Comparisons of the therapeutic safety of seven oral antimuscarinic drugs in patients with overactive bladder: a network meta-analysis

Objectives This network meta-analysis aimed to assess the safety profiles of seven commonly used oral antimuscarinic drugs (darifenacin, fesoterodine, imidafenacin, oxybutynin, propiverine, solifenacin, and tolterodine) in patients with overactive bladder (OAB). Methods PubMed, Cochrane Library, EMBASE, CNKI, and Wanfang databases were searched for randomized controlled trials (RCTs). Studies comparing one or more antimuscarinic drugs for treating OAB with reported adverse effects (AEs) were eligible. Data were extracted, and a network meta-analysis was performed by two authors independently. Results Forty-five RCTs and 124,587 patients were included. The results demonstrated that tolterodine had better safety outcomes for 7 out of 12 major AEs, including dry mouth, constipation, urinary retention, dizziness, urinary tract infection, dry eyes, and dry skin. Darifenacin, fesoterodine, imidafenacin, oxybutynin, and solifenacin presented comparable safety profiles. Conclusions Tolterodine may be preferable as it showed a reduced association with important AEs. Darifenacin, fesoterodine, imidafenacin, oxybutynin, and solifenacin have similar safety profiles in treating patients with OAB. Taken together, this analysis provides a valuable overview of the therapeutic safety for oral antimuscarinic drugs and is useful for personalized medicine in patients with OAB. Trial registration: This trial was retrospectively registered at INPLASY ( https://inplasy.com/ ) with the registration number 202170095.

PD-L1 chimeric costimulatory receptor improves the efficacy of CAR-T cells for PD-L1-positive solid tumors and reduces toxicity in vivo

Background: On-target off-tumor toxicity impedes the clinical application of chimeric antigen receptor-modified T cells (CAR-T cells) in the treatment of solid tumors. The combinatorial antigen recognition strategy can improve the therapeutic safety of CAR-T cells by targeting two different tumor-associated antigens (TAAs) using a CAR and a chimeric costimulatory receptor (CCR). Although programmed death-ligand 1 (PD-L1, also known as B7-H1) is expressed on multiple tumors, the potential of PD-L1 as a universal target for designing CCR remains unknown.Methods: A first-generation CD19 or HER2 CAR and a PD-L1 CCR containing the CD28 signaling domain were constructed and delivered into Jurkat T cells or primary T cells by a pseudotyped lentivirus. The release of cytokines, including IL-2, IFN-γ and TNF-α, was quantified using enzyme-linked immunosorbent assay (ELISA) kits or a cytometric bead array (CBA). The in vitro cytotoxicity of CAR-T cells was detected with a luciferase-based killing assay. The in vitro proliferation of CAR-T cells was assessed by flow cytometry. The therapeutic safety and efficacy of CAR-T cells was evaluated using a subcutaneous dual-tumor model in vivo.Results: Jurkat T cells or primary T cells expressing both the CD19/HER2 CAR and PD-L1 CCR produced higher levels of cytokines in the presence of CD19/HER2 and PD-L1 than in the presence of HER2/CD19. Compared to HER2-z-engineered T cells, HER2-z-PD-L1-28-engineered T cells had higher in vitro cytotoxicity potential against PD-L1-positive tumor cells. CD19/HER2-z-PD-L1-28-engineered T cells showed higher proliferation potential in the presence of CD19/HER2 and PD-L1 than in the absence of PD-L1. CD19/HER2-z-PD-L1-28-engineered T cells preferably destroyed xenograft tumors expressing CD19/HER2 and PD-L1 in vivo and did not significantly affect CD19/HER2-expressing tumors. The PD-L1 CCR improved the antitumor efficacy of low-affinity HER2 CAR-T cells against PD-L1-positive tumors expressing high levels of HER2.Conclusion: Our findings confirmed that PD-L1 can be used as a universal target antigen for designing CCR, improving the efficacy of CAR-T cells in the treatment of PD-L1-positive solid tumors but reducing toxicity within PD-L1-negative normal tissues expressing low levels of TAA in vivo.

U.S. Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018

Background/Aims: The U.S. Food and Drug Administration (FDA) outlines clinical studies as postmarketing requirements and commitments to be fulfilled following FDA approval of new drugs and biologics ("therapeutics"). As regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy, yet little is known about how often clinical studies are outlined or the indications they investigate. To assess FDA's use of postmarket clinical studies to generate evidence of therapeutic safety and efficacy, we characterized FDA postmarketing requirements and commitments for new therapeutics approved from 2009-2018. Methods: We conducted a cross-sectional study of all novel therapeutics, including small molecule drugs and biologics, receiving original FDA approval from 2009-2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of FDA postmarketing requirements and commitments for new therapeutics at original approval, including types of studies outlined, indications to be investigated, and clinical evidence to be generated. Results: From 2009-2018, FDA approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements nor commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median = 2 (IQR, 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not significantly change from 2009 (median 2 (IQR, 1-4)) to 2018 (median 2 (IQR, 1-3); P = .54). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. Conclusions: Most therapeutics are approved by FDA with at least 1 postmarketing requirement or commitment for a clinical study, which outline investigations of safety or efficacy for both approved and unapproved indications. However, the median number of 2 clinical studies outlined has remained relatively constant over the last decade, despite increasing emphasis on lifecycle evaluation of approved therapeutics.

Como fazer uma correta prescrição medicamentosa e quais os importantes cuidados?

RESUMOA inadequada prescrição de medicamentos na clínica odontológica deve-se, principalmente, ao escasso conhecimento dos acadêmicos de odontologia a respeito da farmacologia e da terapêutica. A falta de informação adequada aos estudantes acerca da indicação, da forma de administração, da posologia e dos efeitos adversos resultam em insegurança no momento de prescrever uma correta receita. É necessário que o medicamento seja prescrito adequadamente bem como ressalte a forma farmacêutica, a dose e o período de duração do tratamento. Nesse contexto, baseado nos principais livros de farmacologia da odontologia, foi criado uma tabela com os medicamentos indispensáveis na clínica odontológica associado com o correspondente nome de princípio ativo, o nome fantasia, a apresentação, a posologia, a via de administração e as possíveis observações acerca do fármaco. Além da descrição de uma receita com as principais normas, configurando-se como um manual de prescrição medicamentosa de fácil acesso para que os estudantes esclareçam suas possíveis dúvidas. Assim sendo, o objetivo deste trabalho é facilitar o entendimento dos alunos quanto a forma de prescrever medicamentos a fim de evitar incoerências e possíveis erros de prescrição advindas de alunos. Dessa forma, uma prescrição clara e objetiva tem como resultado a minimização de possíveis erros e, consequentemente, oferece maior segurança terapêutica e maior eficácia ao tratamento.Palavras – Chave: Prescrição; Farmacologia; Odontologia. ABSTRACTAn inadequate prescription of medicines in the dental clinic must be, mainly, due to the little knowledge of dentistry students and respect to pharmacology and therapeutics. The lack of adequate information for students about indication, form of administration, dosage and adverse effects results in insecurity when prescribing a correct prescription. It is necessary that the drug is prescribed, as well as the pharmaceutical form, the dose and the duration of the treatment. In this context, based on the main pharmacology of dentistry books, a table was created with the essential medicines in the dental clinic associated with the name of active active ingredient, the active fancy name, the fancy name, a presentation, a dosage, route of administration and the following uses for making a drug. In addition to the description of a recipe with the main rules, configure it as a prescription drug manual easily accessible to students who clarify their possible doubts. Therefore, the objective of this work is to facilitate students' understanding of how to prescribe medications to avoid inconsistencies and possible errors of advanced prescription by students. Thus, a clear and objective prescription results in the minimization of possible errors and, consequently, offers greater therapeutic safety and greater efficacy to treatment.Key words: Prescription; Pharmacology; Dentistry.

Como fazer uma correta prescrição medicamentosa e quais os importantes cuidados?

RESUMOA inadequada prescrição de medicamentos na clínica odontológica deve-se, principalmente, ao escasso conhecimento dos acadêmicos de odontologia a respeito da farmacologia e da terapêutica. A falta de informação adequada aos estudantes acerca da indicação, da forma de administração, da posologia e dos efeitos adversos resultam em insegurança no momento de prescrever uma correta receita. É necessário que o medicamento seja prescrito adequadamente bem como ressalte a forma farmacêutica, a dose e o período de duração do tratamento. Nesse contexto, baseado nos principais livros de farmacologia da odontologia, foi criado uma tabela com os medicamentos indispensáveis na clínica odontológica associado com o correspondente nome de princípio ativo, o nome fantasia, a apresentação, a posologia, a via de administração e as possíveis observações acerca do fármaco. Além da descrição de uma receita com as principais normas, configurando-se como um manual de prescrição medicamentosa de fácil acesso para que os estudantes esclareçam suas possíveis dúvidas. Assim sendo, o objetivo deste trabalho é facilitar o entendimento dos alunos quanto a forma de prescrever medicamentos a fim de evitar incoerências e possíveis erros de prescrição advindas de alunos. Dessa forma, uma prescrição clara e objetiva tem como resultado a minimização de possíveis erros e, consequentemente, oferece maior segurança terapêutica e maior eficácia ao tratamento.Palavras – Chave: Prescrição; Farmacologia; Odontologia. ABSTRACTAn inadequate prescription of medicines in the dental clinic must be, mainly, due to the little knowledge of dentistry students and respect to pharmacology and therapeutics. The lack of adequate information for students about indication, form of administration, dosage and adverse effects results in insecurity when prescribing a correct prescription. It is necessary that the drug is prescribed, as well as the pharmaceutical form, the dose and the duration of the treatment. In this context, based on the main pharmacology of dentistry books, a table was created with the essential medicines in the dental clinic associated with the name of active active ingredient, the active fancy name, the fancy name, a presentation, a dosage, route of administration and the following uses for making a drug. In addition to the description of a recipe with the main rules, configure it as a prescription drug manual easily accessible to students who clarify their possible doubts. Therefore, the objective of this work is to facilitate students' understanding of how to prescribe medications to avoid inconsistencies and possible errors of advanced prescription by students. Thus, a clear and objective prescription results in the minimization of possible errors and, consequently, offers greater therapeutic safety and greater efficacy to treatment.Key words: Prescription; Pharmacology; Dentistry.

Anti-inflammatory Compound Shows Therapeutic Safety and Efficacy against Flavivirus Infection

ABSTRACT Flaviviruses comprise several medically important viruses, including Japanese encephalitis virus, West Nile virus, dengue virus (DENV), yellow fever virus, and Zika virus (ZIKV). A large outbreak of DENV and ZIKV occurred recently, leading to many cases of illness and death. However, despite decades of effort, we have no clinically specific therapeutic drugs against DENV and ZIKV. Previous studies showed that inflammatory responses play a critical role in dengue and Zika virus pathogenesis. Thus, in this study, we examined a series of novel anti-inflammatory compounds and found that treatment with compound 2d could dose dependently reduce viral protein expression and viral progeny production in HEK-293 and Raw264.7 cells infected with four serotypes of DENV and ZIKV. In addition, considering medication safety, compound 2d could not suppress cyclooxygenase-1 (COX-1) enzymatic activities and thus could prevent the side effect of bleeding. Moreover, compound 2d significantly inhibited COX-2 enzymatic activities and prostaglandin E2 levels, associated with viral replication, compared to results with a selective COX-2 inhibitor, celecoxib. Furthermore, administering 5 mg/kg compound 2d to DENV-2-infected AG129 mice prolonged survival and reduced viremia and serum cytokine levels. Overall, compound 2d showed therapeutic safety and efficacy in vitro and in vivo and could be further developed as a potential therapeutic agent for flavivirus infection.