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Development of a novel inhibitor targeting Gyrase B and Topoisomerase IV offers a potential opportunity to combat the drug resistance. In the present study, we extensively investigated the efficacy of RBx 10080758, a novel fluorobenzothiazole, against skin and respiratory infections caused by Staphylococci and Streptococci in in vitro and in vivo models. RBx 10080758 showed a potent IC50 of 0.06 μM against Gyrase and Topoisomerase IV and also exhibited a strong whole cell in vitro activity with MIC ranges of 0.015-0.06, 0.015-0.03, 0.008-0.03, 0.008-0.03, 0.008-0.0.06, 0.015-0.06 μg/ml against Staphylococcus. aureus, Streptococcus pneumoniae, Coagulase negative Staphylococci, Streptococcus viridans, Streptococcus pyogenes and Enterococcus, respectively. As expected from the novel class of molecule, it retains potent even against linezolid and vancomycin resistant strains. Interesting, in mouse systemic infection 10 mg/kg, IV dose protected 100% mice from lethal infections. In rat thigh infection model with MRSA WCUH29 at 45 mg/kg exhibited >3-log10 cfu reduction in thigh muscles. RBx 10080758 displayed potent in vitro and in vivo activity against a panel of MDR Gram-positive bacteria. As a novel chemical class, the fluorobenzothiazoles have the potential to become clinically viable antibiotics, to address the drug resistance problem by its unique dual targeting mechanism of action.

Asafoetida (Ferula asafoetida) also known as heeng, Devil’s drug, ferula, food of Gods, incense of Devil, stinking gum is an important spice crop belonging to family Apiaceae. It is native to Iran and Afghanistan. Its dried latex (gum oleoresin) is generally used for flavouring curries, sauces, and pickles. Therapeutically, it stimulates the intestinal and respiratory tracts as well as the nervous system. It is beneficial in asthma, whooping cough, and chronic bronchitis. Its essential oil is also used in medicines, food and cosmetic industries. Besides, it is also used as an alternative for pesticides in organic farming. The major constituents of asafoetida are the resin (40–64%), gum (25%) and essential oil (10–17%). The butyl propenyl disulphide is responsible for the aroma of asafoetida. The asaresinotannol is the major constituent present in the resin. It can be grown on unproductive cold deserts of dry temperate areas of Himalayas. It is mainly propagated by seeds. The seeds are sown either in winters or spring. It becomes ready for harvesting after 5 years of planting and yields around 900g per plant. The oleo gum resin and essential oil derived from this plant are sold at premium prices in the international market. The small and marginal farmers of Kinnaur, Lahaul-Spiti and Chamba can benefit from this new emerging crop.

We present a case series of 5 patients who were found to have COVID-19 encephalitis. There is still no disease defining test for diagnosis so the mainstay of diagnosis is the exclusion of all common causes of encephalitis. Brain MRI and CSF analysis perform an ancillary in the diagnostic tools.

Dengue is a serious public health concern worldwide, with ∼3 billion people at risk of contracting dengue virus (DENV) infections, with some suffering severe consequences of disease and leading to death. Currently, there is no broad use vaccine or drug available for the prevention or treatment of dengue, which leaves only anti-mosquito strategies to combat the dengue menace. The present study is an extension of our earlier study aimed at determining the in vitro and in vivo protective effects of a plant-derived phytopharmaceutical drug for the treatment of dengue. In our previous report, we had identified a methanolic extract of aerial parts of Cissampelos pareira to exhibit in vitro and in vivo anti-dengue activity against all the four DENV serotypes. The dried aerial parts of C. pareira supplied by local vendors were often found to be mixed with aerial parts of another plant of the same Menispermaceae family, Cocculus hirsutus, which shares common homology with C. pareira. In the current study, we have found C. hirsutus to have more potent anti-dengue activity as compared with C. pareira. The stem part of C. hirsutus was found to be more potent (∼25 times) than the aerial part (stem and leaf) irrespective of the extraction solvent used, viz., denatured spirit, hydro-alcohol (50:50), and aqueous. Moreover, the anti-dengue activity of stem extract in all the solvents was comparable. Hence, an aqueous extract of the stem of C. hirsutus (AQCH) was selected due to greater regulatory compliance. Five chemical markers, viz., Sinococuline, 20-Hydroxyecdysone, Makisterone-A, Magnoflorine, and Coniferyl alcohol, were identified in fingerprinting analysis. In a test of primary dengue infection in the AG129 mice model, AQCH extract at 25 mg/kg body weight exhibited protection when administered four and three times a day. The AQCH was also protective in the secondary DENV-infected AG129 mice model at 25 mg/kg/dose when administered four and three times a day. Additionally, the AQCH extract reduced serum viremia and small intestinal pathologies, viz., viral load, pro-inflammatory cytokines, and vascular leakage. Based on these findings, we have undertaken the potential preclinical development of C. hirsutus-based phytopharmaceutical, which could be studied further for its clinical development for treating dengue.

BackgroundDengue is a serious public health concern worldwide, with ~3 billion people at risk of contracting dengue virus (DENV) infections. Currently, no effective vaccine or drug is available for the prevention or treatment of dengue, which leaves only anti-mosquito strategies to combat this disease. The present study was initiated to determine the in-vitro and in vivo protective effects of a plant-derived phytopharmaceutical drug for the treatment of dengue.Methodology/Principal FindingsIn our previous report, we had identified methanolic extract of the aerial parts of Cissampelos pareira to exhibit in vitro and in vivo anti-dengue activity against all the four DENV serotypes. In the current study, we have identified another Indian medicinal plant, Cocculus hirsutus, which has a more potent anti-dengue activity than C. pareira. The activity has been evaluated through flow-cytometry-based virus inhibition assay. Interestingly, the stem of C. hirsutus was found to be more potent than the aerial part irrespective of the extraction solvent used viz., denatured spirit, hydro-alcohol (50:50) and water. Hence, the aqueous extract of stem of C. hirsutus (AQCH) was further advanced for investigations because of greater regulatory acceptance. The AQCH exhibited dose-dependent inhibition of release of DENV and its secretory antigen, NS1. Five chemical markers viz. Sinococuline, 20-Hydroxyecdysone, Makisterone-A, Magnoflorine and Coniferyl alcohol were identified as the major chemical ingredients of the AQCH extract. These chemicals were subsequently used for extract standardisation. Importantly, AQCH completely protected AG129 mice at 25 mg/kg/dose body weight when fed 4 times a day post-infection with a lethal dose of DENV-2 S221 strain. Because of its potential as an effective phytopharmaceutical drug against dengue, AQCH, has been formulated into tablets for further pre-clinical and clinical developments.Conclusions/SignificanceWe provide evidence of the pan anti-dengue potential of C. hirsutus-based phytopharmaceutical drug as determined through in vitro and in vivo experiments. We have also characterized five chemical entities in the drug substance, which provides means for standardization of drug substance and drug product. Based on these findings, a program to develop a safe and effective C. hirsutus-derived phytopharmaceutical drug for the treatment of dengue has been initiated.Author summaryThere is an urgent need to develop a safe and effective drug against dengue, which is a rapidly expanding mosquito-borne viral disease. Half of the world’s population has been estimated to be at risk of contracting this disease and the situation remains grim due to lack of an approved drug. We aimed to develop an ethnopharmacological drug against dengue by exploring traditional Indian medicinal science, Ayurveda. This led us to identify a creeper, Cocculus hirsutus, as a more potent anti-dengue plant than Cissampelos pareira, reported in our earlier published study. The stem part of C. hirsutus was found to be more efficacious in inhibiting the propagation of dengue viruses (DENVs) in cell culture than its aerial part. Hence, we chose to advance aqueous extract of stem of C. hirsutus (AQCH) for further studies. Importantly, AQCH also protected immune-compromised mice from lethal DENV infection, which is suggestive of its potential clinical relevance. We have identified five chemical marker compounds in AQCH to gauge the quality and consistency of extract preparation and its formulation into stable tablets. Based on the findings of this study, we have undertaken the development of a safe and effective C. hirsutus-derived phytopharmaceutical drug for the treatment of dengue.

A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycobacterium tuberculosis (Mtb.H37Rv strain) around the identified hit 1. A scaffold hopping approach was used to identify compounds 14a, 14b and 24a with improved activity against MTb.H37Rv.

Background: Rifampicin is known to degrade at the acidic pH of the stomach, especially in the presence of isoniazid. Although isoniazid also degrades partially, its degradation is reversible. Objective: Presently, we provide a proof of the fact that the simultaneous oral administration of rifampicin (RIF), upon incorporation into solid lipid nanoparticles (RIF-SLNs), with isoniazid (INH) overcomes its INH-induced degradation and improves its oral bioavailability in rats. Methods: Solid lipid nanoparticles of RIF (RIF-SLNs) were prepared using a novel and patented method. The effect of INH was investigated on in vivo bioavailability of RIF both in its free and encapsulated (RIF-SLNs) form, after oral administration to rats. Results: Cmax and AUC0-∞ of RIF increased 158 % and 125 %, respectively, upon incorporation into SLNs versus free RIF when combined with INH. The Tmax decreased from 5.67 h to 3.3 h, and the plasma concentration of RIF remained above its MIC (8 μg/ml) at all the tested time points starting with 15 min, when administered as RIF-SLNs in combination with INH. Conclusions: The results confirm the scope of combining RIF-SLNs with INH to overcome the bioavailability of free RIF when combined with INH, especially in fixed dose combinations.

Pulmonary hypertension (PH) is associated with poor outcomes in the dialysis and general populations, but its effect in CKD is unclear. We evaluated the prevalence and predictors of PH measures and their associations with long–term clinical outcomes in patients with nondialysis-dependent CKD. Chronic Renal Insufficiency Cohort (CRIC) Study participants who had Doppler echocardiography performed were considered for inclusion. PH was defined as the presence of estimated pulmonary artery systolic pressure (PASP) >35 mmHg and/or tricuspid regurgitant velocity (TRV) >2.5 m/s. Associations between PH, PASP, and TRV and cardiovascular events, renal events, and all-cause mortality were examined using Cox proportional hazards models. Of 2959 eligible participants, 21% (n=625) had PH, with higher rates among those with lower levels of kidney function. In the multivariate model, older age, anemia, lower left ventricular ejection fraction, and presence of left ventricular hypertrophy were associated with greater odds of having PH. After adjusting for relevant confounding variables, PH was independently associated with higher risk for death (hazard ratio, 1.38; 95% confidence interval, 1.10 to 1.72) and cardiovascular events (hazard ratio, 1.23; 95% confidence interval, 1.00 to 1.52) but not renal events. Similarly, TRV and PASP were associated with death and cardiovascular events but not renal events. In this study of patients with CKD and preserved left ventricular systolic function, we report a high prevalence of PH. PH and higher TRV and PASP (echocardiographic measures of PH) are associated with adverse outcomes in CKD. Future studies may explain the mechanisms that underlie these findings.

The study examined the impacts of climate change on water resources, viz., surplus / deficit water balance, snowfall trends and surface water flow of major rivers of Himachal Pradesh. The analysis on surplus water balance clearly showed decreasing trends in all the agro-climatic zones during past three decades. Maximum availability of surplus water balance period showed a shift during July to August and registered a decrease of 35.7 percent. The low hill regions exhibited water surplus during kharif season and water deficit during rabi season, while, mid hill regions exhibited water deficit during kharif season and water surplus during rabi season during past three decades. The Mann-Kendall trend test of snowfall indicated a decrease in monthly average snowfall from September to December. The trend analysis further showed increasing trends of snowfall during January and February indicating delay in snowfall during winters. The decreasing trends of snowfall were observed during September to December and March to May indicating shrinking winter period. The significant decreasing trend of snowfall was observed during December and May. The trend test revealed significant decrease of surface water flow of river Beas at Manali and Parvati at Aut in Kullu district during all the months. The water flow of river Sutlej at Songtong in Kinnaur district also showed significant decreasing trends during winter months. Similarly, the annual water inflow of the Sutlej River at Bhakhra Dam showed decreasing trend also. Thus, the studies clearly indicated that water resources have been impacted due to changes in climatic conditions in mountains of Himachal Pradesh during past three decades.

Knowledge of the magnitude of genetic variability for marketable fruit yield and quality traits, and relationships among these traits, is needed to improve quality breeding in bell pepper (Capsicum annuum L. var. grossum Sendt.). The study was undertaken to assess genetic variation for marketable fruit yield, fruits per plant, average fruit weight, pericarp thickness, number of lobes per fruit, TSS, and ascorbic acid and capsaicin contents and to quantify the relationship among these traits in diverse bell pepper germplasm. Significant difference among bell pepper genotypes indicated presence of significant variation for all the traits. The phenotypic coefficient of variation (PCV) indicated higher values than genotypic coefficient of variation (GCV) for all traits, indicating close association between phenotype and genotype. High heritability estimates along with high genetic advance was recorded for fruits per plant, marketable fruits per plant, pericarp thickness, and lobes per fruit, indicating the ro...

The effects of growth regulator applications (kinetin, IAA and Paclobutrazol) on field grown Salvia sclarea L. were studied during 2005 to 2006 at the Institute of Himalayan Bioresource Technology, Palampur, India. Growth was monitored by measuring plant height, canopy spread, leaf number, primary branches, and yield characteristics (inflorescence length and flower and oil yield). Quality was evaluated. Maximum height and leaf numbers were observed after application of kinetin 10 μL L−1 and IAA 50 μL L−1, respectively. Maximum flower and oil yield were observed after application with 40 μL L−1 paclobutrazol (PBZ) application. Application of 80 μL L−1 paclobutrazol application increased the linalool-linalyl acetate content of the plant about 12% higher than the untreated control.

Background Dengue, a mosquito-borne viral disease, poses a significant global public health risk. In tropical countries such as India where periodic dengue outbreaks can be correlated to the high prevalence of the mosquito vector, circulation of all four dengue viruses (DENVs) and the high population density, a drug for dengue is being increasingly recognized as an unmet public health need. Methodology/Principal findings Using the knowledge of traditional Indian medicine, Ayurveda, we developed a systematic bioassay-guided screening approach to explore the indigenous herbal bio-resource to identify plants with pan-DENV inhibitory activity. Our results show that the alcoholic extract of Cissampelos pariera Linn (Cipa extract) was a potent inhibitor of all four DENVs in cell-based assays, assessed in terms of viral NS1 antigen secretion using ELISA, as well as viral replication, based on plaque assays. Virus yield reduction assays showed that Cipa extract could decrease viral titers by an order of magnitude. The extract conferred statistically significant protection against DENV infection using the AG129 mouse model. A preliminary evaluation of the clinical relevance of Cipa extract showed that it had no adverse effects on platelet counts and RBC viability. In addition to inherent antipyretic activity in Wistar rats, it possessed the ability to down-regulate the production of TNF-α, a cytokine implicated in severe dengue disease. Importantly, it showed no evidence of toxicity in Wistar rats, when administered at doses as high as 2g/Kg body weight for up to 1 week. Conclusions/Significance Our findings above, taken in the context of the human safety of Cipa, based on its use in Indian traditional medicine, warrant further work to explore Cipa as a source for the development of an inexpensive herbal formulation for dengue therapy. This may be of practical relevance to a dengue-endemic resource-poor country such as India., Author Summary India represents ~50% of the global population estimated to be at risk of dengue. Severe dengue, which is potentially fatal, correlates with very high virus load, reduction in platelet counts and haemorrhage. Antiviral therapy to reduce high virus load may be beneficial in attenuating disease severity. We have explored Indian traditional medicine, Ayurveda, to identify plants that could be a source of dengue inhibitory activity. We show that an alcoholic extract prepared from Cissampelos pareira Linn inhibited the replication of dengue viruses in living cells in culture and protected mice against dengue infection. It also showed antipyretic and anti-inflammatory effects. Importantly, this extract did not show any toxic effects in rats and did not affect platelets and red blood cells. This observation is critical as dengue fever is commonly treated with antipyretics. In a dengue-endemic resource-poor country as India, the C. pareira plant may serve as a source for the development of an inexpensive herbal formulation against dengue.

Lung cancer is the leading cause of cancer-related death in both developed and developing countries with unacceptably high mortality even for early-stage cancers. Present guidelines do not recommend adjuvant chemotherapy for stage I non-small cell lung carcinoma and prompts a search for a prognostic marker that would separate stage I patients into 2 groups, those who would benefit and those who would not benefit from adjuvant treatment. Studies during the last decade showed that the gene expression profiling can be the biomarker being sought. Many gene expression profiling have been found and reported from the analysis of surgical specimens of resected lung cancers during the last decade, and many of them had been shown to have an excellent predictive accuracy. These profiles used in the studies had not only different gene combinations but also different number of genes and methods of identification. Researchers have used microarray assays, RT-quantitative polymerase chain reaction, and more recently microRNA-based techniques to achieve this goal. Unfortunately, most of the profiles were not sufficiently validated and/or were not used in prospective phase III studies. This review focuses on major studies in the field, future prospects, as well as the lessons learned so far. It is shown that the gene expression profiles have a good chance of being implemented in future everyday practice.

A 67-year-old female who was diagnosed with ulcerative colitis in 2001, presented with a soft tissue mass in the middle of her back of 4 months duration in April 2011. It was excised; however it recurred at the same site in September 2011. Wide excision of the mass was done. Pathology revealed T1aNxM0 pleomorphic malignant fibrous histiocytoma or undifferentiated pleomorphic sarcoma. Whole body bones scan and staging CT scan of the chest, abdomen and pelvis was negative for distant metastasis. She received local radiotherapy at the site of excision. No chemotherapy was given.

RBx 1000075 and RBx 1000276, the new investigational oxazolidinones, have an extended spectrum of in vitro activity against Gram-positive pathogens and showed minimum inhibitory concentrations (MICs) lower than comparator drugs. MIC for 90% of the organisms (MIC(90)) values of RBx 1000075, RBx 1000276 and linezolid against the isolates tested were, respectively: methicillin-sensitive Staphylococcus aureus, 0.25, 1 and 4 microg/mL; methicillin-resistant S. aureus (MRSA), 0.5, 2 and 4 microg/mL; methicillin-sensitive Staphylococcus epidermidis, 0.25, 1 and 2 microg/mL; methicillin-resistant S. epidermidis, 0.5, 1 and 2 microg/mL; and enterococci, 0.25, 1 and 4 microg/mL. Against respiratory pathogens, MIC(90) values were: Streptococcus pneumoniae, 0.125, 0.5 and 2 microg/mL; Streptococcus pyogenes, 1, 0.5 and 2 microg/mL; and Moraxella catarrhalis, 0.5, 2 and 4 microg/mL. In vivo efficacies of RBx 1000075 and RBx 1000276 were evaluated in murine systemic infection against S. aureus (MRSA 562) and in a pulmonary infection model against S. pneumoniae ATCC 6303. In murine systemic infection, RBx 1000075 and RBx 1000276 showed efficacy against MRSA 562, exhibiting a 50% effective dose (ED(50)) of 6.25 and 9.92 mg/kg body weight for once-daily administration and 4.96 and 5.56 mg/kg body weight for twice-daily administration, respectively, whereas for linezolid the corresponding ED(50) values were 9.9 and 5.56 mg/kg body weight. In pulmonary infection with S. pneumoniae ATCC 6303, 50% survival was observed with RBx 1000075 at 50mg/kg once daily, whereas 60% survival was observed with RBx 1000276 at 50mg/kg thrice daily. The absolute oral bioavailabilities of RBx 1000075 and RBx 1000276 were 48% and 73%, with half-lives of 13.5 and 3.2h, respectively. RBx 1000075 and RBx 1000276 are promising investigational oxazolidinones against Gram-positive pathogens.

Oxazolidinones are a new class of totally synthetic antibacterial agents with wide spectrum of activity against a variety of clinically significant susceptible and resistant bacteria. These compounds have been shown to inhibit translation at the initiation phase of protein synthesis. DuP-721, the first oxazolidinone showed good activity against M. tuberculosis when given orally or parenterally to experimental animals but was not developed further due to lethal toxicity in animal models. Later two oxazolidinones, PNU-100480 and Linezolid, demonstrated promising antimycobacterial activities in the murine model. While Linezolid has been approved for clinical use, PNU-100480 was not been developed further. DA- 7867 showed good in vitro and better in vivo efficacy than Linezolid but was poorly tolerated in rat toxicology studies. The antimycobacterial activity of AZD-2563 has not been explored. RBx 7644 had modest antimycobacterial activity while RBx 8700 has potent antibacterial and concentration dependent activity against all slow growing mycobacteria. It demonstrated better activity than RBx 7644 against MDR strains of M. tuberculosis along with intracellular activity. Toxicity, especially myelosuppression, has been an important limiting factor for development of an oxazolidinones. The GM-CSF assay has helped in selecting molecules with less myleosuppressive potential. We report, a review on the promising antituberculosis activities of the class oxazolidinones.

RBx 8700, an investigational oxazolidinone, has excellent activity against respiratory pathogens. We evaluated the In Vitro minimum inhibitory concentration (MIC) and bactericidal activity of RBx 8700 against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) isolates. RBx 8700 had an MIC of 1 μg/ml against M. tuberculosis isolates resistant to both isoniazid (INH) and rifampicin (RIF), whereas its MIC against M. tuberculosis isolates resistant to either INH or RIF was 0.5 μg/ml.