New drugs in the treatment of bacterial infections

Background. The use of antibacterials has become increasingly strained due to increased rates of resistance coupled with reduced rates of development of new agents. As a result, multi-, extensively-, and pan-drug resistant bacterial strains are now frequently encountered. Objective of the study. To highlight recently developed antibacterial medicines and their role in clinical practice. Material and Methods. From the PubMed and Scopus databases, the articles published during the years 2017-2022 were selected. Results. Of 11 new antibiotics that have been approved since 2017, only two – Vaborbactam + Meropenem and Lefamulin – represent a new class. Pretomanid was approved as part of a three-drug combination for the treatment of adult patients with XDR-TB and treatment of intolerant or non-responsive MDR pulmonary TB. Cefiderocol is against to three critical priority pathogens. Ceftazidime - Avibactam licensed for carbapenemase producers. In adults, is specifically addressing the use of Fidaxomicin and Bezlotoxumab for the treatment of C. difficile infection. Macozinone is the antibacterial drug in pipeline developing against M. tuberculosis and Rindinilazole is for C. difficile. Conclusion. New antibacterial agents are mainly derivatives of existing classes. The clinical “traditional” pipeline is still insufficient against priority pathogens. There is a significant need for novel antibacterial drugs research and development

FORMULATION, EVALUATION AND OPTIMIZATION OF SUSTAINED-RELEASE DRUG DELIVERY SYSTEM OF CISAPRIDE TABLET

Objective: Cisapride is a novel prokinetic agent is best candidate for GERD. Cisapride 20 mg can be given thrice in a day given along with Proton pump inhibitor. By developing the sustain release formulation of Cisapride, the frequency of both drug can be reduce to once only to obtain good therapeutic response. Methods: Cisapride SR Tablets were prepared by direct compression technique with HPMC K4M and HPMC K100M polymers. Followed by various evaluation tests including in vitro disintegration and dissolution, the formulation was optimized by 32 full factorial designs with drug release kinetic analysis, compatibility studies (FTIR) and stability studies. Results: Results of Preformulation studies of the Cisapride indicate that it has poor flow property and compressibility property. To improve the flow and compressibility property, it was beneficial to use the directly compressible grade components in the formulation of tablet. Results of DSC study shown that there is no change in drug’s melting peak after the preparation of tablet. Hydrophilic matrix of HPMC K4M and HPMC K100M in combination sustained the Cisapride release effectively for more than 12h. The result indicates that the combination of HPMCK4M and HPMCK100M can be successfully, On the basis of the preliminary trials in the present study a32 full factorial design was employed to study the effect of independent variables, i.e. concentration of HPMCK4M(X1) and concentration of HPMCK100M(X2)on dependent variables like% drug release Q2, Q6 and Q10. Drug release is also dependent on the size of matrix tablets so, size and surface area was kept constant. Factorial batches F018, F019, F020, and F021 give the f2 value 75-100. Factorial batch F019 gives the highest f2 value 86.04 and also all the hour’s drug release was within the specified limits. Conclusion: The prepared formulation of Cisapride sustains release matrix tablet was stable and effective in treatment

New drugs in the treatment of bacterial infections

Introduction. The use of antibacterials has become increasingly strained due to increased rates of resistance & with less development of new agents. As a result, multi-, extensively-, and pan-drug resistant bacterial strains are now frequently encountered. Purpose. To highlight recently developed antibacterial medicines and their role in clinical practice. results. 11 new antibiotics that have been approved since 2017, New drug Pretomanid is an antimycobacterial indicated, as part of a combination regimen(fig-1). Cefiderocol for the treatment of urinary tract infections and acute pyelonephritis. Also as first-line therapy for Infection-related Ventilator-Associated Complications, Hospital-acquired pneumonia & Ventilator-associated pneumonia (fig 2). Ceftazidime-avibactam licensed for carbapenemase producers(fig 3). In adults specifically addressing the use of fidaxomicin and bezlotoxumab for the treatment of C. difficile infection (fig 4). Conclusions. New antibacterial agents are mainly derivatives of existing classes. There is a significant need for novel antibacterial drugs and research

Feasibility of Late Transplanted Summer Pearl Millet for Prolonged rabi Season With Integrated Nitrogen Management Under Indian Coastal Region

Experiments were conducted in coastal South Gujarat region of India to evaluate the feasibility of late transplanted summer pearl millet under prolonged rabi season with integrated nitrogen management (INM) during 2014, 2015 and 2016. INM treatments were consisted of four combinations of biocompost and inorganic nitrogen fertilizers. Two planting methods were evaluated, namely drilling and transplanting. Premature heading in transplanted pearl millet was observed up to 8-10% population during all the three experimental years, the possible causes for this are slow nitrogen availability, weather conditions, the thickness of the seedlings, root pruning and seedling age at transplanting. Application of 100% Recommended Dose of Fertilizer (RDF) + 5 t biocompost had significantly increased growth, yield (3862 kg ha-1), benefit-cost ratio (B:C ratio) (3.52) and quality of parameters of pearl millet followed by 75% Recommended Dose of Nitrogen (RDN) + 25% RDN through biocompost. Late transplanted summer pearl millet was little feasible to grow over timely drilled pearl millet as it had reduced pearl millet grain yield by 6.07% and also reduced the net profit by 72.46 US $ ha-1. However, overall, it was feasible to grow late transplanted pearl millet and gave yield up to 3150 kg ha-1 in prolonged rabi season condition for brining summer season well in time

Structural Basis of Cytotoxicity Mediated by the Type III Secretion Toxin ExoU from Pseudomonas aeruginosa

The type III secretion system (T3SS) is a complex macromolecular machinery employed by a number of Gram-negative pathogens to inject effectors directly into the cytoplasm of eukaryotic cells. ExoU from the opportunistic pathogen Pseudomonas aeruginosa is one of the most aggressive toxins injected by a T3SS, leading to rapid cell necrosis. Here we report the crystal structure of ExoU in complex with its chaperone, SpcU. ExoU folds into membrane-binding, bridging, and phospholipase domains. SpcU maintains the N-terminus of ExoU in an unfolded state, required for secretion. The phospholipase domain carries an embedded catalytic site whose position within ExoU does not permit direct interaction with the bilayer, which suggests that ExoU must undergo a conformational rearrangement in order to access lipids within the target membrane. The bridging domain connects catalytic domain and membrane-binding domains, the latter of which displays specificity to PI(4,5)P2. Both transfection experiments and infection of eukaryotic cells with ExoU-secreting bacteria show that ExoU ubiquitination results in its co-localization with endosomal markers. This could reflect an attempt of the infected cell to target ExoU for degradation in order to protect itself from its aggressive cytotoxic action

Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Pattern of expression of engrailed in relation to gamma-aminobutyric acid immunoreactivity in the central nervous system of the adult grasshopper.

Engrailed (En) protein expression in neurons of the mesothoracic and metathoracic ganglia of the adult grasshopper, Schistocerca americana, was examined by immunohistochemistry. Each neuromere had a dorsally located cluster of En-positive neurons within the dorsal unpaired median (DUM) group, comprising one cluster in the mesothoracic ganglion (T2) and four clusters in the metathoracic ganglion, one for each component neuromere (T3, A1, A2, A3). Ventrally, En-positive neurons occurred in the posterior one-third of each neuromere. In T2 and T3, three ventral groups of neurons were labeled bilaterally. In the abdominal neuromeres, many fewer ventral neurons were En-positive. These also were bilaterally symmetrical, but did not occur in patterns that allowed assignment of homology with the T2 and T3 groups. Altogether, En-positive neurons comprised roughly 10% of the ganglionic populations. In the bilateral groups, as in the DUM groups, En expression was restricted to interneurons, consistent with the suggestion that En expression contributes to some aspect of interneuronal phenotype. En-positive neurons in the DUM groups also expressed gamma-aminobutyric acid (GABA) immunoreactivity. Further study showed that all neurons in one En-positive bilateral group and some neurons in another bilateral group were GABA immunoreactive, but that neurons in a third bilateral group were En-positive only. Additionally, several discrete clusters of neurons were GABA-immunoreactive but En-negative. A provisional morphological scheme is presented, which relates the several neuronal clusters to their likely neuroblasts of origin, as a basis for further research into the composition of neuronal lineages