Role of baricitinib in COVID-19 patients:A systematic review and meta-analysis

BACKGROUND Recent studies have indicated the use of baricitinib in coronavirus disease 2019(COVID-19)patients.However,the use of baricitinib in COVID-19 patients is unclear so far.AIM To determine the precise role of baricitinib in the mortality of COVID-19 patients.METHODS The relevant studies were searched in PubMed,Google scholar,and Clinical trials registries till July 13,2021 and sorted out based on inclusion and exclusion criteria.The quality of studies was assessed using Newcastle-Ottawa Scale.A random-effect model was used,and the pooled estimate was calculated as the odds ratio with a 95%confidence interval using Rev Man 5.RESULTS A total of 11 studies(4 observational and 7 clinical trials)were found relevant for analysis.The overall estimate measure in terms of odds ratio for observational studies was 0.42[0.11,1.67],whereas for clinical trials it was 0.37[0.09,1.46],indicating a non-significant reduction in COVID-19 patient deaths in the baricitinib group versus the non-baricitinib group.CONCLUSION More studies are required to confirm the role of baricitinib in the deaths of COVID-19 patients.

Antiarthritic effects of Ajuga bracteosa Wall ex Benth.in acute and chronic models of arthritis in albino rats

Objective:To evaluate the antiarthritic activity of Ajuga bracteosa using albino rats.Methods: The antiarthritic activity of 70%ethanolic extract of Ajuga bracteosa(EEAB) was evaluated against turpentine oil- and formaldehyde- induced acute non immunological and complete freund's adjuvant(CFA)-induced chronic immunological arthritis in albino rats.Results:EEAB showed a significant(P<0.05) and dose dependent inhibitory effect against acute and chronic models of arthritis.EEAB exhibited better antiarthritic activity than the standard aspirin.Conclusions: EEAB exhibits a significant and promising antiarthritic activity against acute and chronic arthritis and supports the traditional use of Ajuga bracteosa for rheumatism and other inflammatory diseases.

Thermo-mechanical and micro-structural properties of xylanase containing whole wheat bread

Xylanase is a hemicellulase that can hydrolyses the complex polysaccharides.Hemicelluloses are main components of cell walls of cereal grains.Moreover,hemicelluloses are considered as potential sources of mono-and oligosaccharides.In this study,influence of xylanase on the physicochemical properties and sensory qualities of the whole wheat bread during storage was investigated.Studies of whole wheat bread on microstructure,texture,thermotics,Scanning Electron Microscopic(SEM),X-Ray Diffraction(XRD)were conducted at ambient temperature of 25 and 4◦C respectively.During storage at different temperatures,bread containing xylanase exhibited less firmness but larger volume with whiter crumb color and longer shelf life as compared to control bread.Results of firmness,enthalpy,Fourier Transformation Infra Red(FTIR)and X-Ray Diffraction(XRD)studies suggested a lower staling rate of bread containing xylanase as compared to control one.Bread containing xylanase showed a smoother surface and more uniform pore size than the control.Significant differences in microstructure of control and bread containing xylanase were observed which might be attributed due to the change in water starch gluten interaction.These differences were also found to be interrelated to the textural properties of bread.Better sensory features were achieved in bread containing xylanase.

An understanding of mitochondria and its role in targeting nanocarriers for diagnosis and treatment of cancer

Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be utilized for the better treatment of disease. Mitochondria, the so-called powerhouse of cell, portrays significant role in the survival and death of cells, and has emerged as potential target for cancer therapy. Direct targeting and nanotechnology based approaches can be tailor-made to target mitochondria and thus improve the survival rate of patients suffering from cancer. With this backdrop, in present review, we have reemphasized the role of mitochondria in cancer progression and inhibition, highlighting the different targets that can be explored for targeting of disease. Moreover, we have also summarized different nanoparticulate systems that have been used for treatment of cancer via mitochondrial targeting.

Rapid LC-ESI-MS-MS Method for the Simultaneous Determination of Sitagliptin and Pioglitazone in Rat Plasma and Its Application to Pharmacokinetic Study

A liquid chromatography tandem mass spectrometry (LC-MS/MS) based method was developed for the simultaneous monitoring plasma levels of Sitagliptin (STG) and Pioglitazone (PIO) for applicability to pharmacokinetic studies. The method was based on HPLC separation on the reversed phase Phenomenex Synergy C18 column (30 mm length, 4.6 mm internal diameter, and 4.0 μm particle size) at a temperature of 40?C using a binary gradient mobile phase consisting of methanol and 2 mM ammonium acetate buffer pH adjusted to 4.5 with acetic acid, at a flow rate of 1 mL?min?1. Tolbutamide was used as an internal standard. Detection of analytes was achieved with LC-MS/MS system in Multiple Reaction Monitoring (MRM) mode. The method was validated over concentration range of 10.98 - 2091.77 ng?mL?1 for SIT and 8.25 - 1571.63 ng?mL?1 for PIO and lower limit of quantification was 10.98 ng?mL?1 and 8.25 ng?mL?1 for STG and PIO respectively. Recoveries from spiked controls were within acceptance criteria for all the analytes and internal standard at all QC levels. Within batch and between batch accuracy for STG was found within 96.9% - 100.3% and for PIO was found within 100.0% - 104.3%. Within batch and between batch precision for STG was less than 3.1% CV (coefficient of variation) and for PIO was less than 5.3% CV at all concentrations levels. This method was successfully applied to monitor pharmacokinetics profile of both STG and PIO on simultaneous oral administration to rats. This method can be applicable for pharmacokinetic drug-drug interaction studies.

Efficacy and safety of pharmacotherapeutic interventions used in visceral leishmaniasis clinical trials:A systematic review and network meta-analysis

Objective:To compare the efficacy and safety outcomes of different antileishmanial agents used in visceral leishmaniasis clinical trials.Methods:A systematic literature search in PubMed/MEDLINE,EMBASE,Cochrane,and Google Scholar was done using keywords“randomized controlled trials”,“antileishmanial”and“visceral leishmaniasis”.The outcomes included were cure rate,overall withdrawals,relapse rate,and treatment-emergent adverse events.Effect estimates through the frequentist network meta-analysis approach were presented as OR with 95%CI.Rankogram plots were used for identifying the“best intervention”based on p-scores obtained using the surface under the cumulative ranking.The risk of bias was evaluated by using Pedro Scale.Results:Seventeen randomized controlled trials with 5143 visceral leishmaniasis patients who received different antileishmanial agents(amphotericin B,miltefosine,paromomycin,meglumine antimoniate,sodium stibogluconate,sitamaquine,and pentavalent antimonials)and met the inclusion criteria were included.For efficacy outcomes of the treatments,the rankogram of the network meta-analysis revealed that paromomycin(p-score=0.8148)has the highest probability of being best in the pool,followed by sodium stibogluconate(OR 0.82,95%CI 0.24-2.79,p-score=0.7580),amphotericin B+miltefosine(OR 0.66,95%CI 0.02-19.04,p-score=0.7329)as compared to the remaining treatments;however,the most of the treatment-emergent adverse events were reported with sitamaquine.Conclusions:Paromomycin reported the highest cure rates,while the maximum treatment-emergent adverse events were seen with sitamaquine.

Association ofβ-lactam antimicrobial's exposure with carbapenem-resistant Pseudomonas aeruginosa infection:a cumulative meta-analysis

Background:Carbapenems are effective against severe Pseudomonas aeruginosa nosocomial infections.Therefore,carbapenem-resistant Pseudomonas aeruginosa is a serious public health threat.An understanding of the risk of inappropriate exposure to different antimicrobials in resistant Pseudomonas aeruginosa infection could help in elucidating the effective approach towards using antimicrobials in vulnerable patients with CRPA infection.Object:To investigate the association between exposure ofβ-lactam antimicrobials and CRPA infection relative to control patients.Methods:The MEDLINE/PubMed and OVID/Embase databases were used to search case-control and cohort studies in English language which reported antimicrobial exposure as risk factors for CRPA infection.The pooled odds ratios(OR)were calculated using a random-effect and fixed-effect model,and forest plots from a cumulative meta-analysis method were used to better show how pooled OR changed as updated evidence accumulated.Results:A total of 24 studies comprising 7039 participants were included for cumulative meta-analysis.A positive correlation was found between development of CRPA infection and exposure of beta-lactam antimicrobials:carbapenems(OR=7.60,95%CI:3.95 to 14.62,P<0.0001),imipenem(OR=9.81,95%CI:5.56 to 17.33),ampicillin(OR=1.86,95%CI:1.14 to 2.41),piperacillin(OR=2.82,95%CI:1.46 to 2.43),penicillins(OR=1.42,95%CI:0.90 to 2.24),cephalosporins(OR=1.88,95%CI:1.46 to 2.43)andβlactamase inhibitors(OR=1.96,95%CI:1.44 to 2.67).Further,exposure of other antimicrobial agents like quinolone(OR=2.35,95%CI:1.78 to 3.10),ciprofloxacin(OR=2.35,95%CI:1.66 to 3.95),aminoglycoside(OR=2.17,95%CI:1.60 to 2.95),amikacin(OR=3.11,95%CI:2.10 to 4.61),glycopeptides(OR=3.02,95%CI:1.92 to 4.75)and vancomycin(OR=3.26,95%CI:1.48 to 7.18),were also found to be positively associated with development of CRPA infection.Conclusions:Exposure of all kinds ofβ-lactams is significantly associated with development of carbapenemresistant Pseudomonas aeruginosa infection.These findings provide an impetus to take a more active approach while usingβ-lactam antimicrobials in patients with resistant Pseudomonas aeruginosa infections.

Statin use and risk of cancer:An overview of meta-analyses

AIM To conduct an overview of meta-analyses to critically appraise the evidence and present a comprehensive evaluation of the association between statin use and risk of site specific cancers.METHODS MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and Web of Science databases were searched from inception until 31 st May 2016. The electronic database search was supplemented by a hand search in PROSPERO and relevant journals which are not indexed in above databases. Meta-analyses that examined the association between statin use and risk of site specific cancers were included. Two reviewers independently screened the literature, abstracted data, and assessed study quality using the Assessment of Multiple Systematic Reviews(AMSTAR) tool.RESULTS Overal, 38 meta-analyses covered 13 site specific cancers were included. More than half(68%) of the meta-analyses were moderate in quality with an AMSTAR score 4-7 out of a possible 11. Based on current evidence from meta-analyses, use of statin decreases the risk of certain cancers, such as colorectal(8%-12%), gastric(27%-44%), hematological(19%), liver(37%-42%), oesophageal(14%-28%), ovarian(21%) and prostate cancer(7%). On the other side, evidence from metaanalyses also suggests that there is no association between statin use and risk of bladder, breast, endometrial, kidney, lung, pancreatic and skin cancers. CONCLUSION This overview of meta-analyses with variable quality has been shown that the statins may have a potential role in cancer chemoprevention and reduce the risk of some site specific cancers, but not all.

Exposure to Electromagnetic Fields from Mobile Phones and Fructose consumption Coalesce to Perturb Metabolic Regulators AMPK/SIRT1-UCP2/FOXO1 in Growing Rats

Objective In this study,the combined effect of two stressors,namely,electromagnetic fields(EMFs)from mobile phones and fructose consumption,on hypothalamic and hepatic master metabolic regulators of the AMPK/SIRT1-UCP2/FOXO1 pathway were elucidated to delineate the underlying molecular mechanisms of insulin resistance.Methods Weaned Wistar rats(28 days old)were divided into 4 groups:Normal,Exposure Only(ExpO),Fructose Only(FruO),and Exposure and Fructose(EF).Each group was provided standard laboratory chow ad libitum for 8 weeks.Additionally,the control groups,namely,the Normal and FruO groups,had unrestricted access to drinking water and fructose solution(15%),respectively.Furthermore,the respective treatment groups,namely,the ExpO and EF groups,received EMF exposure(1,760 MHz,2 h/day x 8 weeks).In early adulthood,mitochondrial function,insulin receptor signaling,and oxidative stress signals in hypothalamic and hepatic tissues were assessed using western blotting and biochemical analysis.Result In the hypothalamic tissue of EF,SIRT1,FOXO 1,p-PI3K,p-AKT,ComplexⅢ,UCP2,MnSOD,and catalase expressions and OXPHOS and GSH activities were significantly decreased(P<0.05)compared to the Normal,ExpO,and FruO groups.In hepatic tissue of EF,the p-AMPKα,SIRT1,FOXO1,IRS1,p-PI3K,ComplexⅠ,Ⅱ,Ⅲ,Ⅳ,Ⅴ,UCP2,and MnSOD expressions and the activity of OXPHOS,SOD,catalase,and GSH were significantly reduced compared to the Normal group(P<0.05).Conclusion The findings suggest that the combination of EMF exposure and fructose consumption during childhood and adolescence in Wistar rats disrupts the closely interlinked and multi-regulated crosstalk of insulin receptor signals,mitochondrial OXPHOS,and the antioxidant defense system in the hypothalamus and liver.

Cellulose based polymers in development of amorphous solid dispersions

Cellulose derivatives have gained immense popularity as stabilizers for amorphous solid dispersion owing to their diverse physicochemical properties. More than 20 amorphous solid dispersion-based products that have been approved for marketing consist of cellulose derivatives as stabilizers, thus highlighting their importance in generation of amorphous solid dispersions. These polymers offer numerous advantages like drug solubilization, crystallization inhibition and improvement in release patterns of drugs. Exploring their potential and exploiting their chemistry and p H responsive behaviour have led to the synthesis of new derivatives that has broadened the scope of the use of cellulose derivatives in amorphous formulation development. The present review aims to provide an overview of different mechanisms by which these cellulose derivatives inhibit the crystallization of drugs in the solid state and from supersaturated solution. A summary of different categories of cellulose derivatives along with the newly explored polymers has been provided. A special segment on strengths, weaknesses, opportunities, and threats(SWOT) analysis and critical quality attributes(CQAs) which affect the performance of the cellulose based amorphous solid dispersion will aid the researchers in identifying the major challenges in the development of cellulose based solid dispersion and serve as a guide for further formulation development.

Recognition of Natural Products as Potential Inhibitors of COVID-19 Main Protease (Mpro): In-Silico Evidences

SARS-CoV-2(2019-nCoV)emerged in 2019 and proliferated rapidly across the globe.Scientists are attempting to investigate antivirals specific to COVID-19 treatment.The 2019-nCoV and SARS-CoV utilize the same receptor of the host which is COVID-19 of the main protease(Mpro).COVID-19 caused by SARS-CoV-2 is burdensome to overcome by presently acquired antiviral candidates.So the objective and purpose of this work was to investigate the plants with reported potential antiviral activity.With the aid of in silico techniques such as molecular docking and druggability studies,we have proposed several natural active compounds including glycyrrhizin,bicylogermecrene,tryptanthrine,β-sitosterol,indirubin,indican,indigo,hesperetin,crysophanic acid,rhein,berberine andβ-caryophyllene which can be encountered as potential herbal candidate exhibiting anti-viral activity against SARS-CoV-2.Promising docking outcomes have been executed which evidenced the worthy of these selected herbal remedies for future drug development to combat coronavirus disease.

Poly(ADP-ribose) polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain

Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that jimit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially per- oxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly（ADP-ribose） polymerase （PARP） upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neu- ronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the in- volvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.

Pioglitazone:A review of analytical methods

Pioglitazone is an oral anti-hyperglycemic agent. It is used for the treatment of diabetes mellitus type 2. It selectively stimulates nuclear receptor peroxisome proliferator-activated receptor gamma （PPAR-gamma）. It was the tenth-best-selling drug in the U.S. in 2008. This article examines published analytical methods reported so far in the literature for the determination of pioglitazone in biological samples and pharmaceutical formulations. They include various techniques like electrochemical methods, spectrophotometry, capillary electrophoresis, high-performance liquid chromatography, liquid chromatography-electrospray ionization-tandem mass spectrometry and high-performance thin layer chromatography.

Novel potential for optimization of antitubercular therapy:Pulmonary delivery of rifampicin lipospheres

The aim of the present work is to develop rifampicin loaded phospholipid lipospheres containing sulfphobutyl etherβ-cyclodextrin and Vitamin C for inhalation to test their potential for deep lung delivery.The findings of the solid state characterization revealed the amorphous nature of the lipospheres.These exhibited a better flowability,an aerodynamic diameter in the range of 1.76 to 3.99μm.Moreover,the fine particle fraction and emitted dose was found in the range of 68.84–83.73% and 80–93%,respectively.Moreover,lipospheres exhibited enhanced/equivalent efficacy in vitro in H37Rv strain.Hence,the results show the potential of lipospheres for pulmonary delivery of rifampicin.

Multiple facets of poly(ADP-ribose) polymerase-1 in neurological diseases

The highly conserved abundant nuclear protein poly （ADP-ribose） polymerase-1 （PARP-1） is activated by DNA damage. PARP-1 activation is associated in DNA repair, cell death and inflammation. Since oxidative stress induced robust DNA damage and wide spread inflamma- tory responses are common pathologies of various CNS diseases, the attention towards PARP-1 as a therapeutic target has been amplifying. This review highlights the multiple roles of PARP- 1 in neurological diseases and po- tential of PARP- 1 inhibitors to enter clinical translation.

Comparative drug susceptibility study of five clonal strains of Trichomonas vaginalis in vitro

Objective:To produce comparative data on a group of Trichomonas vaginalis clonal strains with varied drug responses using identical methods and materials.Methods:Five clonal strains of Trichomonas vaginalis were isolated from reference strain using agar plate technique.The variability of growth kinetic and susceptibility of clonal strain to metronidazole,tinidazole, satranidazole and nitazoxanide were observed in 96 well microlilre plate.Results:Among these clonal strains there was a good correlation between rates of growth with the relative susceptibility of the strains to drugs in vitro.Regarding metronidazole,tinidazole and satranidazole susceptibility,different degrees of susceptibility were determined.However,no difference in nitazoxanide susceptibility was found between the clonal strain tested and a reference strain. Conclusions:This is the first description of biological variability in clonal stock of Trichomonas vaginalis.Different degrees of drug susceptibility were determined among clonal strains tested. Further studies will be necessary to ascertain the importance of this variability in clinical infection.

Comparative quantitative analysis of fruit oil from Hippophae rhamnoides(seabuckthorn) by qNMR, FTIR and GC–MS

Objective: To develop a qNMR method for quantitative analysis of triacylglycerols in fruit oil of Hippophae rhamnoides(seabuckthorn, SBT) and analyze commercial samples of SBT oils using GC–MS and FTIR.Methods: SBT fruit oil(IPHRFH) was extracted with hexane and the triglyceride(TAG) was isolated by vacuum liquid chromatography. Six different branded SBT oils purchased from e-commerce suppliers(Amazon) and in-house prepared SBT oil was analyzed by qNMR and fatty acyl composition of TAGs determined by using NMR. In-house oil was also analysed by GC–MS and FTIR spectroscopy.Results: The qNMR results showed that the oil contained 80.3% of triacylglycerol(TAG). The SBT oil TAGs comprised of linolenate 6.6%, palmitoleate/oleate 65.4%, and total saturated fatty acyl chain including palmitate 28% as determined by qNMR. GC–MS analysis revealed that the major acyl functionalities present in the TAG were palmitoleic acid 36.5%, oleic acid 12.9%, palmitic acid 21.2%, and linoleic acid 18%. Of the six commercial samples analyzed, samples from only one supplier(SW) were fruit oil;All others were the seed oils or mix of fruit oil and seed oil. The labels for samples except for the SW did not indicate whether it was fruit oil or seed oil.Conclusion: The results suggest that SBT oil should be analyzed by combination of GC–MS, FTIR and qNMR for factual content of free fatty acid or TAGs, which are chemically different in nature and affect the quality of oil. GC–MS showed the content of omega free fatty acids after hydrolysis, while qNMR and FTIR showed the content of TAGs. The major acyl functionalities found in SBT fruit oil TAGs are palmitoleate/palmitate/oleate, while linoleate and linonelate make up a minor fraction. Furthermore,analysis of commercial samples showed discrepancies between label claims and actual content.

Aspects of xenobiotics and their receptors in stroke

Stroke is devastating and the second leading cause of disability and death worldwide.The pathophysiology of stroke is intricate involving oxidative stress,ionic imbalance,and excitotoxicity leading to cell death.The current therapeutic strategies for ischemic stroke primarily aim to restore cerebral blood flow by removing clots using intravenous thrombolysis and mechanical thrombectomy.However,hemorrhagic stroke requires different therapeutic interventions,where intravenous thrombolysis worsens the persistent condition.Nevertheless,the present treatment strategies do not provide effective neuroprotection as they have limitations such as narrow time window,specialized clinics and personnel,and higher expense.Therefore,studies on novel therapeutic strategies that can render neuroprotection over an extended time with minimum adverse effects are solicited.Xenobiotics are agents that are foreign to the biological system but can regulate their metabolism by binding to different xenobiotic receptors(XRs)to produce toxic substances.Modulation of XRs in different preclinical studies have shown benefits in the stroke outcome.Therefore,targeting XRs may be a future therapeutic strategy for stroke intervention.The present review briefly discusses various implications of xenobiotics and their receptors to evolve as a potential therapeutic target for prospective use as an adjunctive therapy for stroke.

Role of autophagy and histone deacetylases in diabetic nephropathy:Current status and future perspectives

The prevalence of diabetes and its complications is increasing at an alarming rate in both developed and deve1oping nations.The emerging evidences highlighted that both genetic and epigenetic mechanisms including histone modifications play a significant role in the pathogenesis of diabetic nephropathy(DN).Histone deacetylases(HDACs)and acetylation are involved in the regulation of autophagy as well as pathogenesis of DN.Both HDACs and histone acetyltransferases(HATs)play a key role in chromatin remodeling and affect the transcription of various genes involved in the cellular homeostasis,apoptosis,immunity and angiogenesis.Further,HDAC inhibitors are exert the renoprotective effects in DN and other diabetic complications.Thus,the cellular acetylation plays a crucial role in the regulation of autophagy and can be explored as a new therapeutic target for the treatment of DN.This review aimed to delineate the role of HDACs and associated molecular signaling/pathways in the regulation of autophagy with an emphasis on promising targets for the treatment of DN.

Sodium glucose cotransporter-2 inhibitors: Are we targeting old devil with new problems?

Dear editor,The advent of modern molecular mechanism’s approach to disease treatment is highly advancing to mitigate/normalize the symptoms of disease i.e.hyperglycemia by targeting at least eight different pathophysiological approaches popularly known as omnious octet[1].Importantly,type 2 diabetes is a