Single Regimen Research Articles

Implementing best practices on data generation and reporting of Mycobacterium tuberculosis in vitro assays within the ERA4TB consortium

Tuberculosis (TB) is the historical leading cause of death by a single infectious agent. The European Regimen Accelerator for Tuberculosis (ERA4TB) is a public-private partnership of 30+ institutions with the objective to progress new anti-TB regimens into the clinic. Thus, robust and replicable results across independent laboratories are essential for reliable interpretation of treatment efficacy. A standardization workgroup unified invitro protocols and data reporting templates. Time-kill assays provide essential input data for pharmacometric model-informed translation of single agents and regimens activity from invitro to invivo and the clinic. Five conditions were assessed by time-kill assays in six independent laboratories using four bacterial plating methods. Baseline bacterial burden varied between laboratories but variability was limited in net drug effect, confirming 2.5μL equally robust as 100μL plating. This exercise establishes the foundations of collaborative data generation, reporting, and integration within the overarching Antimicrobial Resistance Accelerator program.

One-compartment stochastic pharmacokinetic model

In this work, we consider a pharmacokinetic (PK) model with first-order drug absorption and first-order elimination that represent the concentration of drugs in the body, including both the absorption and elimination parts, and we also add a random factor to describe the variability between patients and the environment. Using Itô’s lemma and the Laplace transform, we obtain the solutions in integral form for a single and constant dosage regimen in time. Moreover, formulas for the expected value and the variance for each case of study are presented, which allows the statistical assessment of the proposed models, as well as predicting the ideal path of drug concentration and its uncertainty. These results are important in the long-term analysis of drug concentration and the persistence of therapeutic level. Further, a numerical method for the solution of the stochastic differential equation (SDE) is introducedand developed.

Compare the Effectiveness of Carbimazole Single Dose and Divided Dose Regimens for Euthyroid Induction in Hyperthyroid Patients

Objective: The purpose of the current study was to examine the effectiveness of carbimazole administered as a single dose with a divided dose regimen for inducing euthyroidism in hyperthyroid patients. Study Design: Prospective/Randomized study Place and Duration: This Prospective/Randomized study was conducted at Khyber Teaching Hospital Peshawar in the duration from June, 2022 to November, 2022. Methods: There were 92 patients of hyperthyroidism were presented in this study. Age, sex, BMI, and residency details for each enrolled case were recorded after receiving informed written consent. Patients were divided into two groups equally. Carbimazole (OD-CMZ) was administered as a single dosage to 46 patients in group I, and as two separate doses to 46 patients in group II (DD-CMZ). For six months, the effectiveness of the treatment was monitored on a regular basis (every four weeks). SPSS 22.0 was used to analyze all data. Results: There were 54 (58.7%) females and 38 (41.3%) males in this study. In group I mean age was 35.13±6.60 years and in group II mean age was 40.10±8.86 years. Mean duration of disease was 3.6±10.57 months in group I and in group II mean duration was 4.3 ±8.35 months. There was no discernible difference between the two groups in terms of baseline TSH and T4 concentrations or their cumulative rates of reduction (p-value, 0.014). Frequency of euthyroidism in group I after final follow up was 46 (100%) and in group II found in 45 (97.8%) cases but difference is insignificance. Conclusion: In this study, we came to the conclusion that a single dosage regimen is a more effective way to treat hyperthyroidism since there is no discernible difference in efficacy and a greater risk of developing hypothyroidism with a split dose strategy. Keywords: Hyperthyroidism, Drug therapy, Single dose, Carbimazole, Multidose

Efficacy of sequential perioperative FOLFIRNOX plus gemcitabine nab-paclitaxel for resected pancreatic and periampullary cancers.

724 Background: Perioperative chemotherapy with single regimen either FOLFIRINOX (FFX) or gemcitabine/nab-paclitaxel (Gem/NabP) is the current standard of care for pancreatic and periampullary cancers (PC) with overall survival (OS) of 2-3 years without pre-selected CA19-9 level. Sequential chemotherapy with FFX plus Gem/NabP has recently been investigated in metastatic PC and shown to improve OS. We investigated the outcome of patients who received sequential perioperative chemotherapy FFX plus Gem/NabP. Methods: Patients treated with curative intent surgery for PC who received perioperative sequential chemotherapy FFX plus Gem/NabP (each regimen was given at least two months) were identified. OS and recurrence-free survival (RFS) were calculated from the date of initial treatment (neoadjuvant chemotherapy or resection) to the date of last follow-up/death or recurrence via Kaplan-Meier analysis. Results: A total of 29 patients were identified: 24 (83%) patients had pancreatic cancer, 5 (17%) patients had periampullary cancer; 16 (55%) patients received neoadjuvant chemotherapy FFX plus Gem/NabP; 13 (45%) patients underwent upfront surgery and received adjuvant FFX plus Gem/NabP chemotherapy; 22 (76%) patients had resectable disease, the rest 7 (24%) patients had borderline or unresectable disease were all in the neoadjuvant cohort; node positivity was higher in the adjuvant cohort (n=8, 62%) than in the neoadjuvant cohort (n=8, 50%); 5 (17%) patients were found to have homologous recombination deficiency (HRD: BRCA2, CHEK, BARD, ATM) and received PARP inhibitors as part of the perioperative therapy combination. 10 (34%) patients had CA19-9 ≥ 500. Median age was 65 years (range, 45-79 years), 20 (69%) were male. During the study period, 4 (14%) patients died, and 6 (21%) patients had disease recurrence. Median RFS and OS were not reached with a median follow-up of 28 months (range, 10.9–119 months). The longest RFS was 10 years. The 2-years RFS and OS for the entire cohort was 76.7% and 88.8%, respectively. There was no statistical difference in RFS (log rank HR 1.72, 95% CI 0.23-13.15) or OS (log rank HR 0.99, 95% CI 0.20-4.93) for patients in the neoadjuvant cohort versus adjuvant cohort. Conclusions: Sequential perioperative chemotherapy combined FFX plus Gem/NabP for resected PC is effective and potentially prolongs survival, compared to historical controls who received single regimen.[Table: see text]

RON Receptor Tyrosine Kinase in Tumorigenic Stemness as a Therapeutic Target of Antibody-drug Conjugates for Eradication of Triple-negative Breast Cancer Stem Cells.

Cancer stem-like cells in triple-negative breast cancer (TNBC-SLCs) are the tumorigenic core for malignancy. Aberrant expression of the RON receptor tyrosine kinase has implications in TNBC tumorigenesis and malignancy. In this study, we identified the RON receptor as a pathogenic factor contributing to TNBC cell stemness and validated anti-RON antibody-drug conjugate Zt/g4-MMAE for eradication of RONexpressing TNBC-SLCs. Immunofluorescence and Western blotting were used for analyzing cellular marker expression. TNBC-SLCs were isolated by magnetic-immunofluorescence cell-sorting techniques. Spheroids were generated using the ultralow adhesion culture methods. Levels of TNBC-SLC chemosensitivity were determined by MTS assays. TNBC-SLC mediated tumor growth was determined in athymic nude mice. The effectiveness of Zt/g4-induced RON internalization was measured by immunofluorescence analysis. Efficacies of Zt/g4-MMAE in killing TNBC-SLCs in vitro and in eradicating TNBC-SLCmediated tumors were determined in mouse models. All data were statistically analyzed using the GraphPad Prism 7 software. Increased RON expression existed in TNBC-SLCs with CD44+/CD24- phenotypes and ALDH activities and facilitated epithelial to mesenchymal transition. RON-positive TNBC-SLCs enhanced spheroid-formatting capability compared to RON-negative TNBC-SLCs, which were sensitive to small molecule kinase inhibitor BMS-777607. Increased RON expression also promoted TNBC-SLC chemoresistance and facilitated tumor growth at an accelerated rate. In vitro, Zt/g4-MMAE caused massive TNBC-SLC death with an average IC50 value of ~1.56 μg per/ml and impaired TNBC cell spheroid formation. In mice, Zt/g4-MMAE effectively inhibited and/or eradicated TNBC-SLC mediated tumors in a single agent regimen. Sustained RON expression contributes to TNBC-SLC tumorigenesis. Zt/g4-MMAE is found to be effective in vivo in killing TNBC-SLC-mediated xenograft tumors. Our findings highlight the feasibility of Zt/g4-MMAE for the eradication of TNBC-SLCs in the future.

Multifunctional Integrated Nanozymes Facilitate Spinal Cord Regeneration by Remodeling the Extrinsic Neural Environment.

High levels of reactive oxygen species (ROS) and inflammation create a complicated extrinsic neural environment that dominates the initial post-injury period after spinal cord injury (SCI). The compensatory pathways between ROS and inflammation limited the efficacy of modulating the above single treatment regimen after SCI. Here, novel "nanoflower" Mn3 O4 integrated with "pollen" IRF-5 SiRNA was designed as a combination antioxidant and anti-inflammatory treatment after SCI. The "nanoflower" and "pollen" structure was encapsulated with a neutrophil membrane for protective and targeted delivery. Furthermore, valence-engineered nanozyme Mn3 O4 imitated the cascade response of antioxidant enzymes with a higher substrate affinity compared to natural antioxidant enzymes. Nanozymes effectively catalyzed ROS to generate O2 , which is advantageous for reducing oxidative stress and promoting angiogenesis. The screened "pollen" IRF-5 SiRNA could reverse the inflammatory phenotype by reducing interferon regulatory factors-5 (IRF-5) expression (protein level: 73.08% and mRNA level: 63.10%). The decreased expression of pro-inflammatory factors reduced the infiltration of inflammatory cells, resulting in less neural scarring. In SCI rats, multifunctional nanozymes enhanced the proliferation of various neuronal subtypes (motor neurons, interneurons, and sensory neurons) and the recovery of locomotor function, demonstrating that the remodeling of the extrinsic neural environment is a promising strategy to facilitate nerve regeneration.

Adherence to Capecitabine Among Patients With Gastrointestinal Cancer: A Prospective Cohort Study

Adherence to capecitabine, an effective oral chemotherapy agent, is essential in achieving treatment response in cancer. In this study, we aimed to investigate factors associated with non-adherence to capecitabine in a sample of patients with gastrointestinal cancer. We enrolled 98 patients with colon, rectal or gastric cancers who were undergoing treatment with capecitabine as part of their single or multi-agent chemotherapy regimen. The patients were followed during cohort time up to four consecutive cycles of their chemotherapy. For adherence measurement, the participants were asked to bring back the leftover medicines at the time of follow-up visits and were considered adherent if they had taken ≥95% of their prescribed dose. The mean adherence rate was 97.7%, and the patients were adherent to capecitabine in 93.1% of their cycles. The patients who underwent neoadjuvant chemotherapy were significantly less adherent to capecitabine (60%) as compared with adjuvant (95.2%) and palliative chemotherapy (94.6%) [P=0.004]. Multivariable logistic regression revealed that neoadjuvant chemotherapy and the presence of nausea and mucositis were inversely associated with adherence rate. We did not find any association between adherence and any of our laboratory findings. Our findings suggest a high adherence rate to capecitabine among patients with gastrointestinal cancers. Neoadjuvant chemotherapy and the presence of nausea and mucositis may play a significant role in non-adherence to capecitabine.

Factors Associated with Preferences for Long-Acting Injectable Antiretroviral Therapy Among Adolescents and Young People Living with HIV in South Africa

Long-acting injectable anti-retroviral therapy (LAART) may overcome barriers to long-term adherence and improve the survival of adolescents and young people living with HIV (AYLHIV). Research on the acceptability of LAART for this age-group is limited. We asked 953 AYLHIV about their preferred (theoretical) ART mode of delivery (pill, injectable, or other) in 2017–2018, before LAART was available or known to AYLHIV in South Africa. One in eight (12%) AYLHIV preferred LAART over single or multiple pill regimens. In multivariate analyses, six factors were associated with LAART preference: medication stock-outs (aOR = 2.56, 95% CI 1.40–4.68, p = 0.002), experiencing side-effects (aOR = 1.84, 95% CI 1.15–2.97, p = 0.012), pill-burden (aOR = 1.88, 95% CI 1.20–2.94, p = 0.006), past-year treatment changes (aOR = 1.63, 95% CI 1.06–2.51, p = 0.025), any HIV stigma (aOR = 2.22, 95% CI 1.39–3.53, p ≤ 0.001) and recent ART initiation (aOR = 2.02, 95% CI 1.09–3.74, p = 0.025). In marginal effects modelling, 66% of adolescents who experienced all factors were likely to prefer LAART, highlighting the potential high acceptability of LAART among adolescents and young people living with HIV struggling to adhere and have good HIV treatment outcomes. Adolescent boys who reported high ART pill burden were more likely to prefer LAART than their female peers in moderation analyses, suggesting that LAART may be particularly important to improve treatment outcomes among male AYLHIV as they become older. Adding LAART to existing treatment options for AYLHIV, particularly higher risk groups, would support AYLHIV to attain and sustain viral suppression—the third 95, and reduce their risk of AIDS-related mortality.

Mportance of Ritu-Charyain Healthy Living with specialreferenceto Basanta Ritu-Charya

As environmental properties change with the season, it influences our Tridosha constitution. Ayurveda described 6 Ritu(season) and described ritu-charya(seasonal regimen) for living a healthy lifestyle which is necessary for a healthy life. The foremost principle of Ayurveda tantra is to keep individuals healthy, this is an important aspect of preventive medicine in Ayurveda texts. Tridoshagets their different stages(gati) according to Ritu(season); sanchaya(accumulation), prakopa(elevation) and prashamna(alleviation). So particular ritucauses a particular effect on the doshastate, so when someone follows a single diet and lifestyle regimen the whole year this may cause health issues because lifestyle disorders are very common in the modern era and which are originating from ignoring seasonal regimens and following the same or opposite ahara-vihara.This causes Tridoshaimbalance and normal physiology changes into pathology as lifestyle disorders. In this article, various diet and lifestyle modifications and regimens as per ayurvedic texts, as well as their importance on lifestyle disorders are described.

Clinicomicrobiological Profile of Podiatric Infections: A Prospective, Cross-sectional Study

Introduction. Podiatric infections are common in patients with and without diabetes. Biofilm detection would aid in determining the severity of foot infections and preventive strategies to manage them. Objective. The authors studied the clinicomicrobiological profile of podiatric infections. Materials and Methods. Organisms from podiatric specimens were identified and the antibiotic susceptibility of the organisms determined using standard microbiological methods. Organisms were screened for biofilm production using the microtiter plate method. Staphylococcus aureus isolates were screened for ica, cna, and hlg genes by multiplex PCR. Results. A total of 117 patients were included in the study, and specimens from 71 patients were culture positive (60.6%). Gram-negative bacteria were predominant (n = 88 [73.3%]). S aureus (n = 32 [26.7%]) was the most common isolate. The rate of biofilm production was 54.2%. Pseudomonas aeruginosa was the most prevalent biofilm producer (82.8%). The study revealed a statistically significant association of biofilm formation with MDR, MRSA, and prior antibiotic therapy with multiple (≥4) antibiotics. Conclusion. Isolation of MRSA or MDR strain from diabetic foot infections could alert the clinician to the possibility of treatment failure with a single drug regimen owing to associated biofilm production. Detection of biofilm producers and subsequent early debridement and/or cleaning of wounds might prevent chronic infection.

Discovery of rigid biphenyl Plasmodium falciparum DHFR inhibitors using a fragment linking strategy.

Plasmodium falciparum dihydrofolate reductase (PfDHFR), a historical target for antimalarials, has been considered compromised due to resistance inducing mutations caused by pyrimethamine (PYR) overexposure. The clinical candidate P218 has demonstrated that inhibitors could efficiently target both PYR-sensitive and PYR-resistant parasites through careful drug design. Yet, P218 clinical development has been limited by its pharmacokinetic profile, incompatible with single dose regimen. Herein, we report the design of new PfDHFR inhibitors using fragment-based design, aiming at improved lipophilicity and overall drug-like properties. Fragment-based screening identified hits binding in the pABA site of the enzyme. Using structure-guided design, hits were elaborated into leads by fragment linking with 2,4-diaminopyrimidine. Resulting compounds display nM range inhibition of both drug-sensitive and resistant PfDHFR, high selectivity against the human isoform, drug-like lipophilicity and metabolic stability. Compound 4 and its ester derivative 3 kill blood stage TM4/8.2 parasite at nM concentrations while showing no toxicity against Vero cells.

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

PS-BPB05-2: ENDOTHELIN A RECEPTOR BLOCKADE INCREASES RENOPROTECTION IN EXPERIMENTAL MODEL OF CONGESTIVE HEART FAILURE COMBINED WITH CHRONIC KIDNEY DISEASE

Objective: Congestive heart failure (CHF) represents an extreme burden to the public healthcare worldwide. The incidence and prevalence of chronic kidney disease (CKD) is also increasing and CKD is known as one of the strongest risk factors for the development of CHF. CHF coexists with CKD in approximately half of CHF patients and results in a poor survival rate. The aim of this study was therefore to examine if the addition of endothelin type A (ETA) receptor antagonist atrasentan (5 mg/kg/day) to the angiotensin-converting enzyme inhibitor (ACEi trandolapril; 2 mg/L) will bring additional beneficial effects. Design and Methods: CKD was induced by 5/6 renal mass reduction (5/6 NX) at the age of 8 weeks and CHF was elicited by volume overload achieved by the creation of aortocaval fistula (ACF) four weeks later in normotensive Hannover Sprague Dawley rats. The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF. Results: The final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, with no significant difference between the combination and either single treatment regimen. At the end of the study, atrasentan or trandolapril given alone partially reduced albuminuria, but had no effect on albumin/creatinine ratio. In contrast, both parameters were substantially improved by the combined treatment which caused ∼45 % reduction in albuminuria. Moreover, it also reduced markers of renal damage. Conclusions: Our results demonstrated that the treatment with ETA receptor antagonist attenuated the mortality related to CKD or CHF and that the addition of ETA receptor antagonist to the standard blockade of renin angiotensin system by ACEi exhibited additional renoprotective actions.

A revisit to practice of antibiotic prophylaxis in caesarean section

Background: Women undergoing cesarean delivery are 5-20 fold greater risk of infection than women undergoing vaginal delivery. Infectious complications after cesarean delivery are an important cause of maternal morbidity, increase in hospital stay and cost of treatment. The use of antibiotic prophylaxis for cesarean section can reduce the incidence of postoperative infectious morbidity.Material and Methods: This was a prospective case control study involving 140 women undergoing cesarean delivery for various indications, who were divided into two groups, Group A and B with 70 patients in each which was conducted at Maharajah’s Institute Of Medical sciences, vizianagaram, Andhra Pradesh for duration of 1 year. Group A received antibiotic prophylaxis of ceftriaxone 1gm IV 30 minutes before skin incision and another dose at 24 hours, Group B received Ceftriaxone 1gm IV 30 minutes before cesarean section, followed by Ceftriaxone 1gm+ Metronidazole 100ml IV 8th hourly for 48 hours followed by oral cefixime till suture removal. Postoperatively, both groups of patients were followed up for febrile and infectious morbidity and neonatal outcome was followed during hospital stay for infectious morbidity.Results: Total of 140 patients were analysed in both groups of 70 patients in each. Baseline characteristics like age, parity, gestational age, socioeconomic status, were similar in both groups. Postoperative morbidities like Febrile morbidity and surgical site infection (p=0.8) did not differ significantly. The neonatal infectious morbidity in both groups (p=0.66) and recovery was uneventful. Conclusion: Double dose of single antibiotic regimen was equally effective as compared to multiple doses of multiple drugs and extended antibiotic therapy. We can cut down on antibiotic misuse among parturients which has implications in global emergence of antibiotic resistant bacteria and epigenetic and allergic diseases in the offspring.

Clinical Effectiveness of Tetracycline-Class Agents Based Regimens in Patients With Carbapenem-Resistant Acinetobacter baumannii Bacteremia: A Single-Center Retrospective Cohort Study.

This study evaluated the clinical outcome of carbapenem-resistant Acinetobacter baumannii (CRAB) bacteremia and the clinical effectiveness of tetracyclines-based therapy. In a retrospective cohort study over 5 years period, 108 patients were included in the study. The overall 30-day mortality rate was 71.4%. Pitt's bacteremia score (PBS) (adjusted hazard ratio [aHR], 1.32; 95% confidence interval [CI], 1.22-1.42 per 1-point), colistin-single regimens (aHR, 0.34; 95% CI, 0.17-0.69), and tetracyclines single/tetracyclines-colistin combination regimens (aHR, 0.18; 95% CI, 0.07-0.48) were independently associated with 30-day mortality. Among patients with a PBS < 6, only tetracycline-containing regimens were associated with decreased mortality. Among patients receiving appropriate definite antimicrobials, the tetracyclines-colistin combination (7 of 7, 100%) tended to a higher 30-day survival rate compared to a tetracycline (7 of 12, 57.1%) or colistin single regimen (10 of 22, 41.6%, P = 0.073). Our findings suggest tetracyclines might be effective for treating CRAB infections when combined with colistin.

Endothelin type A receptor blockade increases renoprotection in congestive heart failure combined with chronic kidney disease: Studies in 5/6 nephrectomized rats with aorto-caval fistula

BackgroundAssociation of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient’s prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ETA) receptor antagonist to the angiotensin-converting enzyme inhibitor (ACEi) will bring additional beneficial effects in experimental rats. MethodsCKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation. ResultsThe final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, however, the difference between the combination and either single treatment regimen was not significant. The combined treatment exerted best renoprotection, causing additional reduction in albuminuria and reducing renal glomerular and tubulointerstitial injury as compared with ACE inhibition alone. ConclusionsOur results show that treatment with ETA receptor antagonist attenuates the CKD- and CHF-related mortality, and addition of ETA receptor antagonist to the standard blockade of RAS by ACEi exhibits additional renoprotective actions.

Final Results from a Phase2b Randomized, Placebo-Controlled Clinical Trial of RBX2660: A Microbiota-Based Drug for the Prevention of Recurrent Clostridioides difficile Infection.

Effective treatments for recurrent Clostridioides difficile infection (rCDI) are urgently needed. RBX2660 is an investigational microbiota-based live biotherapeutic to reduce CDI recurrence following standard-of-care antibiotic treatment in individuals with rCDI. Here we report the final safety data through 24months of follow-up as well as final efficacy data, reflecting alignment of the pre-specified statistical analysis plan definitions with the data presented. The PUNCHCD2 clinical trial was a prospective, multicenter, randomized, double-blinded, placebo-controlled, three-arm phase2b study conducted to evaluate the efficacy and safety of RBX2660 for the reduction of rCDI compared to placebo. Eligible patients were at least 18years of age and had at least three episodes of CDI and at least two rounds of standard antibiotic treatment or had at least two episodes of severe CDI resulting in hospitalization. Patients were randomized 1:1:1 to groupA, two doses of RBX2660; groupB, two doses of placebo; or groupC, one dose of RBX2660 and one dose of placebo; all administered 7 ± 2days apart. Treatment success was prevention of recurrence, defined as absence of diarrhea and no re-treatment for CDI any time after the first dose until 8weeks after the second dose of the study treatment. Safety was assessed by reports of adverse events and symptoms. The final efficacy and safety are reported for data available through 24months. For the primary endpoint, treatment success at 8weeks, 56.8% (25/45) of participants who received one dose of RBX2660 + one dose of placebo, 55.6% (25/45) of participants who received two doses of RBX2660, and 43.2% (19/44) of participants who received two doses of placebo in the final intention-to-treat (ITT) population were responders (both p = 0.2 vs placebo). In the per-protocol population, 87.5% (21/24) of participants who received one dose of RBX2660 + one dose of placebo and 58.1% (18/31) of those who received two doses of placebo had treatment success (p = 0.017; treatment difference, 29.4 [95%CI 7.6, 51.3]); 75.0% (21/28) of participants in the PP population who received two doses of RBX2660 were responders (p = 0.17 vs placebo). The safety profile of RBX2660, whether delivered as one or two doses, was similar to the placebo group. While the phase2b PUNCHCD2 clinical trial did not meet its pre-defined primary endpoint of treatment success at 8weeks after two doses of RBX2660 vs two doses of placebo, clinically meaningful data were obtained to justify proceeding with the single dose regimen in the phase3 clinical trial, PUNCHCD3, now complete. To date, the cumulative data for RBX2660 demonstrate consistent efficacy and safety outcomes for reduction of CDI recurrence in adults. ClinicalTrials.gov: NCT02299570.

Clinical characteristics and outcomes of non-cystic fibrosis patients with Burkholderia cepacia complex bacteremia at a medical center in Taiwan.

Burkholderia cepacia complex (BCC) represents a group of multidrug-resistant gram-negative bacteria that cause infections among immunocompromised hosts. Bacteremia occurs in patients who are chronically ill and is associated with substantial morbidity and mortality. The aim of this study was to investigate the clinical characteristics and outcomes of BCC bacteremic patients without cystic fibrosis. We conducted a retrospective study at the National Taiwan University Hospital. Adults with BCC bacteremia from January 2015 to May 2019 were enrolled. The primary outcome was 14-day mortality. Multivariable logistic regression was performed for outcome analysis. One-hundred and ninety-five patients were analyzed and their mean age was 67 years. Over 95% of the BCC isolates were susceptible to trimethoprim/sulfomethoxazole (TMP/SXT). Levofloxacin resistance rates were high, with only 25.1% of isolates being susceptible. Pairwise comparisons were made between different definitive regimens including meropenem-monotherapy, ceftazidime-monotherapy, levofloxacin-monotherapy, TMP/SXT-monotherapy, tigecycline-monotherapy as well as combination versus monotherapy. No regimen was significantly associated with survival in our study. Multivariable logistic regression showed that the Pitt bacteremia score (adjust odds ratio [aOR],1.46; 95% confidence interval [CI],1.19-1.79; p<0.001), underlying metastatic cancer (aOR, 2.73; 95% CI, 1.01-7.39; p=0.047), inappropriate definitive treatment independently predicted greater 14-day mortality (aOR, 8.21; 95% CI, 2.49-27.08; p<0.001). No single regimen is associated with improved mortality. After adjusting for other potential confounders, our data suggest selection of an appropriate antibiotic provide better clinical outcomes among patients with BCC bacteremia.

The role of topical capsaicin gel in pain management during microfocused ultrasound treatment for neck laxity.

The transient receptor potential vanilloid 1 (TRPV1) provides a heat and pain sensation (nociception). Capsaicin, a TRPV1 agonist, has been shown to induce a refractory period in the nerve terminal expressing TRPV1 and create long-term nerve terminal defunctionalization. To evaluate the efficacy of capsaicin for pain reduction during microfocused ultrasound with visualization (MFU-V) treatment. A randomized, split-side study including 24 subjects was conducted. A combined 0.025% capsaicin gel and topical anesthetic were randomly applied on one side of the neck, and a topical anesthetic monotherapy was applied on the contralateral side for 30 min before MFU-V treatment. Pain score (visual analog scale, 0-10) was evaluated at T1 (before MFU-V), T2a (after the 4.5-mm transducer treatment), T2b (after the 3.0-mm transducer treatment), and T3 (after the entire treatment). Side effects were recorded. Mean pain scores at T2a for combined and single regimens were 5.19 (±2.26) and 6.91 (±1.72), respectively (p<0.001). The capsaicin-treated side had a lower pain score at T2b and T3 (p<0.001). Redness was longer on the capsaicin-treated side (112.67vs. 10.68 min, p<0.001). No other adverse events including contact dermatitis were reported. A single application of a combined 0.025% capsaicin gel with topical anesthesia produces a significantly lesser pain score during the MFU-V treatment. Defunctionalization of TRPV1 may explain the alleviation of painful sensations caused by heat from MFU-V.

"Big Boom" (4 Gy x 1) Radiation Treatment (RT) Versus "Big Boom" (2 Gy x 2) for Non-Hodgkin Lymphoma (NHL)

Purpose/Objectives Indolent lymphomas are exquisitely sensitive to radiation. Recently, programs of only 4 Gy in 2 daily fractions (Boom-Boom) were shown to be highly effective in controlling irradiated site(s). During the COVID-19 pandemic, the International Lymphoma Radiation Oncology Group (ILROG) proposed guidelines that allowed substitution of the Boom Boom (2 Gy x 2) regimen with Big Boom single fraction regimen of only 4 Gy. This report compares our center's experience with Big Boom to Boom-Boom. Materials/Methods All consecutive indolent lymphomas were included. After April 2020 both options of very low dose as well as choice of a standard full dose of 24 Gy were discussed with the patient and choice was made with consideration of access logistics, patient preference as well as disease site(s). Patients were treated with a definitive or palliative intent depending on disease stage and prior therapy exposure. Patients treated with 24 Gy are not included in this report. Overall response rate was assessed with Lugano PET criteria at the initial post-RT imaging. Differences between the two groups were examined using the Fisher's exact test and Mann-Whitney test. Results We evaluated a total of 440 lesions in 363 patients, including 142 lesions (32%) treated with 4 Gy x 1 ("Big Boom") and 298 lesions (67%) treated with 2 Gy x 2 ("Boom Boom"). Table 1 summarizes the patient and treatment characteristics. Patient age at the time of RT, sex, and the proportion of treated lesions with maximum axial diameter of greater than 5 cm were not significantly different between the two groups. Marginal zone lymphoma comprised 27% of each cohort. The Big Boom cohort was more likely to have follicular lymphomas (66% vs 52%, p = 0 .003), though the proportion of higher-grade follicular lymphomas was similar between cohorts. The overall response rate was 87% for both groups at the first post-RT evaluation (median of 2 months from RT for both cohorts). Furthermore, there was no significance difference in the rate of complete response, partial response, stable disease, or progressive disease between the cohorts at initial post-RT imaging. For both regimens, no directly related short-term side effects were observed. Conclusions Both the Big Boom and Boom Boom regimens demonstrated excellent overall response rates at the initial post-RT imaging assessment among patients with indolent lymphomas. While longer term follow-up is required to confirm durability of these findings, our initial experience suggests that the single dose, single visit Big Boom regimen (4 Gy x 1) recommended by ILROG during the Covid-19 pandemic is an effective treatment approach. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal