BWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections.

The global crisis of antimicrobial resistance (AMR) necessitates the development of broad-spectrum antibacterial drugs effective against multi-drug resistant (MDR) pathogens. BWC0977, a Novel Bacterial Topoisomerase Inhibitor (NBTI) selectively inhibits bacterial DNA replication via inhibition of DNA gyrase and topoisomerase IV. BWC0977 exhibited a minimum inhibitory concentration (MIC) of 0.

A cross-sectional study of the factors influencing adherence to antiretroviral therapy among adults with human immunodeficiency virus infection in a tertiary care hospital in Puducherry, India.

Context: Combating human immunodeficiency virus/acquired immunodeficiency syndrome epidemic has been possible due to advances in prevention strategies and Antiretroviral therapy (ART). Optimal adherence to ART is a major factor in achieving the desired immunological, virological, and patient well-being outcomes. Several socio-demographic, patient, treatment, and health-care system-related factors influence nonadherent behavior to ART.

Comparing Intraocular Pressure, Ocular Blood Flow, and Retinal Nerve Fiber Layer Thickness in Early and Chronic Hypertensives With Normotensives.

Purpose: To compare blood pressure (BP), intraocular pressure (IOP), ophthalmic artery flow (OAF) velocity, retinal nerve fiber layer (RNFL) thickness, and visual fields in newly diagnosed hypertension (HT) patients (before treatment), chronic HT (on antihypertensive medications >5 years) and normotensives.

Methods: A prospective, cross-sectional study at a tertiary care centre in India. Three groups of 45 patients each: group 1 - early HT, group 2 - chronic HT, and Group 3 - normotensives, underwent evaluation of BP, IOP by Goldmann applanation tonometry (GAT), OAF velocity by transcranial doppler (TCD), RNFL analysis by spectral-domain optical coherence tomography (SD-OCT), and visual fields.

Comparing Peribulbar and Topical Anesthesia in Cataract Surgery among Patients with Cardiovascular Disease.

Purpose: To compare topical and peribulbar anesthesia in cataract surgery for hemodynamic changes, rate of complications and pain score in patients with cardiovascular disease.

Methods: A prospective comparative study at a tertiary care center in India. Patients >40 years old with treated/controlled hypertension and cardiovascular disease scheduled for cataract surgery under topical or peribulbar anesthesia were recruited.

Neutropenic Rat Thigh Infection Model for Evaluation of the Pharmacokinetics/Pharmacodynamics of Anti-Infectives.

The neutropenic mouse infection model is extensively used to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of anti-infective agents. However, it is difficult to evaluate agents following intravenous (i.v.

Effect of Blood Pressure Reduction on Intraocular Pressure and Ophthalmic Artery Blood Flow Velocity in Hypertension.

To evaluate the effect of reducing blood pressure (BP) by atenolol and amlodipine on (1) intraocular pressure (IOP) and (2) ophthalmic artery blood flow (OAF) velocity in new hypertensives. A prospective, observational cohort study conducted at a tertiary care center in India after IRB approval. New hypertensives treated with atenolol 25 mg or amlodipine 5 mg were divided into 2 groups of 30 patients each.

A critical review on the formation, fate and degradation of the persistent organic pollutant hexachlorocyclohexane in water systems and waste streams.

The environmental impacts of persistent organic pollutants (POPs) is an increasingly prominent topic in the scientific community. POPs are stable chemicals that are accumulated in living beings and can act as endocrine disruptors or carcinogens on prolonged exposure. Although efforts have been taken to minimize or ban the use of certain POPs, their use is still widespread due to their importance in several industries.

Nano-adsorbents an effective candidate for removal of toxic pharmaceutical compounds from aqueous environment: A critical review on emerging trends.

Advancements in medical research has resulted in the modernization of healthcare facilities, subsequently leading to a higher level of production and usage of pharmaceuticals to sustain better quality of life. Pharmaceutical active compounds (PhACs) possess high genotoxicity and eco-toxicity thus presenting numerous side effects to living beings on long-term exposure. The fate and toxicity of PhACs were explored in detail, aiming to elucidate their occurrence and transmission in wastewater treatment systems (WWTPs).

Anaerobic digestate water for Chlorella pyrenoidosa cultivation and employed as co-substrate with cow dung and chicken manure for methane and hydrogen production: A closed loop approach.

In rural India, unpleasant atmosphere, anthropogenic gas emission, air and soil pollution are caused due to disposal of livestock's wastes (cow dung and chicken waste) in open environment. This study provides zero emission concept for waste disposal and value addition of these wastes for renewable green energy production. In this study, biogas production was carried out with varying proportion of cow dung to chicken waste (1:0, 0:1, 1:1, 2:1, 1:2, 3:1 and 1:3) for duration of 40 days.

Pharmacokinetics/Pharmacodynamics (PK/PD) of Ciprofloxacin in the Complicated Urinary Tract Infection (cUTI) Model in Diabetic Mice.

Background: The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections (cUTI).

Objective: The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients.

Methods: Streptozotocin induced diabetic female BALB/c mice were infected transurethrally with Escherichia coli.

Linear Cyclodextrin Polymer Prodrugs as Novel Therapeutics for Niemann-Pick Type C1 Disorder.

Niemann-Pick Type C1 disorder (NPC) is a rare lysosomal storage disease characterized by the accumulation of cholesterol in lysosomes. NPC has no FDA approved treatments yet, however 2-hydroxypropyl-β-cyclodextrin (HPβCD) has shown efficacy for treating the disease in both mouse and feline NPC models and is currently being investigated in late stage clinical trials. Despite promising results, therapeutic use of HPβCD is limited by the need for high doses, ototoxicity and intrathecal administration.

Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy.

The mechanism of efflux is a tour-de-force in the bacterial armoury that has thwarted the development of novel antibiotics. We report the discovery of a novel chemical series with potent antibacterial properties that was engineered to overcome efflux liability. Compounds liable to efflux specifically via the Resistance Nodulation and cell Division (RND) pump, AcrAB-TolC were chosen for a hit to lead progression.

Metabolism and Disposition of Pacritinib (SB1518), an Orally Active Janus Kinase 2 Inhibitor in Preclinical Species and Humans.

The ADME of Pacritinib (SB1518), an orally active JAK 2 inhibitor, was investigated in vitro and in vivo in preclinical species and humans. Pacritinib showed ~5 fold higher affinity to human plasma proteins relative to mouse in vitro. It was metabolized by human CYP3A4 in vitro, and did not significantly induce CYP3A and 1A2 in human hepatocytes.

VS-5584, a novel and highly selective PI3K/mTOR kinase inhibitor for the treatment of cancer.

Dysregulation of the PI3K/mTOR pathway, either through amplifications, deletions, or as a direct result of mutations, has been closely linked to the development and progression of a wide range of cancers. Moreover, this pathway activation is a poor prognostic marker for many tumor types and confers resistance to various cancer therapies. Here, we describe VS-5584, a novel, low-molecular weight compound with equivalent potent activity against mTOR (IC(50) = 37 nmol/L) and all class I phosphoinositide 3-kinase (PI3K) isoforms IC(50): PI3Kα = 16 nmol/L; PI3Kβ = 68 nmol/L; PI3Kγ = 25 nmol/L; PI3Kδ = 42 nmol/L, without relevant activity on 400 lipid and protein kinases.

Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in multiple lymphoma subtypes.

Purpose: The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma.

Patients And Methods: Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled.

SB1578, a novel inhibitor of JAK2, FLT3, and c-Fms for the treatment of rheumatoid arthritis.

SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses.

Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor.

SB1317 (TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-cancer agent. SB1317 was soluble, highly permeable in Caco-2 cells, and showed > 99% binding to plasma from mice, dog and humans.

Discovery of the macrocycle (9E)-15-(2-(pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a potent inhibitor of janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis.

Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA.

Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kinases (CDKs), Janus kinase 2 (JAK2), and fms-like tyrosine kinase-3 (FLT3) for the treatment of cancer.

Herein, we describe the design, synthesis, and SAR of a series of unique small molecule macrocycles that show spectrum selective kinase inhibition of CDKs, JAK2, and FLT3. The most promising leads were assessed in vitro for their inhibition of cancer cell proliferation, solubility, CYP450 inhibition, and microsomal stability. This screening cascade revealed 26 h as a preferred compound with target IC(50) of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively.

Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase inhibitor, and prediction of human pharmacokinetics.

The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino) ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat.

Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma.

Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC(50) = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC(50) = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC(50) = 1280 and 520 nM, respectively).

Pharmacodynamic evaluation of the target efficacy of SB939, an oral HDAC inhibitor with selectivity for tumor tissue.

SB939 is an oral histone deacetylase (HDAC) inhibitor currently in phase II clinical trials potently inhibiting class I, II, and IV HDACs with favorable pharmacokinetic properties, resulting in tumor tissue accumulation. To show target efficacy, a Western blot assay measuring histone H3 acetylation (acH3) relative to a loading control was developed, validated on cancer cell lines, peripheral blood mononuclear cells (PBMC), and in animal tumor models. Exposure of cells to 60 nmol/L (22 ng/mL) SB939 for 24 hours was sufficient to detect an acH3 signal in 25 μg of protein lysate.

Reorientation of the high mobility plane in pentacene-based carbon nanotube enabled vertical field effect transistors.

The large current densities attained by carbon nanotube enabled vertical field effect transistors using crystalline organic channel materials are somewhat unexpected given the known large anisotropy in the mobility of crystalline organics and their conventional ordering on dielectric surfaces which tends to orient their high mobility axes parallel to the surface. This seeming contradiction is resolved by the finding that the nanotubes induce a molecular ordering that reorients the high mobility axes to favor current flow in a direction perpendicular to the substrate surface.

Glycine and alanine dehydrogenase activities are catalyzed by the same protein in Mycobacterium smegmatis: upregulation of both activities under microaerophilic adaptation.

Microaerophilic adaptation has been described as one of the in vitro dormancy models for tuberculosis. Studies on Mycobacterium tuberculosis adapted to low oxygen levels showed an enhancement of glycine dehydrogenase (deaminating) activity. We studied the physiology of the fast-growing, nonpathogenic strain of Mycobacterium smegmatis ATCC 607 under low oxygen by shifting the actively growing M.