Physicochemical interaction of rifampicin and ritonavir-lopinavir solid dispersion: an in-vitro and ex-vivo investigation.

OBJECTIVE: To investigate the in-situ physicochemical interaction of Rifampicin and Ritonavir - Lopinavir Solid dispersion administered for the treatment of comorbid conditions i.e. Tuberculosis and HIV/AIDS. METHODS: pH-shift dissolution of Rifampicin (RIF) in presence of Ritonavir-Lopinavir solid dispersion (RL-SD) was carried out in USP phosphate buffer 6.8 and FaSSIF. Equilibrium and amorphous solubility were determined for the drugs. Pure drugs, their physical mixtures, and pH-shifted co-precipitated samples were characterized using DSC, PXRD, and FTIR. Fluorescence spectroscopy was used to investigate drug-rich and drug-lean phases. In-vitro and ex-vivo flux studies were also carried out. RESULTS: The results showed significant differences in the solubility and dissolution profiles of RTV and LOP in the presence of RIF, while RIF profile remained unchanged. Amorphicity, intermolecular interaction and aggregate formation in pH-shifted samples were revealed in DSC, XRD and FTIR analysis. Fluorescence spectroscopy confirmed the formation of drug-rich phase upon pH-shift. In-vitro and ex-vivo flux studies revealed significant reduction in the flux of all the drugs when studied in presence of second drug. CONCLUSION: RIF, RTV and LOP in presence of each other on pH-shift, results in co-precipitation in the amorphous form (miscible) which leads to reduction in the highest attainable degree of supersaturation. This reduction corresponds to the mole fraction of the RIF, RTV and LOP within the studied system. These findings suggest that the concomitant administration of these drugs may lead to physicochemical interactions and possible ineffective therapy.

Long-Term Management of Migraine With OnabotulinumtoxinA (Botox) vs Calcitonin Gene-Related Peptide Antibodies (Anti-CGRP).

In this literature review, we will evaluate the effectiveness of OnabotulinumtoxinA (Botox) and anti-calcitonin gene-related peptide (anti-CGRP) in the treatment of migraine headaches. Both therapies are frequently prescribed for managing and preventing migraines and have received Food and Drug Administration (FDA) approval. The mechanism of action, side effects, compliance, cost-effectiveness, and migraine treatment provided by these two medicines were compared in the analysis of several studies. Many studies found that as Botox was administered by a doctor every three months and had fewer side effects than anti-CGRP, which is self-administered every month, it was more compliant than anti-CGRP. After examining the data, Botox is believed to be the most effective therapy. Although both therapies are efficient, this article compares them to determine which is the best management strategy.

A computational-based approach to fabricate Ceritinib co-amorphous system using a novel co-former Rutin for bioavailability enhancement.

In this study, we used molecular simulations to design Ceritinib (CRT) co-amorphous materials (CAMs) with concurrent improvement in solubility and bioavailability. Computational modeling enabled us to select the co-former by estimating the binding energy and intermolecular interactions. Rutin (RTH) was selected as a co-former for CRT CAMs using the solvent evaporation method to anticipate simultaneous improvement of solubility and bioavailability. The solid state characterization using DSC, XRPD, FT-IR, and a significant shift in Gordon Taylor experimental Tg values of co-amorphous materials revealed single amorphous phase formation and intermolecular interactions between CRT and RTH. The co-amorphous materials exhibited physical stability for up to 4 months under dry conditions (40 °C). Further, co-amorphous materials maintained the supersaturation for 24 hrs and improved solubility as well as dissolution of CRT. CRT:RTH 1:1 CAMs improved the permeability of CRT by 2 fold, estimated by employing the everted gut sac method. The solubility advantage of CAMs was also reflected in pharmacokinetic parameters, with a 3.1-fold and 2-fold improvement of CRT:RTH 2:1 in CRT exposure (AUC 0-t) and plasma concentration (Cmax) compared to the physical mixture, respectively.

A small cysteine-rich fungal effector, BsCE66 is essential for the virulence of Bipolaris sorokiniana on wheat plants.

The Spot Blotch (SB) caused by hemibiotrophic fungal pathogen Bipolaris sorokiniana is one of the most devastating wheat diseases leading to 15-100% crop loss. However, the biology of Triticum-Bipolaris interactions and host immunity modulation by secreted effector proteins remain underexplored. Here, we identified a total of 692 secretory proteins including 186 predicted effectors encoded by B. sorokiniana genome. Gene Ontology categorization showed that these proteins belong to cellular, metabolic and signaling processes, and exhibit catalytic and binding activities. Further, we functionally characterized a cysteine-rich, B. sorokiniana Candidate Effector 66 (BsCE66) that was induced at 24-96 hpi during host colonization. The Δbsce66 mutant did not show vegetative growth defects or stress sensitivity compared to wild-type, but developed drastically reduced necrotic lesions upon infection in wheat plants. The loss-of-virulence phenotype was rescued upon complementing the Δbsce66 mutant with BsCE66 gene. Moreover, BsCE66 does not form homodimer and conserved cysteine residues form intra-molecular disulphide bonds. BsCE66 localizes to the host nucleus and cytosol, and triggers a strong oxidative burst and cell death in Nicotiana benthamiana. Overall, our findings demonstrate that BsCE66 is a key virulence factor that is necessary for host immunity modulation and SB disease progression. These findings would significantly improve our understanding of Triticum-Bipolaris interactions and assist in the development of SB resistant wheat varieties.

COMPARATIVE EFFICACY OF ANTIVIRAL AGENTS FOR PREVENTION AND MANAGEMENT OF HERPES LABIALIS: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS.

OBJECTIVE: To compare the relative efficacy and safety of antiviral agents used in the prevention and management of herpes labialis through a network meta-analysis of clinical trials. METHODS: A systematic search was performed in Ovid Medline PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus and Clinicaltrials.gov for randomized controlled trials (RCTs) reporting a comparison of antiviral agents in the management and prevention of herpes labialis in healthy/immunocompetent adults. The data extracted from the selected RCTs were assessed and a network meta-analysis (NMA) was performed. The interventions were ranked according to the surface under the cumulative ranking (SUCRA). RESULTS: A total of 52 articles were included for qualitative synthesis and for the quantitative part, 26 articles were analyzed for the primary treatment outcome and 7 studies were analyzed for the primary prevention outcome. The combination therapy of oral valacyclovir and topical clobetasol was the best ranked with a mean reduction in healing time of -3.50 (95% CI -5.22 to -1.78) followed by vidarabine monophosphate of -3.22 (95% CI -4.59 to -1.85). No significant inconsistencies, heterogeneity, and publication bias were reported for TTH outcome analysis. For primary prevention outcomes, only 7 RCTs fulfilled the inclusion criteria, and none of the interventions was shown to be superior to each other. The absence of adverse events was reported by 16 studies, whereas other studies reported mild side effects only. CONCLUSION: NMA highlighted that several agents were effective in the management of herpes labialis among which the combination of oral valacyclovir with topical clobetasol therapy was the most effective in reducing the time to heal. However, further studies are required to determine which intervention is the most effective in preventing the recurrence of herpes labialis.

Treatment of Patients With Schizophrenia and Comorbid Chronic Hepatitis With Paliperidone: A Systematic Review.

Schizophrenia is a severe mental disorder and antipsychotics are drugs usually used to treat this condition. Chronic hepatitis is a condition that can significantly impair hepatic functions. Most antipsychotics are metabolized by the liver, except for paliperidone, which undergoes the least amount of hepatic metabolism. This systematic review was conducted to investigate paliperidone's effectiveness and safety in patients with schizophrenia and concurrent chronic hepatitis. A detailed search using two databases, PubMed and Google Scholar, was done from June 2022 to July 2022. The PubMed search yielded 443 results and three more results were identified from Google Scholar. After a thorough screening, seven results pertinent to our study were taken into consideration for this review. All of the studies suggested that paliperidone is a safe and effective drug for the treatment of schizophrenia and since it does not undergo major hepatic metabolism and has no drug-drug interactions with antiviral drugs given in the treatment of chronic hepatitis, It can be safely used to treat schizophrenia with chronic hepatitis as a comorbid condition.

Chemical characterization and anaerobic treatment of bitumen fume condensate using a membrane bioreactor.

Bitumen fume condensate (BFC) is a hazardous wastewater generated at asphalt reclamation and production sites. BFC contains a wide variety of potentially toxic organic pollutants that negatively affect anaerobic processes. In this study, we chemically characterized BFC produced at an industrial site and evaluated its degradation under anaerobic conditions. Analyses identified about 900 compounds including acetate, polycyclic aromatic hydrocarbons, phenolic compounds, and metal ions. We estimated the half maximal inhibitory concentrations (IC50) of methanogenesis of 120, 224, and 990 mgCOD·L-1 for three types of anaerobic biomass, which indicated the enrichment and adaptation potentials of methanogenic biomass to the wastewater constituents. We operated an AnMBR (7.0 L, 35 °C) for 188 days with a mixture of BFC, phenol, acetate, and nutrients. The reactor showed a maximum average COD removal efficiency of 87.7 ± 7.0 %, that corresponded to an organic conversion rate of 286 ± 71 mgCOD-1·L-1d-1. The microbial characterization of the reactor's biomass showed the acetoclastic methanogen Methanosaeta as the most abundant microorganism (43 %), whereas the aromatic and phenol degrader Syntrophorhabdus was continuously present with abundances up to 11.5 %. The obtained results offer the possibility for the application of AnMBRs for the treatment of BFC or other petrochemical wastewater.

Role of Anticoagulants for Stroke Prevention in Low-Risk Population Having Atrial Fibrillation and Chronic Kidney Disease: A Systematic Review.

Over the last few years, there has been a rising incidence of atrial fibrillation and chronic kidney disease cases. Stroke is the major complication seen in such patients. The combination of both diseases makes patient management more tedious. PubMed and Google Scholar underwent screening with keywords and a Medical Subject Heading (MeSH) combination. The words were "atrial fibrillation," "chronic kidney disease/chronic renal insufficiency," "anticoagulation," "efficacy," and "left atrial appendage occlusion." Articles had screening and appraisal. With the English language as a filter, papers from 2002 to 2022 are part of this review. We reviewed studies including male patients with atrial fibrillation and chronic kidney disease under 65 years to see their risk-benefit from anticoagulation. In addition, left atrial appendage occlusion (LAAO) is also compared. A total of eight articles are part of this systematic review. Age plays a more prominent role than gender regarding the impact of drugs on stroke prevention. LAAO also shows a better outcome than oral anticoagulation, provided people agree to undergo surgery. More studies must be done for this target population, especially comparing results with LAAO and oral anticoagulation.

The Efficacy of Vitamin D Supplementation in Patients With Alzheimer's Disease in Preventing Cognitive Decline: A Systematic Review.

To evaluate the role of vitamin D supplementation in preventing cognitive decline in patients with Alzheimer's disease (AD), five databases such as PubMed, PubMed Central (PMC), Medical Literature Analysis and Retrieval System Online (MEDLINE), ScienceDirect, and Google Scholar were searched for articles relevant to the research question with filters such as English and human studies from 2011 to 2022. Two investigators extracted the data and assessed the quality of the study using the predefined criteria. We identified 24 relevant articles after the critical screening. There were five randomized controlled trials (RCTs), two observational studies, two systematic reviews and meta-analyses, one pilot study, and 14 review articles.  Most RCTs showed no significant improvement in vitamin D supplementation except for one study, which reported significant improvement in cognition on taking vitamin D in Alzheimer's disease but was not taken much into consideration as it had a small sample size (n=210) and was for a shorter duration. Another study evidenced significant improvement in Mini-Mental State Examination (MMSE) score when memantine and vitamin D were taken together compared to when memantine and vitamin D were taken independently. Studies have shown that vitamin D deficiency is associated with an increased risk of developing cognitive impairment. But there is no sufficient evidence indicating vitamin D supplementation can improve cognitive function in Alzheimer's disease.

The Other Sibling: A Systematic Review of the Mental Health Effects on a Healthy Sibling of a Child With a Chronic Disease.

The Center for Disease Control and Prevention (CDC) defines chronic diseases broadly as conditions that last over one year and require ongoing medical attention or limit activities of daily living or both. The diagnosis of a child with a chronic disease affects parents' mental health and functioning, included in this are the siblings of this child. The impact on a sibling of a child with chronic disease involves higher risks of anxiety, depression, feelings of worry about the brother or sister's future, and social problems.Three databases search were performed, and 16 articles were assessed in this systematic review that complies with inclusion and exclusion criteria.The siblings of those with chronic illnesses have higher reported emotional, behavioral, and social problems than those with healthy siblings. More research and studies with control groups and larger samples could contribute to a better understanding of the long-term effects of having a sibling with a chronic disease.

Comparative Efficacy of Interventions for the Management of Oral Submucous Fibrosis: A Systematic Review and Network Meta-Analysis.

Introduction: Oral submucous fibrosis (OSMF) is a chronic premalignant condition and is characterized by fibroblastic change of lamina propria and stiffness of oral mucosa. Though there are several treatment options available, the best agent is not yet identified. This study assessed the comparative efficacy and safety of medical interventions in the management of OSMF. Methods: A systematic review was performed to identify randomized controlled trials (RCTs) that compared the efficacy of interventions for OSMF with each other, or placebo. A network meta-analysis was performed, and the interventions were ranked according to their efficacy based on the surface under the cumulative ranking. (PROSPERO Registration no: CRD42021255094). Results: Thirty-two RCTs comprising 2063 patients were eligible for quantitative analysis. In terms of therapeutic efficacy in the improvement of mouth opening Oxitard, a herbal formulation was ranked as the most efficacious agent, [MD, 10.29 (95%CI 6.34-14.25)] followed by combination therapy of Lycopene with corticosteroids and hyaluronidase [MD, 7.07 (95%CI 1.82-12.31)]. For improvement of burning sensation aloe vera was ranked first [MD, 6.14 (95%CI 4.58-7.70)] followed by corticosteroids with antioxidants [MD, 6.13 (95%CI 4.12-8.14)] and corticosteroids in combination with hyaluronidase with antioxidants [MD, 5.95 (95%CI 3.79-8.11)]. In terms of safety, most of the drugs were reported to cause mild adverse effects only. Significant inconsistencies could be identified in the analysis for both the outcomes assessed and were further explored. Conclusions: Our study highlighted the potential efficacy of several agents over placebo in the improvement of mouth opening and burning sensation in OSMF patients. However, the RCTs lacked methodological soundness. Well-designed studies with a larger number of participants with a rigorous randomization process and stringent methodology are recommended to strengthen the results obtained, which may help to construct a clinical guideline for OSMF management.

Association of proton-pump inhibitor use with adverse health outcomes: A systematic umbrella review of meta-analyses of cohort studies and randomised controlled trials.

AIMS: The aim was to perform an umbrella review to summarise the existing evidence on proton-pump inhibitor (PPI) use and adverse outcomes and to grade the certainty of evidence. METHODS: Electronic databases were searched up to July 2021 for meta-analyses of cohort studies and/or randomised controlled trials (RCTs). Summary effect sizes from a random-effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance and credibility ceilings were devised to classify the credibility of evidence from meta-analyses of cohort studies, whereas the GRADE approach was used for meta-analyses of RCTs. RESULTS: In meta-analyses of cohort studies, 52 of the 91 examined associations were statistically significant (P ≤ .05). Convincing evidence emerged from main analysis for the association between PPI use and risk of all-site fracture and chronic kidney disease in the elderly population. However, none of these associations remained supported by convincing evidence after sensitivity analyses. The use of PPI is also associated with an increased risk of mortality due to COVID-19 infection and other related adverse outcomes, but the quality of evidence was weak. In meta-analyses of RCTs, 38 of the 63 examined associations were statistically significant. However, no associations were supported by high or moderate-quality evidence. CONCLUSION: This study's findings imply that most putative adverse outcomes associated with PPI use may not be supported by high-quality evidence and are likely to have been affected by underlying confounding factors. Future research is needed to confirm the causal association between PPI use and risk of fracture and chronic kidney disease.

The Genetic Discrimination Observatory: confronting novel issues in genetic discrimination.

Genetic discrimination (GD) is the differential or unfair profiling of an individual on the basis of genetic data. This article summarizes the actions of the Genetic Discrimination Observatory (GDO) in addressing GD and recent developments in GD since late 2020. It shows how GD can take many forms in today's rapidly evolving society.

Surviving the odds: From perception to survival of fungal phytopathogens under host-generated oxidative burst.

Fungal phytopathogens pose a serious threat to global crop production. Only a handful of strategies are available to combat these fungal infections, and the increasing incidence of fungicide resistance is making the situation worse. Hence, the molecular understanding of plant-fungus interactions remains a primary focus of plant pathology. One of the hallmarks of host-pathogen interactions is the overproduction of reactive oxygen species (ROS) as a plant defense mechanism, collectively termed the oxidative burst. In general, high accumulation of ROS restricts the growth of pathogenic organisms by causing localized cell death around the site of infection. To survive the oxidative burst and achieve successful host colonization, fungal phytopathogens employ intricate mechanisms for ROS perception, ROS neutralization, and protection from ROS-mediated damage. Together, these countermeasures maintain the physiological redox homeostasis that is essential for cell viability. In addition to intracellular antioxidant systems, phytopathogenic fungi also deploy interesting effector-mediated mechanisms for extracellular ROS modulation. This aspect of plant-pathogen interactions is significantly under-studied and provides enormous scope for future research. These adaptive responses, broadly categorized into "escape" and "exploitation" mechanisms, are poorly understood. In this review, we discuss the oxidative stress response of filamentous fungi, their perception signaling, and recent insights that provide a comprehensive understanding of the distinct survival mechanisms of fungal pathogens in response to the host-generated oxidative burst.

Primary Health-Care Innovations with Superior Allusion to Family Health Centers.

The present case study discusses about the Primary Health Care system of Kerala and the Government's innovative step to promote the Primary Health Centres to Family Health Centres. The case study also deliberates about the FHC working model and its superiority over the current PHCs in the areas of manpower, OP time, lab services, nursing services, social security projects etc. and the transformation of PHCs to a well-functioning PHC, thereby it can become a model for other states.

Considerations for the selection of co-formers in the preparation of co-amorphous formulations.

Co-amorphous drug delivery systems are evolving as a credible alternative to amorphous solid dispersions technology. In Co-amorphous systems (CAMs), a drug is stabilized in amorphous form using small molecular weight compounds called as co-formers. A wide variety of small molecular weight co-formers have been leveraged in the preparation of CAMs. The stability and supersaturation potential of prepared co-amorphous phases largely depend on the type of co-former employed in the CAMs. However, the rationality behind the co-former selection in co-amorphous systems is poorly understood and scarcely compiled in the literature. There are various facets to the rational selection of co-former for CAMs. In this context, the present review compiles various factors affecting the co-former selection. The factors have been broadly classified under Thermodynamic, Kinetic and Pharmacokinetic-Pharmacologically relevant parameters. In particular, the importance of Glass transition, Miscibility, Liquid-Liquid phase separation (LLPS), Crystallization inhibition has been deliberated in detail.

Screening of phytocompounds, molecular docking studies, and in vivo anti-inflammatory activity of heartwood aqueous extract of Pterocarpus santalinus L.f

Objective:To evaluate the anti-inflammatory potential of aqueous extract of Pterocarpus santalinus L.f. heartwood using molecular docking and in vivo experiment. Methods:An aqueous extract of Pterocarpus santalinus heartwood was prepared using a Soxhlet apparatus. Phytocompounds in the extract were tentatively identified using high-resolution mass spectrometry. Molecular docking experiments were carried out to evaluate the binding affinity of selected compounds, phloridzin to cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), prostaglandin E synthase-1 (PGES-1) and 5-lipoxygenase (5-LOX). Anti-inflammatory potential was evaluated by carageenan induced paw edema model in rats. Results:The presence of major component phloridzin along with quercetin, parthenin, ginkgolide B, picrotoxinin, usnic acid, octopine, and epigallocatechin was detected in the extract. Molecular docking study showed that phloridzin inhibited COX-1, COX-2, PGES-1 and 5-LOX with more affinity than ibuprofen and paracetamol. Pterocarpus santalinus heartwood extract at 200 and 400 mg/kg BW showed significant reduction in carageenan-induced hind paw edema in a dose-dependent manner, but the effect was slow when compared with the standard ibuprofen (30 mg/kg p.o.). Conclusions:The study indicated that after clinical trials, the aqueous extract of Pterocarpus santalinus heartwood can be effectively used in phytotherapy to treat inflammation.

Overview of Extensively Employed Polymeric Carriers in Solid Dispersion Technology.

Solid dispersion is the preferred technology to prepare efficacious forms of BCS class-II/IV APIs. To prepare solid dispersions, there exist a wide variety of polymeric carriers with interesting physicochemical and thermochemical characteristics available at the disposal of a formulation scientist. Since the advent of the solid dispersion technology in the early 1960s, there have been more than 5000 scientific papers published in the subject area. This review discusses the polymeric carrier properties of most extensively used polymers PVP, Copovidone, PEG, HPMC, HPMCAS, and Soluplus® in the solid dispersion technology. The literature trends about preparation techniques, dissolution, and stability improvement are analyzed from the Scopus® database to enable a formulator to make an informed choice of polymeric carrier. The stability and extent of dissolution improvement are largely dependent upon the type of polymeric carrier employed to formulate solid dispersions. With the increasing acceptance of transfer dissolution setup in the research community, it is required to evaluate the crystallization/precipitation inhibition potential of polymers under dynamic pH shift conditions. Further, there is a need to develop a regulatory framework which provides definition and complete classification along with necessarily recommended studies to characterize and evaluate solid dispersions.

Evaluation of performance of direct disk diffusion test from positively flagged blood culture broth: A large scale study from South India.

BACKGROUND: Rapid turnaround time of blood culture reports should be the main motive for a clinical microbiologist for optimal patient care. Categorical agreement (CA) between direct disk diffusion (dDD) and reference disk diffusion (rDD) may vary between laboratories. AIMS AND OBJECTIVES: This study was designed to determine the CA and understand various types of errors associated with antibiotic organism combination, so that caution can be derived while interpreting and reporting dDD results in the earliest meaningful time frame. MATERIALS AND METHODS: In the present study, dDD results were compared to the rDD results from the positive blood culture bottles. CA and various types of errors were evaluated. RESULTS: A total of 965 pathogens and 7106 organism antibiotic combinations were evaluated in this study. Overall, there was a CA of 96% which was extremely satisfactory. The categorical disagreement was found only in 4% of organism antibiotic combinations; majority of which were major error (ME, 2.1%) followed by very ME (1%) and minor error (0.9%). The errors were marginally high for Enterobacteriaceae testing against ß lactam- ß lactamase inhibitor combinations, for Pseudomonas species against aminoglycosides and ciprofloxacin and Staphylococcus species against cefoxitin, one should be vigilant while reporting dDD result of these antibiotic organism combinations. CONCLUSION: dDD is of paramount importance for early institution of targeted therapy and is considered as one of the key stewardship intervention. Our study gives an insight that every laboratory must perform dDD for positively flagged blood culture specimens; the result of which should be confirmed later by performing rDD. One should be vigilant while reporting dDD result of BL BLI for Enterobacteriaceae; aminoglycosides and CF for Pseudomonas species; cefoxitin for Staphylococcus species and HLG for Enterococcus species. Supplementary tests such as MRSA latex should be included when necessary.