otoendoscopy together greatly increase the chances of detecting AOM and OME thus improving diagnostic accuracy, reducing financial costs associated with over or mis-diagnosis.
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http://dx.doi.org/10.1007/s12070-021-02701-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242284PMC
June 2021

Structure and function at the lipid-protein interface of a pentameric ligand-gated ion channel.

Proc Natl Acad Sci U S A 2021 Jun;118(23)

Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;

Although it has long been proposed that membrane proteins may contain tightly bound lipids, their identity, the structure of their binding sites, and their functional and structural relevance have remained elusive. To some extent, this is because tightly bound lipids are often located at the periphery of proteins, where the quality of density maps is usually poorer, and because they may be outcompeted by detergent molecules used during standard purification procedures. As a step toward characterizing natively bound lipids in the superfamily of pentameric ligand-gated ion channels (pLGICs), we applied single-particle cryogenic electron microscopy to fragments of native membrane obtained in the complete absence of detergent-solubilization steps. Because of the heterogeneous lipid composition of membranes in the secretory pathway of eukaryotic cells, we chose to study a bacterial pLGIC (ELIC) expressed in 's inner membrane. We obtained a three-dimensional reconstruction of unliganded ELIC (2.5-Å resolution) that shows clear evidence for two types of tightly bound lipid at the protein-bulk-membrane interface. One of them was consistent with a "regular" diacylated phospholipid, in the cytoplasmic leaflet, whereas the other one was consistent with the tetra-acylated structure of cardiolipin, in the periplasmic leaflet. Upon reconstitution in polar-lipid bilayers, ELIC retained the functional properties characteristic of members of this superfamily, and thus, the fitted atomic model is expected to represent the (long-debated) unliganded-closed, "resting" conformation of this ion channel. Notably, the addition of cardiolipin to phosphatidylcholine membranes restored the ion-channel activity that is largely lost in phosphatidylcholine-only bilayers.
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http://dx.doi.org/10.1073/pnas.2100164118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201805PMC
June 2021

Polyphenolic-Rich Compounds From (Roxb.) Attenuates the Doxorubicin-Induced Cardiotoxicity: A High-Frequency Ultrasonography Assisted Approach.

Front Pharmacol 2021 17;12:624706. Epub 2021 May 17.

Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research-Guwahati, Assam, India.

Cardiovascular complications are the foremost concern in patients undergoing anticancer therapy There is an unmet need to address the problems arising from the drug-induced toxicity for the long-term benefit of the patients undergoing chemotherapy. Alternative medicines are gaining their prosperity in addressing the various drug-induced organ toxicity. Roxb (DP) is an ethnomedicinal plant rich in flavonoids and phenolic contents. In India & Nepal, DP is a common ingredient of traditional medicines used to treat multiple ailments like inflammation, cancer, and diabetes. However, its protective role against doxorubicin (Dox) induced cardiotoxicity remains unexplored. Herein, we investigated the potential effects of various extracts/fractions obtained from the DP's bark against Dox-induced cardiotoxicity, both and . The anti-oxidant content of the extracts/fractions was evaluated by using DPPH, ABTS and FRAP chemical assays. The results indicated that the hydroalcoholic (HA) extract of DP has intense anti-oxidant potential. Further fractionation of DP revealed that the phenolic-rich fraction (F1) has a high anti-oxidant potential. The protective effect of extract/fraction was also investigated in the H9c2 cell line following the Dox-induced cardiotoxicity model. We observed that the pre-treatment of extract/fraction in cardiomyocytes had exhibited increased cell viability. Fluorescence-based chemical assays indicated a decreased ROS levels in the treated groups in comparison to the Dox control group. The effect of DP was evaluated further in balb/c mice by the Dox-induced cardiotoxicity model. Non-invasive techniques like high-frequency ultrasonography and electrocardiogram revealed that the mice pre-treated with DP had improved cardiac functionality (left ventricular ejection fraction and stroke volume) and normalized the electrocardiograms compared to the Dox control group. Further, biochemical analysis with the cardiac tissues revealed that the cytoprotective proteins like HO-1, SOD-2, and Nrf-2 were elevated in the DP treated groups compared to the Dox control group. Overall, our results suggested that the bioactive extract/fractions of DP helped alleviate the Dox-induced cardiotoxicity. LC-QTOF-ESI-MS analysis of DP and F1 indicated that polyphenolic anti-oxidant compounds like gallic acid, syringic acid, and sinapic acid could be responsible for the potent -cardioprotective effect. Future understanding of the pharmacokinetics and pharmacodynamic parameters can help translate from the bench to the bedside.
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http://dx.doi.org/10.3389/fphar.2021.624706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166202PMC
May 2021

Clinical features and outcomes of COVID-19 in older adults: a systematic review and meta-analysis.

BMC Geriatr 2021 05 19;21(1):321. Epub 2021 May 19.

Department of Geriatric Medicine, All India Institute of Medical Sciences, Ansari Nagar, Delhi, 110029, India.

Background: Few studies have focused on exploring the clinical characteristics and outcomes of COVID-19 in older patients. We conducted this systematic review and meta-analysis to have a better understanding of the clinical characteristics of older COVID-19 patients.

Methods: A systematic search of PubMed and Scopus was performed from December 2019 to May 3rd, 2020. Observational studies including older adults (age ≥ 60 years) with COVID-19 infection and reporting clinical characteristics or outcome were included. Primary outcome was assessing weighted pooled prevalence (WPP) of severity and outcomes. Secondary outcomes were clinical features including comorbidities and need of respiratory support.

Result: Forty-six studies with 13,624 older patients were included. Severe infection was seen in 51% (95% CI- 36-65%, I-95%) patients while 22% (95% CI- 16-28%, I-88%) were critically ill. Overall, 11% (95% CI- 5-21%, I-98%) patients died. The common comorbidities were hypertension (48, 95% CI- 36-60% I-92%), diabetes mellitus (22, 95% CI- 13-32%, I-86%) and cardiovascular disease (19, 95% CI - 11-28%, I-85%). Common symptoms were fever (83, 95% CI- 66-97%, I-91%), cough (60, 95% CI- 50-70%, I-71%) and dyspnoea (42, 95% CI- 19-67%, I-94%). Overall, 84% (95% CI- 60-100%, I-81%) required oxygen support and 21% (95% CI- 0-49%, I-91%) required mechanical ventilation. Majority of studies had medium to high risk of bias and overall quality of evidence was low for all outcomes.

Conclusion: Approximately half of older patients with COVID-19 have severe infection, one in five are critically ill and one in ten die. More high-quality evidence is needed to study outcomes in this vulnerable patient population and factors affecting these outcomes.
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http://dx.doi.org/10.1186/s12877-021-02261-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133052PMC
May 2021

Favipiravir-induced Liver Injury in Patients with Coronavirus Disease 2019.

J Clin Transl Hepatol 2021 Apr 15;9(2):276-278. Epub 2021 Apr 15.

Department of Gastroenterology, Asian Institute of Gastroenterology Hospitals, Hyderabad, India.

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http://dx.doi.org/10.14218/JCTH.2021.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111097PMC
April 2021

Stimuli-responsive mesoporous silica nanoparticles: A custom-tailored next generation approach in cargo delivery.

Mater Sci Eng C Mater Biol Appl 2021 May 31;124:112084. Epub 2021 Mar 31.

PDX Pharmaceuticals, Inc., Portland, OR 97239, USA; Biomedical Engineering, OHSU School of Medicine, Portland, OR 97239, USA. Electronic address:

The pre-mature release of therapeutic cargos in the bloodstream or off-target sites is a major hurdle in drug delivery. However, stimuli-specific drug release responses are capable of providing greater control over the cargo release. Herein, various types of nanocarriers have been employed for such applications. Among various types of nanoparticles, mesoporous silica nanoparticles (MSNPs) have several attractive characteristics, such as high loading capacity, biocompatibility, small size, porous structure, high surface area, tunable pore size and ease of functionalization of the external and internal surfaces, which facilitates the entrapment and development of stimuli-dependent release of drugs. MSNPs could be modified with such stimuli-responsive entities like nucleic acid, peptides, polymers, organic molecules, etc., to prevent pre-mature cargo release, improving the therapeutic outcome. This controlled drug release system could be modulated to function upon extracellular or intracellular specific stimuli, including pH, enzyme, glucose, glutathione, light, temperature, etc., and thus provide minimal side effects at non-target sites. This system has great potential applications for the targeted delivery of therapeutics to treat clinically challenging diseases like cancer. This review summarizes the synthesis and design of stimuli-responsive release strategies of MSNP-based drug delivery systems along with investigations in biomedical applications.
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http://dx.doi.org/10.1016/j.msec.2021.112084DOI Listing
May 2021

Improvements in HOMA indices and pancreatic endocrinal tissues in type 2-diabetic rats by DPP-4 inhibition and antioxidant potential of an ethanol fruit extract of Withania coagulans.

Nutr Metab (Lond) 2021 Apr 21;18(1):43. Epub 2021 Apr 21.

Department of Agriculture and Environmental Sciences (AES), National Institute of Food Technology Entrepreneurship and Management (NIFTEM), Sonepat, 131028, Haryana, India.

Context: Withania coagulans (Stocks) Dunal fruits are used in the therapeutics of several ailments due to possessing of potent phytoconstituents which is also used traditionally for curing the diabetes.

Objective: The present study was assessing the amelioration potential of the phytochemicals of an ethanol fruit extract of W. coagulans (Stocks) Dunal in the HOMA (Homeostatic model assessment) indices and pancreatic endocrinal tissues by inhibition of DPP-4 and antioxidants activities.

Material And Methods: The identification of phytoconstituents of the test extract was performed by LCMS. Further, assessments of in-vitro, in-vivo and in-silico were achieved by following standard methods. In-vivo studies were conducted on type-2 diabetic rats.

Results: The chosen extract inhibited DPP-4 activity by 63.2% in an in vitro assay as well as significantly inhibit serum DPP-4 levels. Accordingly, the administration of the ethanol fruit extract resulted in a significant (P ≤ 0.001) alterations in the lipid profile, antioxidant levels, and HOMA indices. Moreover, pancreatic endocrinal tissues (islet of Langerhans) appeared to have the restoration of normal histoarchitecture as evidenced by increased cellular mass. Molecular docking (Protein-ligands) of identified phytoconstituents with DPP-4 (target enzyme) shown incredibly low binding energy (Kcal/mol) as required for ideal interactions. ADMET analysis of the pharmacokinetics of the identified phytoconstituents indicated an ideal profile as per Lipinski laws.

Conclusion: It can be concluded that the phytoconstituents of an ethanol fruit extract of W. coagulans have the potential to inhibit DPP-4 which result in improved glucose homeostasis and restoration of pancreatic endocrinal tissues in type-2 diabetic rats.
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http://dx.doi.org/10.1186/s12986-021-00547-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059290PMC
April 2021

Phosphorus containing porous organic polymers: synthetic techniques and applications in organic synthesis and catalysis.

Org Biomol Chem 2021 May 19;19(19):4174-4192. Epub 2021 Apr 19.

Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India.

The phosphorus-containing porous organic polymer is a trending material for the synthesis of heterogeneous catalysts. Decades of investigations have established phosphines as versatile ligands in homogeneous catalysis. Recently, phosphine-based heterogeneous catalysts were synthesized to exploit the same electronic properties while leveraging extra stability and reusability. In the last few decades, the catalysts were applied in diverse organic transformations, including hydroformylation, hydrogenation, C-C, C-N and C-X coupling, hydrosilylation, oxidative-carbonylation reactions, and so on. However, even though these polymers possess a multifunctional character, they face multiple synthetic issues in controlling the pore size, increasing the surface area, and creating a single type of active site. This review summarizes the developments in this field over the last few decades, highlighting the current limitation and future scope.
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http://dx.doi.org/10.1039/d1ob00137jDOI Listing
May 2021

Azathioprine weekly pulse versus methotrexate for the treatment of chronic plaque psoriasis: A randomized controlled trial.

Indian J Dermatol Venereol Leprol 2021 [SEASON];87(4):509-514

Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India.

Background: Methotrexate is the most commonly used drug in the treatment of psoriasis with good efficacy and safety. Recently, weekly azathioprine pulse has been shown to be effective in this disease.

Aim: The aim of this study is to compare the effectiveness and safety of weekly pulse doses of azathioprine and methotrexate for the treatment of chronic plaque psoriasis.

Methods: In this randomized controlled trial, 80 patients with chronic plaque psoriasis were recruited. After detailed clinical and laboratory evaluation, patients were randomized to 2 groups to receive either weekly 300 mg azathioprine (n = 40) or 15 mg methotrexate every week (n = 40) for 20 weeks, following which the response to treatment and adverse effects were assessed. The patients were then followed up every 4 weeks for 3 months to determine any relapse.

Results: Overall, 48 (60%) patients achieved PASI 75, while 36 (45%) and 59 (73.8%) patients achieved PASI 100 and 50, respectively. On intention to treat analysis, PASI ≥ 75 was achieved in 47.5% (19/40) patients in group 1 compared to 85% (34/40) patients in group 2 (p < 0.001). However, on per protocol analysis, PASI ≥ 75 was achieved in 86% (19/22) patients in group 1 and 92% (34/37) patients in group 2 (p = 0.497). Minor clinical and biochemical adverse effects were noted in both the groups, which were comparable. One (7.7%) patient in group 1 and 4 (17.4%) in group 2 relapsed during follow-up.

Limitations: Limitations of study include small sample size and short follow-up.

Conclusion: Weekly azathioprine pulse appears to be beneficial in the management of chronic plaque psoriasis. However, it is less effective than weekly methotrexate. It can thus be of use as a therapeutic option in patients with contraindication to methotrexate or other similar agents in this disease.
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http://dx.doi.org/10.25259/IJDVL_718_18DOI Listing
August 2018

Trends in referrals to liaison psychiatry teams from UK emergency departments for patients over 65.

Int J Geriatr Psychiatry 2021 09 29;36(9):1415-1422. Epub 2021 Apr 29.

Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK.

Introduction: The number of people over the age of 65 attending Emergency Departments (ED) in the United Kingdom (UK) is increasing. Those who attend with a mental health related problem may be referred to liaison psychiatry for assessment. Improving responsiveness and integration of liaison psychiatry in general hospital settings is a national priority. To do this psychiatry teams must be adequately resourced and organised. However, it is unknown how trends in the number and type referrals of older people to liaison psychiatry teams by EDs are changing, making this difficult.

Methods: We performed a national multi-centre retrospective service evaluation, analysing existing psychiatry referral data from EDs of people over 65. We described trends in the number, rate, age, mental health presentation, and time taken to assessment over a 7 years period.

Results: Referral data from 28 EDs across England and Scotland were analysed (n = 18,828 referrals). There was a general trend towards increasing numbers of people referred to liaison psychiatry year on year. Variability in referral numbers between different departments, ranged from 0.1 to 24.3 per 1000 ED attendances. The most common reasons for referral were mood disorders, self-harm and suicidal ideas. The majority of referrals were assessed within 60 min, however there is variability between departments, some recording waits over 11 h.

Discussion: The data suggests great inter-departmental variability in referral numbers. Is not possible to establish the cause of variability. However, the data highlights the importance of asking further questions about why the differences exist, and the impact that has on patient care.
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http://dx.doi.org/10.1002/gps.5547DOI Listing
September 2021

Single Molecule Study of the Polymerization of RecA on dsDNA: The Dynamics of Individual Domains.

Front Mol Biosci 2021 22;8:609076. Epub 2021 Mar 22.

Department of Physics, Ben Gurion University of the Negev, Beer Sheva, Israel.

In the , RecA plays a central role in the recombination and repair of the DNA. For homologous recombination, RecA binds to ssDNA forming a nucleoprotein filament. The RecA-ssDNA filament searches for a homologous sequence on a dsDNA and, subsequently, RecA mediates strand exchange between the ssDNA and the dsDNA. , RecA binds to both ssDNA and dsDNA. Despite a wide range of studies of the polymerization of RecA on dsDNA, both at the single molecule level and by means of biochemical methods, important aspects of this process are still awaiting a better understanding. Specifically, a detailed, quantitative description of the nucleation and growth dynamics of the RecA-dsDNA filaments is still lacking. Here, we use Optical Tweezers together with a single molecule analysis approach to measure the dynamics of the individual RecA domains on dsDNA and the corresponding growth rates for each of their fronts. We focus on the regime where the nucleation and growth rate constants, and , are comparable, leading to a coverage of the dsDNA molecule that consists of a small number of RecA domains. For the case of essentially irreversible binding (using ATPγS instead of ATP), we find that domain growth is highly asymmetric with a ratio of about 10:1 between the fast and slow fronts growth rates.
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http://dx.doi.org/10.3389/fmolb.2021.609076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025788PMC
March 2021

Chemosensitivity assessments of curdlan-doped smart nanocomposites containing erlotinib HCl.

Int J Biol Macromol 2021 Jun 26;181:169-179. Epub 2021 Mar 26.

Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah, Malaysia.

Curdlan (CN)-doped montmorillonite/poly(N-isopropylacrylamide-co-N,N'-methylene-bis-acrylamide) [CN/MT/P(NIPA-co-MBA)] smart nanocomposites (NCs) were developed for efficient erlotinib HCl (ERL) delivery to lung cancer cells. The placebo NCs demonstrated excellent biodegradability, pH/thermo-responsive swelling profiles and declined molar mass (M¯c) between the crosslinks with increasing temperature. The XRD, FTIR, DSC, TGA, and SEM analyses revealed the architectural chemistry of these NC scaffolds. The NCs loaded with ERL (F-1-F-3) displayed acceptable diameter (734-1120 nm) and zeta potential (+1.16 to -11.17 mV), outstanding drug entrapping capability (DEE, 78-99%) and sustained biphasic ERL elution patterns (Q, 53-91%). The ERL release kinetics of the optimal matrices (F-3) obeyed Higuchi model and their transport occurred through anomalous diffusion. The mucin adsorption behaviour of these matrices followed Freudlich isotherms. As compared to pure ERL, the formulation (F-3) displayed an improved anti-proliferative potential and induced apoptosis more effectively on A549 cells. Thus, the CN-doped smart NCs could be utilized as promising drug-cargoes for lung cancer therapy.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.03.152DOI Listing
June 2021

Adipocyte Fatty Acid-Binding Protein as a Predictor of Outcome in Alcohol-induced Acute-On-Chronic Liver Failure.

J Clin Exp Hepatol 2021 Mar-Apr;11(2):201-208. Epub 2020 Jul 28.

Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India.

Background: Alcohol is the leading cause of acute-on-chronic liver failure (ACLF). Several severity scores predict the outcome of ACLF. However, there is a lack of simple biomarkers in predicting the outcome of these sick patients. Fatty acid-binding proteins (FABPs) are small cytosolic proteins that play a major role in lipid metabolism, energy homeostasis, and inflammation, but, have not been investigated in alcohol-induced ACLF (A-ACLF).

Objectives: The primary objective was to assess the correlation between serum adipocyte-FABP (A-FABP) and liver-FABP (L-FABP) levels on mortality at day 90. Secondary objectives were to compare the levels between controls and A-ACLF, correlate L-FABP, and A-FABP levels on the development of organ failure/sepsis at day 90.

Methods: In this prospective observational pilot study, we included patients with A-ACLF and age-matched healthy controls. FABP's were analyzed by enzyme-linked immunosorbent assay method. The patients were followed up for 90 days.

Results: Twenty-five patients with A-ACLF (mean age: 40years; mean model for end-stage liver disease NA: 29.8; median Modified Maddrey's discriminant function [mDF]: 95) and 12 controls (mean age: 36.83yrs) were included in the study. A-FABP and L-FABP levels were significantly high in patients with A-ACLF than controls. Forty-four percent of patients with A-ACLF developed sepsis, 48% developed organ failure, and 44% expired by day 90. On multivariate Cox regression analysis, A-FABP (hazard ratio [HR]: 1.27 1.08-1.5; = 0.003), Asian Pacific Association for the Study of Liver ACLF research consortium score HR 3.31.15-9.54; = 0.02, L-FABP HR 0.69 0.52-0.91; = 0.009 and serum protein levels HR 0.03 0.003-0.36; = 0.005 predicted mortality. A-FABP 1.17 1.07-1.29; = 0.001, and serum bilirubin 1.05 0.99-1.12; = 0.06 predicted development of organ failure and only mDF HR 1.04 1.01-1.07; = 0.009 predicted the development of sepsis on multivariate analysis. Fifteen patients received steroid therapy, of which 13.34% were nonresponders.

Conclusions: In a selected group of patients with A-ACLF, A-FABP is highly sensitive at predicting mortality and outcome. If validated in a large, diverse sample, A-FABP can be used as a simple biomarker for prognostication in A-ACLF.
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http://dx.doi.org/10.1016/j.jceh.2020.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953014PMC
July 2020

Downregulation of Candidate Gene Expression and Neuroprotection by Piperine in Streptozotocin-Induced Hyperglycemia and Memory Impairment in Rats.

Front Pharmacol 2020 2;11:595471. Epub 2021 Mar 2.

Government Meera Girls College, Mohanlal Sukhadia University, Udaipur, India.

There is accumulating evidence showing that hyperglycemia conditions like diabetes possess a greater risk of impairment to the neuronal system because high glucose levels exacerbate oxidative stress, accumulation of amyloid-beta peptides, and mitochondrial dysfunction, and impair cognitive functions and cause neurodegeneration conditions like Alzheimer's diseases. Due to the extensive focus on pharmacological intervention to prevent neuronal cells' impairment induced by hyperglycemia, the underlying molecular mechanism that links between Diabetes and Alzheimer's is still lacking. Given this, the present study aimed to evaluate the protective effect of piperine on streptozotocin (STZ) induced hyperglycemia and candidate gene expression. In the present study, rats were divided into four groups: control (Vehicle only), diabetic control (STZ only), piperine treated (20 mg/kg day, i.p), and sitagliptin (Positive control) treated. The memory function was assessed by Morris water maze and probe test. After treatment, biochemical parameters such as HOMA index and lipid profile were estimated in the serum, whereas histopathology was evaluated in pancreatic and brain tissue samples. Gene expression studies were done by real-time PCR technique. Present data indicated that piperine caused significant memory improvement as compared to diabetic (STZ) control. The assessment of HOMA indices in serum samples showed that piperine and sitagliptin (positive control, PC) caused significant alterations of insulin resistance, cell function, and insulin sensitivity. Assessment of brain and pancreas histopathology shows significant improvement in tissue architecture in piperine and sitagliptin treated groups compared to diabetic control. The gene expression profile in brain tissue shows significantly reduced BACE1, PSEN1, APAF1, CASPASE3, and CATALASE genes in the piperine and sitagliptin (PC) treated groups compared to Diabetic (STZ) control. The present study demonstrated that piperine not only improves memory in diabetic rats but also reduces the expression of specific AD-related genes that can help design a novel strategy for therapeutic intervention at the molecular level.
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http://dx.doi.org/10.3389/fphar.2020.595471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962412PMC
March 2021

Identification and characterization of Prothionamide degradation impurities by mass spectrometry, NMR spectroscopy, and ultra high performance liquid chromatography method development.

J Sep Sci 2021 May 9;44(10):2078-2088. Epub 2021 Apr 9.

Micro Labs Ltd, API R&D Centre, Bengaluru, Karnataka, India.

Stability-indicating and liquid chromatography-mass spectrometry compatible ultra high performance liquid chromatography method was developed for the degradation and drug substances related impurities of Prothionamide. Forced degradation of Prothionamide was carried out under acidic, basic, thermal, oxidative, and photolytic stress conditions. The impurities separation was achieved on Acquity UPLC BEH-C18 (50 mm × 2.1 mm, 1.7 μm) with the mobile phase of 10 mm ammonium acetate pH 6.0 and Acetonitrile in a time gradient mode. Related substances by ultra-performance liquid chromatography method was validated according to ICH tripartite guidelines. Degradation products were isolated by Column chromatography and characterized by liquid chromatography-mass spectrometry, H, and C nuclear magnetic resonance spectroscopy. The developed related substances method showed adequate specificity, sensitivity, accuracy, linearity (0.4-1.5 μg/mL), precision, and robustness in line with ICH tripartite guidelines for validation of analytical procedures. Limits of detection and quantitation were 0.1 and 0.4 μg/mL, respectively, for Prothionamide and all the impurities. The method was found to be linear with a correlation coefficient > 0.99, precise (%RSD < 5.0), robust and accurate (%recovery 85-115%).
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http://dx.doi.org/10.1002/jssc.202100050DOI Listing
May 2021

Efficacy and safety of obeticholic acid in liver disease-A systematic review and meta-analysis.

Clin Res Hepatol Gastroenterol 2021 May 17;45(3):101675. Epub 2021 Mar 17.

Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India.

Background And Aims: Currently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic cholestatic liver disease for which ursodeoxycholic acid (UDCA) is the drug of choice. However, 50% of PBC patients may not respond to UDCA. Obeticholic acid (OCA) is emerging as a vital pharmacotherapy for these chronic disorders. We aimed to analyse the safety and efficacy of OCA.

Methods: We performed an extensive search of electronic databases from 01/01/2000 to 31/03/2020. We included randomized controlled trials of OCA in patients with NASH, PBC, and primary sclerosing cholangitis (PSC). We assessed the histological improvement in NASH, reduction in alkaline phosphatase (≤1.67 ULN) in PBC, and the adverse effects of OCA.

Results: Seven RCTs (n = 2834) were included. Of the total RCTs, there were three on both NASH and PBC and one on PSC. OCA improved NASH fibrosis [OR: 1.95 (1.47-2.59; p < 0.001)]. With the 10 mg OCA dose, the odds of improvement was 1.61 (1.03-2.51; p = 0.03), while with the 25 mg dose, it was 2.23 (1.55-3.18; p < 0.001). However, 25 mg OCA led to significant adverse events and discontinuation of the drug [2.8 (1.42-3.02); p < 0.001)] compared with 10 mg OCA [0.95 (0.6-1.5); p = 0.84] in NASH patients. In PBC patients, the response to 5 mg OCA was better than with the higher doses [5 mg: 7.66 (3.12-18.81; p < 0.001), 10 mg: 5.18 (2-13.41; p = 0.001), 25 mg: 2.36 (0.94-5.93; p = 0.06), 50 mg: 4.08 (1.05-15.78; p = 0.04)]. The risk of pruritus was lowest with 5 mg OCA.

Conclusions: Lower doses of OCA are effective and safe in NASH and cholestatic liver disease. While 10 mg OCA is effective for NASH fibrosis regression, only 5 mg OCA is required for PBC.
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http://dx.doi.org/10.1016/j.clinre.2021.101675DOI Listing
May 2021

Selenium-Based Novel Epigenetic Regulators Offer Effective Chemotherapeutic Alternative with Wider Safety Margins in Experimental Colorectal Cancer.

Biol Trace Elem Res 2021 Mar 6. Epub 2021 Mar 6.

Department of Biophysics, Panjab University, BMS Block II, Sector 25, Chandigarh, 160014, India.

Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide. Despite the critical involvement of epigenetic modifications in CRC, the studies on the chemotherapeutic efficacy of various epigenetic regulators remain limited. Considering the key roles of histone deacetylases (HDACs) in the regulation of diverse cellular processes, several HDAC inhibitors are implied as effective therapeutic strategies. In this context, suberoylanilide hydroxamic acid (SAHA), a 2-generation HDAC inhibitor, showed limited efficacy in solid tumors. Also, side effects associated with SAHA limit its clinical application. Based on the redox-modulatory and HDAC inhbitiory activities of essential trace element selenium (Se), the anti-carcinogenic potential of Se substituted SAHA, namely, SelSA-1 (25 mg kg), was screened for it enhanced anti-tumorigenic role and wider safety profiles in DMH-induced CRC in Balb/c mice. A multipronged approach such as in silico, biochemical, and pharmacokinetics (PK) has been used to screen, characterize, and evaluate these novel compounds in comparison to existing HDAC inhibitor SAHA. This is the first in vivo study indicating the chemotherapeutic potential of Se-based novel epigenetic regulators such as SelSA-1 in any in vivo experimental model of carcinogenesis. Pharmcological and toxicity data indicated better safety margins, bioavailability, tolerance, and elimination rate of SelSA-1 compared to classical HDAC inhibitor SAHA. Further, histological and morphological evidence demonstrated enhanced chemotherapeutic potential of SelSA-1 even at lower pharmacological doses than SAHA. This is the first in vivo study suggesting Se-based novel epigenetic regulators as potential chemotherapeutic alternatives with wider safety margins and enhanced anticancer activities.
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http://dx.doi.org/10.1007/s12011-021-02659-5DOI Listing
March 2021

Case 3: Apnea in Preterm Neonates.

Neoreviews 2021 03;22(3):e198-e200

Departments of Neonatology and.

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http://dx.doi.org/10.1542/neo.22-3-e198DOI Listing
March 2021

Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail.

J Clin Transl Hepatol 2021 Feb 9;9(1):40-50. Epub 2020 Dec 9.

Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India.

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic that is likely to become the most common cause of chronic liver disease in the next decade, worldwide. Though numerous drugs have been evaluated in clinical trials, most of them have returned inconclusive results and shown poorly-tolerated adverse effects. None of the drugs have been approved by the Food and Drug Administration for treating biopsy-proven non-alcoholic steatohepatitis (NASH). Vitamin E and pioglitazone have been extensively used in treatment of biopsy-proven nondiabetic NASH patients. Although some amelioration of inflammation has been seen, these drugs did not improve the fibrosis component of NASH. Therefore, dietary modification and weight reduction have remained the cornerstone of treatment of NASH; moreover, they have shown to improve histological activity as well as fibrosis. The search for an ideal drug or 'Holy Grail' within this landscape of possible agents continues, as weight reduction is achieved only in less than 10% of patients. In this current review, we summarize the drugs for NASH which are under investigation, and we provide a critical analysis of their up-to-date results and outcomes.
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http://dx.doi.org/10.14218/JCTH.2020.00055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868704PMC
February 2021

Inflammatory bowel disease: tri-directional relationship between microbiota, immune system and intestinal epithelium.

Crit Rev Microbiol 2021 Mar 12;47(2):254-273. Epub 2021 Feb 12.

Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India.

Human gut microbiota contributes to host nutrition and metabolism, sustains intestinal cell proliferation and differentiation, and modulates host immune system. The alterations in their composition lead to severe gut disorders, including inflammatory bowel disease (IBD) or inflammatory bowel syndrome (IBS). IBD including ulcerative colitis (UC) and Crohn's disease (CD) are gamut of chronic inflammatory disorders of gut, mediated by complex interrelations among genetic, environmental, and internal factors. IBD has debateable aetiology, however in recent years, exploring the central role of a tri-directional relationship between gut microbiota, mucosal immune system, and intestinal epithelium in pathogenesis is getting the most attention. Increasing incidences and early onset explains the exponential rise in IBD burden on health-care systems. Industrialization, hypersensitivity to allergens, lifestyle, hygiene hypothesis, loss of intestinal worms, and gut microbial composition, explains this shifted rise. Hitherto, the interventions modulating gut microbiota composition, microfluidics-based gastrointestinal models, non-allergic functional foods, nutraceuticals, and faecal microbiota transplantation (FMT) from healthy donors are some of the futuristic approaches for the disease management.
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http://dx.doi.org/10.1080/1040841X.2021.1876631DOI Listing
March 2021

Investigations of process parameters during dissolution studies of drug loaded 3D printed tablets.

Proc Inst Mech Eng H 2021 May 11;235(5):523-529. Epub 2021 Feb 11.

Department of Chemistry, BITS Pilani, Rajasthan, India.

The present research paper attempts to study the effect of different process parameters on the dissolution rate during 3D printed tablets. Three-dimensional printing has the potential of serving tailored made tablets to cater personalized drug delivery systems. Fluorescein loaded PVA filaments through impregnation route was used to fabricate tablets based on Taguchi based design of experimentation using Fused Deposition Modelling (FDM). The effect of print speed, infill percentage and layer thickness were analyzed to study the effect on rate of dissolution. Infill percentage followed by print speed were found to be critical parameters affecting dissolution rate. The data analysis provided an insight into the study of interaction among different 3D printing parameters to develop an empirical relation for percentage release of the drug in human body.
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http://dx.doi.org/10.1177/0954411921993582DOI Listing
May 2021
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