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Introduction: Advancements in monoclonal antibodies, tyrosine kinase inhibitors, and antibody drug conjugates (ADCs) have notably enhanced outcomes for metastatic HER2-positive breast cancer patients. Despite the expanding treatment options and clinical complexities, determining the optimal sequence of HER2-targeted therapies remains partly uncertain, influenced by various factors., Methods: To refine HER2-positive metastatic breast cancer management, particularly regarding tucatinib's position, a Steering Committee of leading oncologists in breast cancer care devised a panel of statements via a Delphi approach, focusing on five key topics: general clinical management, therapeutic approaches for patients with HER2-positive breast cancer and brain metastases, treatment sequence, and tucatinib's safety and efficacy., Results: A total of 29 statements were deliberated, with strong consensus achieved for most. However, no consensus emerged regarding the management of brain progression alongside stable extracranial disease: 48 % advocated for switching to tucatinib, while 53 % favored a stereotactic brain radiotherapy (SBRT) approach if feasible., Conclusion: The unanimous consensus attained in this Delphi panel, particularly regarding tucatinib's efficacy and safety, underscores oncologists' recognition of its clinical significance based on existing trial data. These findings align closely with current literature, shedding light on areas necessitating further investigation, not thoroughly explored in prior studies. Moreover, the results underscore the scarcity of data on managing brain progression alongside stable extracranial disease, emphasizing the imperative for dedicated research to address these gaps and yield definitive insights., Competing Interests: Declaration of competing interest PC: Consulting or Advisory Role: Daiichi Sankyo/Lilly, Reveal Genomics, Gilead Sciences; Speakers' Bureau: Roche/Genentech, Novartis, AstraZeneca, Lilly, BMS; Research Funding: Merck KGaA (Inst); Patents, Royalties, Other Intellectual Property: HER2Dx patent; Expert Testimony: AstraZeneca. EC: reports consulting fees from Novartis, Lilly, Pfizer, Roche, AstraZeneca, and Daiichi Sankyo; speaker's bureau from Lilly, Pfizer, AstraZeneca, and Daiichi Sankyo; and travel and accommodations from Pfizer and Roche. GC: received honoraria for speaker's engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; Honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; Honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medi-cine, Samsung, Celltrion, Mylan; Honoraria for writing engagement: Novartis, BMS; Honoraria for participation in Ellipsis Scientific Affairs Group; Institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, MedI- mmune MDL: advisory boards, activities as a speaker, travel grants, consultancy: Eli Lilly, Novartis, Seagen, Takeda, Roche, Daiichi Sankyo, Tomalab, Gilead, Genetic, Menarini, Sophos, AstraZeneca, Pfizer, Sanofi, Ipsen, Pierre Fabre, GSK. AG: research funding to the Institution: AstraZeneca, Pfizer, Janssen, Roche, MSD, Daichii-Sankyo, GSK/Tesaro, HiFiBio, Merck, Boehringer-Ingelheim, Exelixis, Bayer, Incyte, Bayer, Aileron; travel, accommodation, expenses: Gentili. LDM: advisory role for Agendia, Amgen, AstraZeneca, Collage SpA, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Havas Life, Pfizer, Pierre Fabre, Roche, Seagen Int, Stemline Menarini and Uvet; personal fees as an invited speaker for Accademia Nazionale Medicina, Andromeda E20, Aristea, Delphi international, Editree, Eli Lilly, Ipsen, Meeting SrL, MSD, Novartis, Over Srl, Prex Srl, Symposia and Vyvamed Srl; personal fees for writing engagements for Edizioni Minerva Medica, Pensiero Scientifico Editore and Roche; personal consultancy fees from Eli Lilly, Gilead, Kardo Srl and Sharing Progress in Cancer Care (SPCC)—Switzerland; personal fees for author slide kits from Forum service and Think2it; personal fees for interviews from Infomedica Srl and Think2it; institutional funding as a local PI from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Novartis, Novella Clinical, Roche and Seagen; institutional funding as a national coordinating PI from Roche; institutional research grant from Pfizer; and non-remunerated product samples from FoundationOne. AG: received advisory role from AstraZeneca, Daiichi, Eisai, Lilly, Novartis, Pfizer, Roche, Seagen, Gilead, Teva, and Gentili; lecture honoraria from Novartis, Pfizer, Gilead, Roche, Eisai, Seagen, Teva, and Gentili; and research support from Roche, Eisai, Gilead, and Pharmanutra AL: Research support: Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp&Dhome, Gilead, Daiichi Sankyo; Consulting/advisor: Lilly, Roche, Pfizer, Novartis; Speaker's Bureaus: Lilly, Astrazeneca, Merck Sharp&Dhome, Pfizer, Novartis; Travel support: Roche, Pfizer, Astrazeneca, Merck Sharp&Dhome. MM: Honoraria: Roche/Genentech, Lilly, Pfizer, Novartis, Pierre Fabre, Seagen; Consulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi-Sankyo; Speakers' Bureau: Lilly/ImClone, Lilly/ImClone, Roche/Genentech, Pierre Fabre; Research Funding: Novartis (Inst), Roche (Inst), Puma Biotechnology (Inst); Travel, Accommodations, Expenses: Daiichi-Sankyo; Other Relationship: Roche, Novartis. FPo: advisory board from AstraZeneca; speaking honoraria and travel grants from Eli Lilly, Novartis, Seagen, Daichii Sankyo, and Gilead. AP: reports grants and personal fees from NanoString Technologies, Veracyte, Novartis, AstraZeneca, DaiichiSankyo, and Roche; in addition, A. Prat has a patent for DNADX pending. FPu: reports honoraria for advisory boards, activities as a speaker, travel grants, research grants from Amgen - Astrazeneca - Daiichi Sankyo - Celgene - Eisai - Eli Lilly- Exact Sciences- Gilead - Ipsen – Menarini- MSD - Novartis - Pierre Fabre - Pfizer - Roche - Seagen - Takeda – Viatris; Research funding from Astrazeneca – Eisai – Roche. CS: consultancy or advisory role for AstraZeneca, Ax's Consulting, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter, F. Hoffmann-La Roche Ltd., International Society for the Study and Exchange of evidence from Clinical research And Medical experience (ISSECAM), Medical Statistics Consulting, MediTech, Merck Sharp and Dohme Corp, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche, Sanofi, Seagen, Zymeworks, and research funding from Aragon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Byondis, CytomX, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Genentech, German Breast Group Forchungs, GlaxoSmithKline, Immunomedics, Innoup, International Breast Cancer Study Group (IBCSG), Lilly, Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merck Sharp and Dohme Corp, Merus, Millennium, Novartis, Pfizer, Piqur, Puma, Roche, Sanofi, Seagen, Synthon, and Zenith., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The treatment of multidrug-resistant tracheobronchial tuberculosis poses challenges, and research investigating the efficacy of bedaquiline or delamanid as treatment for this condition is limited. This retrospective cohort study was conducted from 2017 to 2021. The study extracted data of patients with multidrug-resistant tracheobronchial tuberculosis from medical records and followed up on prognoses. Participants were divided into three groups: the bedaquiline, delamanid, and control group. Clinical outcomes and the risk factors associated with early culture conversion were analyzed. This study included 101 patients, with 32, 25, and 44 patients in the bedaquiline, delamanid, and control groups respectively. The differences in the treatment success rates among the three groups did not show statistical significance. Both the bedaquiline and delamanid groups had significantly higher culture conversion rates compared to the control after 2 or 6 months of treatment, with significantly shorter median times to culture conversion (bedaquiline group: 2 weeks, delamanid group: 2 weeks, control group: 12 weeks, P < 0.001). Treatment with bedaquiline or delamanid were identified as independent predictors of culture conversion at 2 months (bedaquiline group: aOR = 13.417, 95% CI 4.067-44.260, delamanid group: aOR = 9.333, 95% CI 2.498-34.878) or 6 months (bedaquiline group: aOR = 13.333, 95% CI 3.379-52.610, delamanid group: aOR = 5.000, 95% CI 1.357-18.426) of treatment through multivariable logistic regression analyses. The delamanid group showed better improvement in lumen stenosis compared to bedaquiline. Regimens containing bedaquiline or delamanid may accelerate the culture conversion during the early treatment phase in multidrug-resistant tracheobronchial tuberculosis, and delamanid appears to have the potential to effectively improve airway stenosis., (© 2024. The Author(s).)

Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.

Background: Pharmacokinetic studies of bedaquiline and delamanid in patients with pre-extensively drug-resistant tuberculosis (pre-XDR TB) will help in the optimization of these drugs for both culture conversion and adverse events., Methods: A prospective cohort of 165 adult patients (56% male with mean [SD] age 29 [9.7] years) with pre-XDR TB was treated with bedaquiline, delamanid, clofazimine, and linezolid for 24 weeks at 5 sites in India. Bedaquiline was administered at 400 mg daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks, whereas delamanid was administered at 100 mg twice daily. In 23 consenting participants at 8 and 16 weeks of treatment, blood was collected at 0, 2, 4, 5, 6, 8, 12, and 24 hours postdosing for an intense pharmacokinetic study. Pharmacokinetic parameters were correlated with sputum culture conversion and adverse events., Results: The mean (SD) age and weight of patients were 30 (10) years and 54 kg, respectively. The median minimum concentration (C min ) and time-concentration curve (AUC) for bedaquiline, respectively, were 0.6 mcg/mL and 27 mcg/mL·h at week 8 and 0.8 mcg/mL and 36 mcg/mL·h at week 16, suggesting drug accumulation over time. The median C min and AUC of delamanid, respectively, were 0.17 mcg/mL and 5.1 mcg/mL·h at week 8 and 0.20 mcg/mL and 7.5 mcg/mL·h at week 16. Delay in sputum conversion was observed in patients with drug concentrations lower than the targeted concentration. At weeks 8 and 16, 13 adverse events were observed. Adverse events were resolved through symptomatic treatment. Body mass index was found to be significantly associated with drug-exposure parameters., Conclusions: Bedaquiline and delamanid when co-administered exhibit plasma drug levels within the targeted concentrations, showing an exposure-response relationship., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Background: In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control., Patients and Methods: Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant., Results: Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months., Conclusions: PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Sputum culture reversion after conversion is an indicator of tuberculosis (TB) treatment failure. We analyze data from the endTB multi-country prospective observational cohort (NCT03259269) to estimate the frequency (primary endpoint) among individuals receiving a longer (18-to-20 month) regimen for multidrug- or rifampicin-resistant (MDR/RR) TB who experienced culture conversion. We also conduct Cox proportional hazard regression analyses to identify factors associated with reversion, including comorbidities, previous treatment, cavitary disease at conversion, low body mass index (BMI) at conversion, time to conversion, and number of likely-effective drugs. Of 1,286 patients, 54 (4.2%) experienced reversion, a median of 173 days (97-306) after conversion. Cavitary disease, BMI < 18.5, hepatitis C, prior treatment with second-line drugs, and longer time to initial culture conversion were positively associated with reversion. Reversion was uncommon. Those with cavitary disease, low BMI, hepatitis C, prior treatment with second-line drugs, and in whom culture conversion is delayed may benefit from close monitoring following conversion., (© 2024. The Author(s).)

Background: There are scarce data on the clinical outcomes of persons retreated with new/companion anti-tuberculosis (TB) drugs for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). We sought to evaluate the efficacy and safety of bedaquiline and delamanid containing regimens among patients with and without prior exposure to the new/companion drugs (bedaquiline, delamanid, linezolid, clofazimine, and fluoroquinolones)., Methods: We conducted a retrospective cohort study among patients with pulmonary MDR/RR-TB in Georgia who received bedaquiline and delamanid combination as a part of a salvage regimen from November 2017 to December 2020 in a programmatic setting., Results: Among 106 persons with a median age of 39.5 years, 44 (41.5%) were previously treated with new/companion TB drugs. Patients with prior exposure to new/companion drugs had higher rates of baseline resistance compared to those without exposure to new/companion TB drugs (bedaquiline 15.2% vs 1.8%, linezolid 22.2% vs 16.7%). Sputum culture conversion rates among patients exposed and not exposed to new/companion drugs were 65.9% vs 98.0%, respectively (P < .001). Among patients with and without prior new/companion TB drug use, favorable outcome rates were 41.0% and 82.3%, respectively (P < .001). Treatment adherence in 32 (30.2%) patients was ≤80%. Five of 21 patients (23.8%) who had a baseline and repeat susceptibility test had acquired bedaquiline resistance. QTC/F prolongation (>500 ms) was rare (2.8%)., Conclusions: Prior exposure to new/companion TB drugs was associated with poor clinical outcomes and acquired drug resistance. Tailoring the TB regimen to each patient's drug susceptibility test results and burden of disease and enhancing adherence support may improve outcomes., Competing Interests: Potential conflicts of interest. M. C. S. reports institutional funding from National Institute for Minority Health and Health Disparities and American Diabetes Association; and payment for lectures from Symposium on Advanced Wound Care. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Bedaquiline is one of the core drugs used to treat multidrug-resistant TB (MDR-TB). Delamanid is one of the companion drugs in group C which is used to complete the treatment regimen when drugs in groups A and B can not be used. This study was conducted to analyze the efficacy and safety between individual regimens containing bedaquiline with delamanid and bedaquiline without delamanid., Methods: This was an observational analytic study with a retrospective design in MDR-TB patients treated with individual regimens containing bedaquiline with delamanid (bedaquiline-delamanid group) and bedaquiline without delamanid (bedaquiline group). Efficacy was measured according to the time to Acid Fast Bacilli (AFB) conversion and Mycobacterium tuberculosis culture conversion, while safety was measured specifically on QTc interval prolongation., Results: The median (range) time to AFB conversion in bedaquiline-delamanid group was faster than bedaquiline group, although there was no significant difference (1.5 (1-4) months vs. 1 (1-6) months, P=0.429), the median time to culture conversion in bedaquiline-delamanid group also faster than bedaquiline group, although there was no significant difference (1 (1-6) months vs. 2 (1-6) months, P=0.089). The incidence of QTc interval prolongation in bedaquiline-delamanid group was less than bedaquiline group, although there was no significant difference (26.9% vs. 40.3%, P=0.223)., Conclusions: Individual regimens containing bedaquiline with delamanid was proven to provide similar efficacy and safety profiles with individual regimens containing bedaquiline without delamanid. Delamanid should be preferred when selecting drugs to complete the treatment regimen when drugs in groups A and B can not be used., (Copyright © 2024 Copyright: © 2024 International Journal of Mycobacteriology.)

Delamanid, bedaquiline, and pretomanid have been recently added in the anti-tuberculosis (anti-TB) treatment regimens and have emerged as potential solutions for combating drug-resistant TB. These drugs have proven to be effective in treating drug-resistant TB when used in combination. However, concerns have been raised about the eventual loss of these drugs due to evolving resistance mechanisms and certain adverse effects such as prolonged QT period, gastrointestinal problems, hepatotoxicity, and renal disorders. This Perspective emphasizes the properties of these first-in-class drugs, including their mechanism of action, pharmacokinetics/pharmacodynamics profiles, clinical studies, adverse events, and underlying resistance mechanisms. A brief coverage of efforts toward the generation of best-in-class leads in each class is also provided. The ongoing clinical trials of new combinations of these drugs are discussed, thus providing a better insight into the use of these drugs while designing an effective treatment regimen for resistant TB cases.

Background: Delamanid (DLM) is a relatively new drug for drug-resistant tuberculosis (DR-TB) that has been used in Indonesia since 2019 despite its limited safety data. DLM is known to inhibit hERG potassium channel with the potential to cause QT prolongation which eventually leads to Torsades de pointes (TdP)., Objective: This study aims to analyse the changes of QTc interval in DR-TB patients on DLM regimen compared to shorter treatment regimens (STR)., Methods: A retrospective cohort was implemented on secondary data obtained from two participating hospitals. The QTc interval and the changes in QTc interval from baseline (ΔQTc) were assessed every 4 weeks for 24 weeks., Results: The maximum increased of QTc interval and ΔQTc interval were smaller in the DLM group with mean difference of 18,6 (95%CI 0.3 to 37.5) and 31.6 milliseconds (95%CI 14.1 to 49.1) respectively. The proportion of QTc interval prolongation in DLM group were smaller than STR group (RR=0.62; 95%CI 0.42 to 0.93)., Conclusion: This study has shown that DLM regimens are less likely to increase QTc interval compared to STR. However, close monitoring of the risk of QT interval prolongation needs to be carried out upon the use of QT interval prolonging antituberculoid drugs.

Multi and extensively drug-resistant tuberculosis is a grave cause of global public health concern due to its high mortality and limited treatment options. We conducted this systemic review and meta-analysis to evaluate the efficacy and safety of bedaquiline and delamanid, which have been added to the WHO-recommended regimen for treating drug-resistant tuberculosis. Electronic databases were searched from their inception until December 1st , 2021, for eligible studies assessing the efficacy and safety of bedaquiline and delamanid for treating drug-resistant tuberculosis. Binary outcomes were pooled using a DerSimonian-Laird random-effects model and arcsine transformation and reported on a log scale with a 95% confidence interval (CIs). Twenty-one studies were shortlisted in which bedaquiline, delamanid, and a combination of both were administered in 2477, 937, and 169 patients. Pooled culture conversion at 6 months was 0.801 (p < 0.001), 0.849 (p = 0.059) for bedaquiline and delamanid, respectively, and 0.823 (p = 0.017), concomitantly. In the bedaquiline cohort, the pooled proportion of all-cause mortality at 6 months was reported as 0.074 (p < 0.001), 0.031 (p = 0.372) in the delamanid cohort, and 0.172 in the combined cohort. The incidence of adverse events in the bedaquiline cohort ranged from 11.1% to 95.2%, from 13.2% to 86.2% in the delamanid cohort, and 92.5% in a study in the combined cohort. The incidence of QTC prolongation reported in each cohort is as follows: bedaquiline 0.163 (p < 0.001), delamanid 0.344 (p = 0.272) and combined 0.340 (p < 0.001). Our review establishes the efficacy of delamanid, bedaquiline, and their combined use in treating drug-resistant tuberculosis with reasonable rates of culture conversion, low mortality rates, and safety of co-administration, as seen with their effect on the QTc interval., Competing Interests: Conflicts of interest The author has none to declare., (Copyright © 2023 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

New classes of antitubercular drugs, diarylquinolines and nitroimidazoles, have been associated with improved outcomes in the treatment of drug-resistant tuberculosis, but that success is threatened by emerging drug resistance. We report a case of bedaquiline and delamanid resistance in a 55-year-old woman in South Africa with extensively drug-resistant tuberculosis and known HIV.

BACKGROUND: Delamanid (DLM) tablets are recommended for the treatment of rifampicin-resistant TB. However, no liquid or dispersible tablet formulation of DLM is currently commercially available for patients with challenges ingesting these tablets. The aim of this study was to develop stable extemporaneous liquid formulations of DLM that can be stored at room temperature for several weeks. METHODS: DLM tablets were suspended in 1) simple syrup and 2) a specially formulated sugar-free vehicle. These suspensions containing DLM 5 mg/mL were stored in plastic prescription bottles at room temperature or 30°C for 30 days. These suspensions were evaluated for appearance, potency, pH, and microbial counts at Days 0, 15, and 30. RESULTS: The potency of DLM in each formulation remained at 98-104% of the theoretical concentration for 30 days. The appearance, pH, and microbial count did not change for the sugar-free formulation during the 30-day storage period. Microbial growth, however, was observed in the simple syrup formulation on Day 30 but not on Day 15. CONCLUSION: DLM can be formulated in sugar or sugar-free suspensions and stored at room temperature or 30°C for at least 15 and 30 days, respectively.

Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to 20-24 months) with second-line drugs resulting in unfavorable outcomes. Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Delamanid and pretomanid are two nitroimidazoles approved by the regulatory agencies for MDR-TB treatment. However, both agents possess unsatisfactory absorption and QTc prolongation. In our search for a safer nitroimidazole, we discovered JBD0131 (2). It exhibited excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, reduced QT prolongation potential of delamanid. JBD0131 is currently in clinical development in China for pulmonary tuberculosis (CTR20202308)., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Multidrug-resistant tuberculosis(MDR-TB) is a major problem in the prevention and treatment of tuberculosis worldwide, but the treatment success rate is low, and it is necessary to develop new anti-tuberculosis drugs and optimize treatment. Delamanid, a drug with good activity against MDR-TB, has been marketed in recent years. However, there is a lack of clinical medication guidance of delamanid for tuberculosis treatment. To standardize the rational application of delamanid in clinical practice, Chinese Tuberculosis Society organized experts in related fields to issue this consensus. This consensus described the molecular structure, anti-tuberculosis mechanism, pharmacodynamics/pharmacokinetics, drug resistance mechanism, and clinical research of delamanid, put forward recommendations for clinical application, and explained its suitable population, contraindications, methods of application, adverse events, and precautions, so as to provide a reference for clinicians to use delamanid.

Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and novel approaches to discover novel drugs are urgently needed. Herein, 2D- and 4D-quantitative structure-activity relationship (QSAR) models were developed for a series of oxazole and oxadiazole derivatives that are active against Leishmania infantum , the causative agent of visceral leishmaniasis. A clustering strategy based on structural similarity was applied with molecular fingerprints to divide the complete set of compounds into two groups. Hierarchical clustering was followed by the development of 2D- ( R 2 = 0.90, R 2 pred = 0.82) and 4D-QSAR models ( R 2 = 0.80, R 2 pred = 0.64), which showed improved statistical robustness and predictive ability.

The efficacy of lotilaner was evaluated in three tick-infested cane toads. A single oral administration of lotilaner eliminated all ticks from all three toads from Day (D)1. Environmental samples collected from toad enclosures were negative for ticks until D30., (© 2021 ESVD and ACVD.)

Two drugs with novel mechanisms of action, the diarylquinoline bedaquiline and the nitroimidazole delamanid-as well as pretomanid from the same class of drugs as delamanid-have recently become available to treat drug-resistant tuberculosis (DR-TB) after many decades of little innovation in the field of DR-TB treatment. Despite evidence of improved efficacy and reduced toxicity of multidrug regimens including the two agents, access to bedaquiline and delamanid has been limited in many settings with a high burden of DR-TB and consistently poor treatment outcomes. Aside from regulatory, logistic and cost barriers at country level, uptake of the novel agents was complicated by gaps in knowledge for optimal use in clinical practice after initial market approval. The main incentives of the current pharmaceutical research and development paradigm are structured around obtaining regulatory approval, which in turn requires efficacy and safety data generated by clinical trials. Recently completed and ongoing clinical trials did not answer critical questions of how to provide shorter, less toxic treatment DR-TB treatment regimens containing bedaquiline and delamanid and improve patient outcomes. Voluntary generation of evidence that is not part of this process-yet essential from a clinical or policy perspective-has been left to non-sponsor partners and researchers, often without collaborative efforts to improve post-regulatory approval access to life-saving drugs. Additionally, these efforts are currently not recognised in the value chain of the research and development process, and there are no incentives to make this critical research happen in a coordinated way., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The aim of the review was to summarize and critically review the key pharmacokinetic and pharmacodynamic aspects of tedizolid. Tedizolid displays linear pharmacokinetics with good tissue penetration. In in vitro susceptibility studies, tedizolid exhibits activity against the majority of Gram-positive bacteria (minimal inhibitory concentration [MIC] of ≤ 0.5 mg/L), is four-fold more potent than linezolid, and has the potential to treat pathogens being less susceptible to linezolid. Area under the unbound concentration-time curve (fAUC) related to MIC (fAUC/MIC) was best correlated with efficacy. In neutropenic mice, fAUC/MIC of ~ 50 and ~ 20 induced bacteriostasis in thigh and pulmonary infection models, respectively, at 24 h. The presence of granulocytes augmented its antibacterial effect. Hence, tedizolid is currently not recommended for immunocompromised patients. Clinical investigations with daily doses of 200 mg for 6 days showed non-inferiority to twice-daily dosing of linezolid 600 mg for 10 days in patients with acute bacterial skin and skin-structure infections. In addition to its use in skin and skin-structure infections, the high pulmonary penetration makes it an attractive option for respiratory infections including Mycobacterium tuberculosis. Resistance against tedizolid is rare yet effective antimicrobial surveillance and defining pharmacokinetic/pharmacodynamic targets for resistance suppression are needed to guide dosing strategies to suppress resistance development., (© 2022. The Author(s).)

Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 and 17 years, enrolled in 2 clinical trials, were utilized for the analysis. The final data set contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two-compartment models for each component with linear elimination were selected to characterize the dispositions of delamanid and DM-6705, respectively. The covariates included in the model were body weight on the apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible versus film-coated tablet) on the mean absorption time; age, formulation, and dose on the bioavailability of delamanid; and age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB [QT corrected by Bazett's formula]) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the model-predicted upper bounds of the 90% confidence intervals of ΔQTc values were <10 ms at the simulated maximum concentration ( C max ) of DM-6705 following the administration of the maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDR-TB who receive delamanid.

GABAkines, or positive allosteric modulators of γ-aminobutyric acid-A (GABA A ) receptors, are used for the treatment of anxiety, epilepsy, sleep, and other disorders. The search for improved GABAkines, with reduced safety liabilities (e.g., dependence) or side-effect profiles (e.g., sedation) constituted multiple discovery and development campaigns that involved a multitude of strategies over the past century. Due to the general lack of success in the development of new GABAkines, there had been a decades-long draught in bringing new GABAkines to market. Recently, however, there has been a resurgence of efforts to bring GABAkines to patients, the FDA approval of the neuroactive steroid brexanolone for post-partum depression in 2019 being the first. Other neuroactive steroids are in various stages of clinical development (ganaxolone, zuranolone, LYT-300, Sage-324, PRAX 114, and ETX-155). These GABAkines and non-steroid compounds (GRX-917, a TSPO binding site ligand), darigabat (CVL-865), an α2/3/5-preferring GABAkine, SAN711, an α3-preferring GABAkine, and the α2/3-preferring GABAkine, KRM-II-81, bring new therapeutic promise to this highly utilized medicinal target in neurology and psychiatry. Herein, we also discuss possible conditions that have enabled the transition to a new age of GABAkines. We highlight the pharmacology of KRM-II-81 that has the most preclinical data reported. KRM-II-81 is the lead compound in a new series of orally bioavailable imidazodiazepines entering IND-enabling safety studies. KRM-II-81 has a preclinical profile predicting efficacy against pharmacoresistant epilepsies, traumatic brain injury, and neuropathic pain. KRM-II-81 also produces anxiolytic- and antidepressant-like effects in rodent models. Other key features of the pharmacology of this compound are its low sedation rate, lack of tolerance development, and the ability to prevent the development of seizure sensitization., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cancer is the world's third deadliest disease. Despite the availability of numerous treatments, researchers are focusing on the development of new drugs with no resistance and toxicity issues. Many newly synthesized drugs fail to reach clinical trials due to poor pharmacokinetic properties. Therefore, there is an imperative requisite to expand novel anticancer agents with in vivo efficacy., Objective: This review emphasizes synthetic methods, contemporary strategies used for the inclusion of oxazole moiety, mechanistic targets, along with comprehensive structure-activity relationship studies to provide perspective into the rational design of highly efficient oxazole-based anticancer drugs., Methods: Literature related to oxazole derivatives engaged in cancer research is reviewed. This article gives a detailed account of synthetic strategies, targets of oxazole in cancer, including STAT3, Microtubules, G-quadruplex, DNA topoisomerases, DNA damage, protein kinases, miscellaneous targets, in vitro studies, and some SAR studies., Results: Oxazole derivatives possess potent anticancer activity by inhibiting novel targets such as STAT3 and Gquadruplex. Oxazoles also inhibit tubulin protein to induce apoptosis in cancer cells. Some other targets such as DNA topoisomerase enzyme, protein kinases, and miscellaneous targets including Cdc25, mitochondrial enzymes, HDAC, LSD1, HPV E2 TAD, NQO1, Aromatase, BCl-6, Estrogen receptor, GRP-78, and Keap-Nrf2 pathway are inhibited by oxazole derivatives. Many derivatives showed excellent potencies on various cancer cell lines with IC50 values in nanomolar concentrations., Conclusion: Oxazole is a five-membered heterocycle, with oxygen and nitrogen at 1 and 3 positions, respectively. It is often combined with other pharmacophores in the expansion of novel anticancer drugs. In summary, oxazole is a promising entity to develop new anticancer drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To evaluate the cost-effectiveness of tucatinib in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastases (BMs) and the subgroup of active BMs from the United States (US) payer perspective., Materials and Methods: A 3-state Markov model was developed to compare the cost-effectiveness of 2 regimens in HER2-positive BC patients with BMs: (1) tucatinib, trastuzumab, and capecitabine (TTC); (2) placebo, trastuzumab, and capecitabine (PTC). And subgroup analysis of active BMs was also performed. Lifetime costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and incremental net-health benefit (INHB) were estimated. The willingness-to-pay (WTP) threshold was $200,000/QALY. The robustness of the model was tested by sensitivity analyses. Additional scenario analysis was also performed., Results: Compared with PTC, the ICER yielded by TTC was $418,007.01/QALY and the INHB was -1.08 QALYs in patients with BMs. In the subgroup of active BMs, the ICER and the INHB were $324,465.03/QALY and -0.71 QALY, respectively. The results were most sensitive to the cost of tucatinib. Probabilistic sensitivity analyses suggested that the cost-effective probability of TTC was low at the current WTP threshold in the patients with BMs and the subgroup of active BMs., Conclusion: Tucatinib is unlikely to be cost-effective in HER2-positive BC patients with BMs from the US payer perspective but shows better economics in patients with active BMs. Selecting a favorable population, reducing the price of tucatinib or offering appropriate drug assistance policies might be considerable options to optimize the cost-effectiveness of tucatinib., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Background: Delamanid (Dlm) is an effective drug against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains, including Multidrug-resistant Mycobacterium tuberculosis (MDR-MTB). There are few reports on the activity and secretion of cytokines caused by Dlm on macrophages infected by MDR-MTB strains. Therefore, this article aims to observe the bactericidal activity and secretion of cytokines of the macrophages infected by MDR-MTB strains after Dlm was administered, so as to provide a basis for further perfecting the mechanism of Dlm., Methods: Samples were respectively collected to count the intracellular colony-forming unit (CFU) of macrophages infected by MDR-MTB or H37Rv strains at 4, 8, 24, and 48 h after Dlm at MIC, 10MIC, and 20MIC were administered. Samples were respectively collected to detect the level of IL-12/23 p40, TNF-α, IL-6, and IL-10 in the culture supernatant of macrophages infected by MDR-MTB or H37Rv strains at 4, 24, and 48 h after Dlm at MIC were administered. The levels of four cytokines in the culture supernatant were measured using the Luminex ® 200™ (Luminex, USA) according to the manufacturer's instructions. Data were analyzed by SPSS 25.0 software. The continuous data in normal distribution were expressed as mean ± standard deviation ( x ¯ ± s ) and analyzed by t or F test. P <0.05 was considered statistically significant., Results: (1) After Dlm was applied to macrophages infected by MDR-MTB strains:(A) The intracellular CFU gradually decreased, reached the lowest value at 48 h, and was lower than that of Dlm before administration and infection group ( P <0.05). (B) The intracellular CFU was further reduced after increasing Dlm dose to 10MIC and 20MIC, and the latter was lower than that of the former ( P <0.05). (C) The intracellular CFU of MDR-MTB group was higher than that of H37Rv group at 4~48 h after administration ( P <0.05). (2) After Dlm at MIC dose was applied to macrophages infected by MDR-MTB strains: (A) The level of IL-12/23 p40 at any time didn't change compared with that of Dlm before administration ( P >0.05), while the level of IL-12/23 p40 at 4 h was higher than that of the infection group ( P <0.05). The levels of TNF-α at 24 and 48 h were higher than that of Dlm before administration ( P <0.05), but were similar to that of the infection group ( P >0.05). In addition, the levels of IL-12/23 p40 and TNF-α at any time were similar to that of the H37Rv group after administration ( P >0.05). (B) The levels of IL-6 at 24 and 48 h were higher than that of Dlm before administration ( P <0.05), but were similar to that of H37Rv group ( P >0.05) and were lower than that of infection group ( P <0.05). The level of IL-10 at any time didn't change compared with that of Dlm before administration ( P >0.05), but was lower than that of the infection group at 4~48 h and was lower than that of the H37Rv group at 24 h ( P <0.05). (C) The level of IL-12/23 p40 and IL-10 didn't change with the change of intracellular CFU ( P <0.05), while the level of TNF-α and IL-6 increased with the intracellular CFU decreasing, and the increase level of TNF-α was lower than that of the infection group ( P <0.05)., Conclusions: Dlm had strong bactericidal activity against intracellular MDR-MTB, which was time-dependent and concentration-dependent. Its bactericidal activity against intracellular MDR-MTB strains was weaker than that against drug-susceptible tuberculosis strains. Dlm might have immunomodulatory effect, inducing low expression of Th2 cytokines IL-6 and IL-10 at different times after administration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lyu, Lin, Gao, Jia, Zhu, Li, Dong, Sun, Shu, Pan, Zhang and Li.)

This study is the first to report a clinical case of simultaneously acquired resistance to bedaquiline (BDQ) and delamanid (DLM). Whole genome sequencing revealed 2 nucleotide insertions (Rv0678 and fbiC) in the Mycobacterium tuberculosis isolate. The minimum inhibitory concentrations for BDQ and DLM were 0.25 µg/mL and >2.0 µg/mL, respectively., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Metastatic breast cancer is the second most common cause of brain metastasis (BM), and this problem is particularly marked for the amplified HER2 subtype (HER2+), with a cumulative incidence reaching up to 49 % in the ER-/HER2+ subgroup. Literature review shows that therapeutic progress has been major since the marketing of systemic anti-HER2+ treatments, with life expectancies now relatively unaffected by brain development. The recommended treatments are, on the one hand, specific treatment for brain development and, on the other hand, appropriate systemic treatment. Regarding local treatments, we will always favor surgery when possible, especially for large metastases, and stereotaxic radiotherapy, possibly iterative. One should be wary of whole brain irradiation which has never been shown to improve overall survival, but which is clearly associated with more cognitive toxicities. All the systemic anti-HER2 treatments currently on the market have shown efficacy on BM from HER2+ breast cancer and must therefore be chosen above all on the basis of their potential activity on the systemic disease at the time of cerebral evolution. If BM evolution happen without concomitant systemic progression, and local treatment can control it, it is not recommended to change the current medical treatment. Finally, randomized clinical studies opened to patients with active brain disease are starting to be published. The first of them showed the benefit of the triple combination tucatinib-trastuzumab-capecitabine in this context., (Copyright © 2021 Société FranÇaise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Rifampicin-resistant/multidrug-resistant (RR/MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis (TB) are serious public health problem in Kazakhstan. In 2012 and 2013, stringent regulatory authorities approved the first new TB drugs in fifty years, bedaquiline and delamanid, offering hope for more effective and less toxic MDR-TB treatment. The endTB Observational Study is a multi-country study that enrolled patients receiving a bedaquiline- or delamanid-containing regimen for RR/MDR-TB between 01 April 2015 and 30 September 2018. In Kazakhstan, 675 patients participated in the study; all had at least 6-months or longer of follow-up after the start of treatment. The present analysis focuses on endTB Observational Study patients living in Kazakhstan who had a positive baseline sputum culture (220 patients) and initiated a bedaquiline- or delamanid-containing regimen between February 1, 2016 and March 31, 2018. Of them, 195 (89%) of patients experienced culture conversion within six months., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: A systematic literature review and network meta-analysis of randomized controlled trials in patients receiving therapy for HER2+ unresectable/metastatic breast cancer after ≥1 HER2-directed therapy was conducted to compare progression-free survival (PFS) and overall survival (OS). Methods: Hazard ratios (HRs) and relative differences from fractional polynomials (FPs) for PFS and OS were assessed by Bayesian network meta-analyses. Results: For PFS, surface under the cumulative rankogram (SUCRA) ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by T-DM1 monotherapy and neratinib plus capecitabine. For OS, SUCRA ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1 monotherapy, with similar scores. Conclusion: Tucatinib plus trastuzumab with capecitabine, and T-DM1 monotherapy, consistently showed improved PFS and OS versus lapatinib/trastuzumab plus capecitabine and non-targeted treatments.

Background: Since 1 September 2016, bedaquiline and delamanid have been administered for the treatment of patients with multidrug-resistant/rifampicin-resistant tuberculosis after the official approval in South Korea. This study aimed to assess and compare the final treatment outcomes of patients who received bedaquiline with those of patients who received delamanid., Methods: This is a nationwide cohort study of patients with multidrug-resistant/rifampicin-resistant tuberculosis in whom bedaquiline or delamanid was administered from 1 September 2016 to 28 February 2018, after receiving the official approval in South Korea. Patients were classified into the bedaquiline and delamanid group according to the first used drug. We evaluated and compared the final treatment outcomes between the groups., Results: During the study period, 284 patients with multidrug-resistant/rifampicin-resistant tuberculosis were approved to use bedaquiline or delamanid and 260 were included in the final analysis; 119 (45.8%) and 141 patients (54.2%) were classified into bedaquiline and delamanid groups, respectively. Among them, 30 patients (11.5%) exhibited additional resistance to second-line injectable drugs, 94 patients (36.2%) had additional resistance to fluoroquinolones, and 37 patients (14.2%) had resistance to both drugs. The overall treatment success rate was 79.2%. Initiation of bedaquiline rather than delamanid was not associated with treatment success (adjusted odds ratio, .671; 95% confidence interval, .350-1.285). Frequencies of adverse events were not significantly different between the 2 groups., Conclusions: Initial choice of bedaquiline or delamanid did not make any significant difference in the final treatment outcome or the frequencies of adverse events among patients with multidrug-resistant/rifampicin-resistant tuberculosis., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose: To evaluate the efficacy of topical lotilaner ophthalmic solution, 0.25%, in patients with Demodex blepharitis. Methods: Eighteen adults with Demodex blepharitis, defined as >10 collarettes on the upper lid and/or mite density of ≥1.5 mites per lash (upper and lower), were treated bid for 42 days with the topical lotilaner ophthalmic solution, 0.25%. Contact lens wear, artificial eyelashes, and lid structural abnormalities were among the exclusion criteria. No other antibacterial, antiparasitic, or anti-inflammatory treatment or lid hygiene products were permitted. One eye of each patient was selected for analysis and assessed on day 7, 14, 28, and 42. Collarettes were graded at each visit, and mite density was evaluated by microscopy at each visit except day 7. Outcome measures were collarette elimination (≤2 lashes with collarettes) and mite eradication (0 mites). Drop tolerability, adverse events, visual acuity, and slit-lamp biomicroscopy were assessed. Results: Collarette elimination was achieved in 13/18 participants (72.2%) by day 42. Mean collarette grade (upper lid) declined from 3.56 ± 0.17 to 0.28 ± 0.11. Mite eradication was achieved in 14/18 participants (77.8%) by day 42. Mean mite density decreased from 2.63 ± 0.39 to 0.12 ± 0.08 mites/lash. Participants reported good tolerability. Adverse events were mild and transient and did not result in treatment discontinuation. Conclusion: Six weeks of at-home topical therapy with the lotilaner ophthalmic solution, 0.25%, was effective in eliminating the most common objective signs of Demodex blepharitis, with a collarette elimination rate of 72% and mite eradication in 78% of eyes by day 42. ISRCTN registration #: 24398865.

Background: The treatment success rate of drug-resistant (DR) tuberculosis is alarmingly low. Therefore, more effective and less complex regimens are urgently required., Methods: We compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg), and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks. This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Relapse was assessed 12 weeks after treatment. Two logistic regression models were developed to compare the efficacy of both regimens., Results: Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only 1 mouse had relapse in the BDL group, while in the HRZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively., Conclusion: The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR tuberculosis., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Many recent studies have investigated the role of drug interventions for coronavirus disease 2019 (COVID-19) infection. However, an important question has been raised about how to select the effective and secure medications for COVID-19 patients. The aim of this analysis was to assess the efficacy and safety of the various medications available for severe and non-severe COVID-19 patients based on randomized placebo-controlled trials (RPCTs)., Methods: We did an updated network meta-analysis. We searched the databases from inception until July 31, 2021, with no language restrictions. We included RPCTs comparing 49 medications and placebo in the treatment of severe and non-severe patients (aged 18 years or older) with COVID-19 infection. We extracted data on the trial and patient characteristics, and the following primary outcomes: all-cause mortality, the ratios of virological cure, and treatment-emergent adverse events. Odds ratio (OR) and their 95% confidence interval (CI) were used as effect estimates., Results: From 3,869 publications, we included 61 articles related to 73 RPCTs (57 in non-severe COVID-19 patients and 16 in severe COVID-19 patients), comprising 20,680 patients. The mean sample size was 160 (interquartile range 96-393) in this study. The median duration of follow-up drugs intervention was 28 days (interquartile range 21-30). For increase in virological cure, we only found that proxalutamide (OR 9.16, 95% CI 3.15-18.30), ivermectin (OR 6.33, 95% CI 1.22-32.86), and low dosage bamlanivimab (OR 5.29, 95% CI 1.12-24.99) seemed to be associated with non-severe COVID-19 patients when compared with placebo, in which proxalutamide seemed to be better than low dosage bamlanivimab (OR 5.69, 95% CI 2.43-17.65). For decrease in all-cause mortality, we found that proxalutamide (OR 0.13, 95% CI 0.09-0.19), imatinib (OR 0.49, 95% CI 0.25-0.96), and baricitinib (OR 0.58, 95% CI 0.42-0.82) seemed to be associated with non-severe COVID-19 patients; however, we only found that immunoglobulin gamma (OR 0.27, 95% CI 0.08-0.89) was related to severe COVID-19 patients when compared with placebo. For change in treatment-emergent adverse events, we only found that sotrovimab (OR 0.21, 95% CI 0.13-0.34) was associated with non-severe COVID-19 patients; however, we did not find any medications that presented a statistical difference when compared with placebo among severe COVID-19 patients., Conclusion: We conclude that marked variations exist in the efficacy and safety of medications between severe and non-severe patients with COVID-19. It seems that monoclonal antibodies (e.g., low dosage bamlanivimab, baricitinib, imatinib, and sotrovimab) are a better choice for treating severe or non-severe COVID-19 patients. Clinical decisions to use preferentially medications should carefully consider the risk-benefit profile based on efficacy and safety of all active interventions in patients with COVID-19 at different levels of infection.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is commonly treated with corticosteroids. However, these drugs have long-term adverse effects, representing an unmet need for new treatments. AD is associated with dysregulation of phosphodiesterase 4 (PDE4) activity in inflammatory cells and the topical PDE4 inhibitor, crisaborole, is approved by the US FDA for mild-to-moderate AD. In this study, we compared the effects of a novel PDE4 inhibitor, AA6216, with those of crisaborole on skin inflammation. We found that AA6216 is a more potent inhibitor of PDE4 and of cytokine production (TNF-α, IL-12/23p40, IL-4, IL-13, and IFN-γ) by human peripheral blood mononuclear cells (PBMCs) stimulated by phytohemagglutinin (PHA) or anti-CD3 antibodies, with IC 50 values ranging from 5.9 to 47 nM. AA6216 also significantly suppressed skin inflammation in three mouse models of dermatitis. In acute and chronic oxazolone-induced dermatitis models, topical AA6216 exhibited stronger inhibitory effects on ear inflammation and cytokine production (TNFα, IL-1β, and IL-4) in skin lesions compared with crisaborole. In a Dermatophagoides farinae-induced dermatitis model, AA6216 significantly reduced the dermatitis score, based on the development of erythema/hemorrhage, scarring/dryness, edema, and excoriation/erosion, compared with a clinically used topical AD drug, tacrolimus. These results suggest the possibility that AA6216 is a novel and effective topical therapeutic agent for the treatment of dermatitis including AD., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The World Health Organization (WHO) recommends countries introduce new anti-TB drugs in the treatment of multidrug-resistant tuberculosis. The aim of the study is to prospectively evaluate the effectiveness of bedaquiline (and/or delamanid)- containing regimens in a large cohort of consecutive TB patients treated globally. This observational, prospective study is based on data collected and provided by Global Tuberculosis Network (GTN) centres and analysed twice a year. All consecutive patients (including children/adolescents) treated with bedaquiline and/or delamanid were enrolled, and managed according to WHO and national guidelines. Overall, 52 centres from 29 countries/regions in all continents reported 883 patients as of January 31st 2021, 24/29 countries/regions providing data on 100% of their consecutive patients (10-80% in the remaining 5 countries). The drug-resistance pattern of the patients was severe (>30% with extensively drug-resistant -TB; median number of resistant drugs 5 (3-7) in the overall cohort and 6 (4-8) among patients with a final outcome). For the patients with a final outcome (477/883, 54.0%) the median (IQR) number of months of anti-TB treatment was 18 (13-23) (in days 553 (385-678)). The proportion of patients achieving sputum smear and culture conversion ranged from 93.4% and 92.8% respectively (whole cohort) to 89.3% and 88.8% respectively (patients with a final outcome), a median (IQR) time to sputum smear and culture conversion of 58 (30-90) days for the whole cohort and 60 (30-100) for patients with a final outcome and, respectively, of 55 (30-90) and 60 (30-90) days for culture conversion. Of 383 patients treated with bedaquiline but not delamanid, 284 (74.2%) achieved treatment success, while 25 (6.5%) died, 11 (2.9%) failed and 63 (16.5%) were lost to follow-up., (Copyright © 2021 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

The management of multidrug-resistant tuberculosis (TB) is associated with low treatment success, high mortality and failure rates. New drugs and novel short-therapeutic regimens have only recently helped overcome these obstacles. We carried out a narrative literature review aimed at summarizing the scientific evidence on the recent therapeutic advances in the field of drug-resistant TB. Experimental and observational studies on novel (i.e. bedaquiline, delamanid, pretomanid) drugs and novel regimens and the main pharmacological characteristics of the newest compounds are described. We also highlight the main scientific evidence on therapeutic strategies complementary to standard chemotherapy (i.e. new approaches to drug delivery, host-directed therapy, surgery, new collapse therapy, rehabilitation, and palliative care)., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aims: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB., Methods: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3-9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit., Results: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm., Conclusions: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases., Clinical Trial Registration: NCT02614794., Competing Interests: Conflict of interest statement V.M. reports consultancy for Amgen, AstraZeneca, ClinSol, Daiichi Sankyo, Eisai, Genomic Health, Hexal, Lilly, MSD Oncology, Novartis, Pierre Fabre, Roche, Seagen, Tesaro and Teva and research funding/grants from Novartis, Roche/Genentech and Seagen. A.W. reports corporate board membership for Andrew Wardley Limited, Manchester Cancer Academy and Outreach Research & Innovation Group Limited; consultancy for Accord Research, AstraZeneca, Athenex, Coleman Expert Network, Coleman Research, Daiichi Sankyo, Gerson Lehrman Group, Guidepoint Global, Lilly, MSD Oncology, NAPP Pharmaceuticals, Novartis, Pfizer and Roche; employment at the Christie NHS Foundation Trust and AstraZeneca (as of 11th January 2021); patents and royalties for Outreach Research & Innovation Group; speaker's bureau participation for AstraZeneca, Eisai, Lilly, Novartis, Pfizer and Roche; travel expenses from Daiichi Sankyo, MSD and Roche and other nonfinancial relationships with the Strategy Director for the Association of Cancer Physicians, Committee Member UK Breast Cancer Group, Committee Member NHS England and Chemo Clinical Reference Group, ESMO Breast Cancer Faculty and NCRI Breast Research Group Chair. E.P. reports consultancy for Mylan, Novartis, Pfizer and R-Pharm; research funding/grants from AbbVie, Cascadian, Corcept Therapeutics, Genentech, Hoosier Cancer Research Network, Merck, Novartis and Seagen and travel expenses from Amgen, Genentech, Merck, Novartis and Tesaro. E.H. reports consultancy for AstraZeneca, Black Diamond Therapeutics, Boehringer Ingelheim, Daiichi Sankyo, Genentech/Roche, Lilly, Mersana, Novartis, Pfizer, Puma Biotechnology and Silverback Therapeutics; research funding/grants from AbbVie, AceraPharma, Aravive, ArQule, Arvinas, AstraZeneca, BerGenBio, Black Diamond Therapeutics, Boehringer, Clovis Oncology, Compugen, Curis, CytomX Therapeutics, Daiichi Sankyo, Deciphera, eFFECTOR, Eisai, EMD Serono, Fochon Pharmaceuticals, Fosun Orinove, Fujifilm, G1 Therapeutics, Pfizer, Puma Biotechnology, Radius Health, Regeneron, Rgenix, Seagen, Sermonix Pharmaceuticals, Silverback Therapeutics, Stemcentrx, Sutro Biopharma, Syndax, Syros Pharmaceuticals, Taiho Pharmaceutical, Takeda, TapImmune, Tesaro, Torque, Unum Therapeutics, Verastem, Zenith Epigenetics, Zymeworks, Genentech/Roche, H3 Biomedicine, Harpoon, Hutchison MediPharma, Immunogenics, InventisBio, Karyopharm Therapeutics, Leap Therapeutics, Lilly, Lycera, MacroGenics, MedImmune, Medivation, Mersana, Merus, Millennium, Molecular Templates, Novartis, NuCana and OncoMed and travel expenses from Amgen, AstraZeneca, Bayer, BMS, Clovis, Eisai, EMD Serono, Foundation Medicine, Genentech/Roche, Genentech, Genzyme, Guardant Health, Helsinn Therapeutics, Heron, Lilly, Medivation, Merck, Novartis, Pfizer, Roche, Sysmex and Tesaro. A.Z. reports consultancy for Norvatis and Pfizer and travel expenses from Immunomedics. E.J. reports consultancy for Lilly, Novartis, Pfizer and Roche. F.B. reports consultancy and honoraria from Lilly, Novartis, Lilly and Roche and travel expenses from Novartis. E.H.B. reports travel expenses from Pierre Fabre, Pfizer and Roche. A.B. reports corporate board membership for NanoTx Therapeutics; consultancy for AlaMab Therapeutics, NanoTx Therapeutics, Plus Therapeutics and Vascular Biogenics; equity ownership in NanoTx and Plus Therapeutics; honoraria from Vascular Biogenics; patents and royalties related to intellectual property interest in NanoTx Therapeutics; research funding/grants from Boston Biomedical, Immunomedics, Medicenna, Mirna Therapeutics, Threshold Pharmaceuticals, Upsher-Smith and Vascular Biogenics and travel expenses from Vascular Biogenics. L.C. reports speaker's bureau participation for Astellas, Ipsen and Janssen and other fees for Astellas, Bristol Myers Squibb, Ipsen, Novartis and Pfizer. C.F. reports honoraria from Pfizer, Bayer, Novartis, AstraZeneca, Merck, Astellas Pharma and Roche Canada; a consulting or advisory role for Genomic Health, Merck, AstraZeneca, Bayer and Odonate Therapeutics; speaker's bureau for Merck; research funding/grants to self from Bayer; research funding/grant to the institution from Astellas Pharma, AstraZeneca, Lilly, Merck, Novartis, Roche/Genentech, Sanofi, Pfizer, Janssen Oncology, Zymeworks, Seagen, Immunomedics, Bicycle Therapeutics and Sermonix Pharmaceuticals and travel expenses from Novartis and Roche. M.M.-M. reports advisory board membership for Pierre Fabre; grants for conference attendance from Roche, Pfizer and Lilly and expert testimony for Novartis, Roche and Eisai. H.T.A. reports advisory board membership for Bayer, BeiGene, Bicycle, BioNTech, iOnctura, Roche and Servier and employment at HCA Healthcare UK and Sarah Cannon. N.I. reports consultancy for Janssen, Merck, Novartis and Pfizer. S.A. reports speaker's bureau participation for Novartis, Pfizer, Puma, Daiichi/AstraZeneca, Merck and Seagen. M.C. reports consultancy for Sanofi and travel expenses from Novartis, Bristol Myers Squibb and Ipsen. T.P. reports research funding/grants from Merck, Pfizer and Seagen. E.S.-R. reports consultancy for Lilly and Mylan, research funding/grants from Susan G. Komen Victory Foundation and speaker's bureau participation for Mylan. D.C. reports consultancy for Daiichi Sankyo, GlaxoSmithKline, Novartis, Roche and Synthon; employment at Edinburgh Cancer Research Centre, Edinburgh, United Kingdom and research funding/grants from Daiichi Sankyo, GlaxoSmithKline, Novartis, Roche and Seagen (all funding is to his institution). G.C. reports consultancy from Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche, Seagen and Daiichi Sankyo; employment at the University of Milano, Istituto Europeo di Oncologia, IRCCS, Milano, Italy and speaker's bureau participation for Lilly, Pfizer, Roche, Seagen and Daiichi Sankyo. K.G. reports consultancy for AstraZeneca, Bristol Myers Squibb, Genentech, Genomic Health, Janssen, Lilly, Merck, Mylan, NanoString, Novartis, Pfizer and Roche and research funding/grants from AstraZeneca, Bristol Myers Squibb, Pfizer and Roche. M.S. reports employment at Seagen Inc. and equity ownership in Seagen Inc. and Moderna Pharma. K.D. reports employment at Seagen Inc. and equity ownership in Seagen Inc. and Roche. J.R. and W.F. report employment at Seagen Inc. and equity ownership in Seagen Inc. M.B., S.C., M.C., E.C., L.F. and O.H. have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Approximately half of melanoma tumors lack a druggable target and are unresponsive to current targeted therapeutics. One proposed approach for treating these therapeutically orphaned tumors is by targeting transcriptional dependencies (oncogene starvation), whereby survival factors are depleted through inhibition of transcriptional regulators. A drug screen identified a CDK9 inhibitor (SNS-032) to have therapeutic selectivity against wild-type (wt) BRAF wt /NRAS wt melanomas compared with BRAF mut /NRAS mut mutated melanomas. We then used two strategies to inhibit CDK9 in vitro-a CDK9 degrader (TS-032) and a selective CDK9 kinase inhibitor (NVP-2). At 500 nM, both TS-032 and NVP-2 demonstrated greater suppression of BRAF wt /NRAS wt /NF1 wt cutaneous and uveal melanomas than mutant melanomas. RNA sequencing analysis of eight melanoma lines with NVP-2 treatment demonstrated that the context of this vulnerability appears to converge on a cell cycle network that includes many transcriptional regulators, such as the E2F family members. The Cancer Genome Atlas human melanoma tumor data further supported a potential oncogenic role for E2F1 and E2F2 in BRAF wt /NRAS wt /NF1 wt tumors and a direct link to CDK9. Our results suggest that transcriptional blockade through selective targeting of CDK9 is an effective method of suppressing therapeutically orphaned BRAF/NRAS/NF1 wt melanomas., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Dilated cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), an inheritable muscle-wasting disease caused by a mutation in the dystrophin gene. Preclinical studies in mouse models of muscular dystrophy have demonstrated reduced cardiomyopathy and improved cardiac function following oral treatment with the potent and selective thromboxane A 2 /prostanoid receptor (TPr) antagonist ifetroban. Furthermore, a phase 2 clinical trial (NCT03340675, Cumberland Pharmaceuticals) is currently recruiting subjects to determine whether ifetroban can improve cardiac function in patients with DMD. Although TPr is a promising therapeutic target for the treatment of dilated cardiomyopathy in DMD, little is known about TPr function in coronary arteries that perfuse blood through the cardiac tissue. In the current study, isolated coronary arteries from young (∼3-5 mo) and aged (∼9-12 mo) mdx mice, a widely used mouse model of DMD, and age-matched controls were examined using wire myography. Vasoconstriction to increasing concentrations of TPr agonist U-46619 (U4) was enhanced in young mdx mice versus controls. In addition, young mdx mice displayed a significant attenuation in endothelial cell-mediated vasodilation to increasing concentrations of the muscarinic agonist acetylcholine (ACh). Since TPr activation was enhanced in young mdx mice, U4-mediated vasoconstriction was measured in the absence and the presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mdx mice and both aged mdx and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mdx mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD. NEW & NOTEWORTHY This investigation revealed 1 ) impaired acetylcholine-mediated vasodilation, 2 ) increased U-46619-mediated vasoconstriction, and 3 ) reversal of the increase in U-46619-mediated vasoconstriction by the thromboxane A 2 /prostanoid receptor (TPr) antagonist ifetroban in left anterior descending coronary arteries isolated from young mdx mice, a model of Duchenne muscular dystrophy (DMD). Ifetroban has been used in preclinical studies to demonstrate improved cardiac function in mouse models of muscular dystrophy and is currently being investigated in a phase 2 clinical trial in patients with DMD. The current study supports the role of ifetroban in improving coronary artery function in preclinical DMD models, which may contribute to improved cardiovascular health.

Background: Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy., Methods: ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8-24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing., Findings: Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and 20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20 (83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and 95% (79-100) for bedaquiline plus delamanid at 24 weeks., Interpretation: Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values., Funding: Division of AIDS, National Institutes of Health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The speed with which acaricides paralyze and kill ticks is relevant to impeding pathogen transmission. The objective of this study was to assess early-onset lotilaner effects on the motility and weights of Amblyomma americanum ticks collected from treated dogs., Methods: Twelve healthy dogs were randomized between two groups to receive either lotilaner (Credelio ® ) on Day 0 or to be sham treated. On Day 7, 25 male and 25 female A. americanum were placed under bandages, two on each flank of each dog. After 30 or 45 min, all unattached ticks were removed and T = 0 was set. At T = 2, 4, 8 and 24 h post attachment, 5 attached ticks removed from each bandage on each dog were weighed, assessed by blinded observers for righting ability and movement recorded., Results: After the infestation period significantly fewer treated than control dogs had 20 ticks attached (50.0% versus 91.7%, P = 0.0015). At 24 h post attachment, mean weights of ticks from treated dogs (males 1.69 mg; females 2.72) were significantly less than ticks from controls (males 2.66 mg; females 4.67) (P male  = 0.0002; P female  < 0.0001). Mean tick weights from the treated group were significantly lower at 24 h than at earlier time points (P male  < 0.0307; P female  = 0.0021). At 4 and 8 h, significantly fewer ticks from treated (14.3%, 0.0%, respectively) than from control dogs could right (73.3%, 70.0%) (P 4h  < 0.0001; P 8h  = 0.0024) (at 24 h, all ticks from treated dogs were dead), and distance moved was significantly less at all time points (P 2h  = 0.0413; P 4h , P 8h  < 0.0001). Mean and maximum velocity of ticks from treated dogs were significantly lower, relative to controls, at 4 and 8 h (P ≤ 0.0001). Within the treated group, collected ticks had significantly lower mean and maximum velocities at 4 and 8 h compared to 2 h (P mean  < 0.0042; P max  < 0.0194)., Conclusion: The observed changes indicate that lotilaner may disrupt tick attachment. In ticks that attached, a progressive impairment of neuromuscular processes began within 2 h. Those irreversible changes could substantially reduce the risk of pathogen transmission from tick to host.

Background: A pivotal randomised, blinded, positive-controlled, multicentre, European field study was conducted to evaluate the effectiveness and safety of a novel combination tablet of lotilaner and milbemycin oxime (Credelio ® Plus) administered orally to client-owned dogs naturally infested with fleas and/or ticks., Methods: In this field study, households with flea- or tick-infested dog(s) were enrolled on Day 0 into the study to provide data for either the tick or flea infestation cohorts. Households were randomised in a 2:1 ratio to receive either the combination investigational product (IP, Credelio Plus ® tablets) or the control product (CP: Nexgard Spectra ® tablets). Dogs were administered IP (flea cohort n = 135; tick cohort: n = 147) or CP (flea cohort: n = 67; tick cohort: n = 74) once every 4 weeks for a total of three times at a dose rate of 20.0-41.5 mg/kg bodyweight lotilaner and 0.75-1.53 mg/kg bodyweight milbemycin oxime (IP) or as recommended (CP). Percentage reduction was calculated by comparing individual dog flea and tick counts at each assessed post-treatment time point to their respective baseline (pre-treatment) infestation. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea-allergic dogs on the days that flea counts were performed., Results: Flea effectiveness of Credelio Plus ® after 3 consecutive monthly treatments was 100% against Ctenocephalides felis, C. canis and Pulex irritans. Tick effectiveness of Credelio Plus ® over the same time frame was 99.3% for Ixodes ricinus and 100% against Rhipicephalus sanguineus (s.l.). Flea effectiveness of the CP after three consecutive monthly treatments was 100% against C. felis, C. canis and P. irritans. Tick effectiveness of the CP over the same time frame was 99.8% for I. ricinus and 100% against R. sanguineus. Credelio Plus ® was well tolerated based on the safety assessments in all treated dogs in this field study. Within both treatment groups there was a reduction in total FAD scores from baseline., Conclusions: This pivotal European field study demonstrated the excellent effectiveness and safety of a combination of lotilaner and milbemycin oxime (Credelio Plus ® ) administered orally to dogs naturally infested with fleas and/or ticks.

Background: Management of acute exacerbations of chronic obstructive pulmonary disease (COPD) is sometimes inadequate leading to either prolonged duration and/or an increased risk of recurrent exacerbations in the period following the initial event., Objective: To evaluate the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ inhibitor, in patients experiencing an acute exacerbation of COPD., Patients and Methods: In this double-blind, placebo-controlled study, COPD patients (40-80 years, ≥10 pack-year smoking history, current moderate/severe acute exacerbation of COPD requiring standard-of-care treatment) were randomized to placebo or nemiralisib 12.5 µg, 50 µg, 100 µg, 250 µg, 500 µg, or 750 µg (ratio of 3:1:1:1:1:1:3; N=938) for 12 weeks with an exploratory 12-week follow-up period. The primary endpoint was change from baseline in post-bronchodilator FEV 1 at week 12. Key secondary endpoints were rate of re-exacerbations, patient-reported outcomes (Exacerbations of Chronic Pulmonary Disease Tool, COPD Assessment Test, St George's Respiratory Questionnaire-COPD), plasma pharmacokinetics (PK) and safety/tolerability., Results: There was no difference in change from baseline FEV 1 at week 12 between the nemiralisib and placebo treatment groups (posterior adjusted median difference, nemiralisib 750 µg and placebo: -0.004L (95% CrI: -0.051L to 0.042L)). Overall, there were also no differences between nemiralisib and placebo in secondary endpoints, including re-exacerbations. Plasma PK increased in a dose proportional manner. The most common adverse event for nemiralisib was post-inhalation cough which appeared to be dose-related., Conclusion: The addition of nemiralisib to standard-of-care treatment for 12 weeks did not improve lung function or re-exacerbations in patients with, and following an acute exacerbation of COPD. However, this study demonstrated that large clinical trials recruiting acutely exacerbating patients can successfully be conducted., Competing Interests: WAF, FHV, AC, JR, WHM, and SW are employees of and hold shares in GlaxoSmithKline. AT, MM, RW, ML, MT and EMH are former employees of and hold shares in GlaxoSmithKline. EMH is named on patents for compound GSK2269557 (nemiralisib). The current affiliation of AT and MM is AstraZeneca, Cambridge, United Kingdom. The current affiliation of RW is DLRC Ltd, Letchworth garden City, United Kingdom. The current affiliation of EMH is Eligo Bioscience, Paris, France. The authors report no other conflicts of interest in this work., (© 2021 Fahy et al.)

Background: The combination of milbemycin oxime (MO) and lotilaner (Credelio ® Plus) is a novel systemic endectocide that provides month-long effectiveness in dogs after a single oral treatment. The safety of Credelio ® Plus flavored chewable tablets was investigated in three target animal safety studies. Two studies (one in juveniles and one in adults) evaluated the long-term safety, and one study evaluated the acute safety of the product when administered orally at the upper end of the recommended dose range (0.75-1.53 mg/kg MO and 20-41 mg/kg lotilaner) and multiples of this dose., Methods: The objectives of these studies were to determine the long-term and acute safety of MO and lotilaner flavored chewable tablets in healthy dogs. All three studies were randomized, blinded, parallel-group design studies in healthy Beagle dogs. In each of the two long-term studies, 32 dogs were randomized among four groups to untreated controls or to treated groups at target doses of 1X, 3X, or 5X. Treatment was administered on seven (adult dogs) or nine (juvenile dogs) occasions with dosing every 4 weeks. In the acute study, 48 dogs were randomized among four groups to untreated controls or to treated groups at 1X, 3X, or 6X. In all three studies, the control group was administered placebo tablets. All dogs were fed 30 to 45 min prior to treatment and the assessment of safety was based on health observations, complete physical/neurological examinations, and food consumption. For the long-term safety studies, safety assessments also included clinical pathology evaluations (hematology, clinical chemistry and urinalysis), body weight, pharmacokinetic blood collections, and macroscopic and microscopic examinations of collected tissues., Results: MO and lotilaner did not induce any treatment-related adverse effects based on health observations, physical/neurological examinations, or food consumption in the long-term or acute studies. Additionally, in the long-term studies, MO and lotilaner did not induce any treatment-related effects on clinical pathology, body weight, and macroscopic and microscopic examinations., Conclusions: These three studies demonstrate that Credelio ® Plus has a wide safety margin when administered at monthly intervals to puppies and dogs at the high end of the commercial dose band.

Background: Dirofilaria immitis, a globally distributed filarial parasite of dogs, is known to cause serious or fatal cardiopulmonary disease. Client-owned dogs were enrolled in a clinical field study in the USA to evaluate the clinical effectiveness and field safety of an orally administered combination investigational product (IP) containing milbemycin oxime and lotilaner (Credelio ® Plus) as compared to a control product (CP) for the prevention of heartworm disease when administered monthly for 11 consecutive months., Methods: In this 11-month field study, 319 dogs ≥ 8 weeks old confirmed to be heartworm-negative were enrolled from eight geographically distinct US veterinary clinics, including sites in the southern USA and Mississippi River Valley. The dogs were treated with either the IP combination product at 0.75-1.53 mg/kg milbemycin oxime and 20-41.5 mg/kg lotilaner (n = 159) or the CP (Sentinel ® Flavor Tabs ® ; milbemycin oxime/lufenuron) at the label-recommended dose rate (n = 158.) On day 330, effectiveness was evaluated in each dog using antigen and microfilarial (modified Knott's) testing to assess the establishment of any patent adult heartworm infections., Results: All dogs treated with the IP combination product and the CP tested negative (100% prevention) for heartworm infection on day 330. The IP combination product tablets containing milbemycin oxime and lotilaner were well tolerated based on the safety assessments in all treated dogs., Conclusions: This multi-site clinical study using client-owned dogs demonstrated that monthly use of flavored, chewable tablets containing a combination of milbemycin oxime and lotilaner administered orally under end use conditions is safe for dogs. None of the enrolled dogs developed heartworm infections. Eleven consecutive monthly treatments of the IP provided 100% prevention of heartworm disease caused by D. immitis.

Background: The ascarid, Toxocara canis, is a common and important zoonotic intestinal nematode parasite that infects dogs globally. An effective treatment that kills any pre-patent stages of immature T. canis could additionally reduce or eliminate the development of patent infections that can result in clinical disease in infected dogs and would further reduce environmental contamination of eggs. Two randomized, blinded, GCP-compliant, pivotal laboratory dose confirmation studies were conducted to assess the effectiveness and safety of a new novel combination of lotilaner and milbemycin oxime tablets (Credelio Plus) administered orally to dogs that were experimentally infected with immature (L4 or immature adult [L5]) stages of T. canis., Methods: The commercial tablet formulation of Credelio Plus ® was administered in a time frame relative to inoculation with infective eggs. This allowed for effectiveness to be assessed against each specific immature stage of T. canis. In each study, dogs were randomized and allocated to one of four treatment groups. Each treatment group contained ten dogs that had been experimentally inoculated on Day 0 with infective T. canis eggs and then were dosed once on Day 14 or Day 24 using either placebo tablets or Credelio Plus tablets (IP) to provide minimum dosages of 0.75 mg/kg of milbemycin oxime and 20 mg/kg of lotilaner. All dogs were necropsied 5 or 6 days after their respective treatment. At necropsy, all nematodes recovered from the gastrointestinal tract were counted by species and stage., Results: In both dose confirmation studies using geometric mean worm counts, effectiveness of Credelio Plus was ≥ 98.6% and ≥ 96.8% against L4 larval stage T. canis and immature adult [L5] T. canis in both studies, respectively., Conclusions: These studies demonstrated that the Credelio Plus combination tablet administered orally to dogs was highly efficacious against experimental infections with L4 and immature adult [L5] stages of T. canis.

Background: A randomised, blinded, positive controlled, multicentre, Good Clinical Practice-compliant, pivotal field study was conducted to evaluate the effectiveness and safety of a new combination of lotilaner + milbemycin oxime tablets (Credelio ® Plus; Elanco Animal Health) administered orally to client-owned dogs naturally infected with intestinal nematodes., Methods: Client-owned dogs presenting to veterinary clinics from households in France, Hungary and Germany were screened for intestinal nematodes. Dogs with an initial positive faecal egg count that was subsequently confirmed with a follow-up faecal examination to demonstrate the presence of naturally occurring mixed or mono-infections with Toxocara canis, Toxascaris leonina, Trichuris vulpis or Ancylostoma caninum were enrolled on Day 0 into the study. Households were randomised in an approximately 2:1 ratio to receive either an investigational product (IP; Credelio Plus tablets) or control product (CP; Nexgard Spectra ® tablets) as treatment. Dogs were administered the IP (n = 278) or CP (n = 117) once on Day 0 at a dose rate of 0.75-1.56 mg/kg bodyweight milbemycin oxime and 20.0-41.5 mg/kg bodyweight lotilaner (IP) or as recommended (CP). Effectiveness of the IP and CP treatments was based on the post-treatment reduction in geometric mean faecal egg counts on Day 8 (range Day 7-10) after treatment as compared to their pre-treatment nematode faecal egg counts., Results: Geometric mean (GM) faecal egg counts for T. canis, A caninum and T. vulpis were reduced by ≥ 97.2% in the Credelio Plus group and  by ≥ 95.3% in the afoxolaner + milbemycin oxime group. There were insufficient data to calculate a percentage reduction in GM faecal egg counts between Day 0 and Day 8 for T. leonina due to low prevalence. Credelio Plus was well tolerated in this field study. Of the 355 total doses administered, 82.3% were accepted free choice in the IP group compared to 80.8% in the CP group., Conclusions: This study demonstrated effectiveness (≥ 97.2% reduction), safety and tablet acceptance of a combination of milbemycin oxime and lotilaner (Credelio Plus) administered orally to dogs with natural intestinal infections of T. canis, A. caninum and T. vulpis.