RESUMO
Prescribing direct oral anticoagulants (DOACs) with off-label dosage and administration is discouraged due to concerns about their effectiveness and safety. Consequently, our hospital pharmacist established a formulary with physicians for oral anticoagulants. Our study aimed to assess the adherence to this formulary by investigating the rate of appropriate DOAC prescribing. We included patients who were newly prescribed or continued on DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) at our hospital. We calculated the percentage of patients prescribed the correct dosage and administration according to the package insert and compared this across three time periods: pre-intervention (period A; April-September 2019), post-intervention phase 1 (period B; August 2021-January 2022), and post-intervention phase 2 (period C; November 2022-April 2023). We also examined the number of inquiries and consultation requests made by hospital pharmacists regarding DOAC dosage and administration. A total of 782 patients were surveyed (191 in period A, 263 in period B, and 328 in period C). The appropriate prescribing rates for DOACs were 79.1% in period A, 84.4% in period B, and 86.6% in period C. The proportion of cases where hospital pharmacists questioned or consulted doctors about DOAC dosage and administration was 3.7% in period A, 6.1% in period B, and 10.1% in period C. These findings indicate that active intervention by hospital pharmacists using the formulary regarding oral anticoagulant formularies may promote appropriate DOAC use.
Assuntos
Anticoagulantes , Dabigatrana , Formulários de Hospitais como Assunto , Farmacêuticos , Serviço de Farmácia Hospitalar , Pirazóis , Piridonas , Tiazóis , Humanos , Administração Oral , Pirazóis/administração & dosagem , Anticoagulantes/administração & dosagem , Dabigatrana/administração & dosagem , Piridonas/administração & dosagem , Tiazóis/administração & dosagem , Masculino , Idoso , Rivaroxabana/administração & dosagem , Piridinas/administração & dosagem , Feminino , Padrões de Prática Médica/estatística & dados numéricos , Idoso de 80 Anos ou mais , Prescrições de Medicamentos/estatística & dados numéricos , Pessoa de Meia-IdadeAssuntos
Anticoagulantes , Fibrilação Atrial , Cirrose Hepática , Pirazóis , Piridonas , Rivaroxabana , Varfarina , Humanos , Rivaroxabana/uso terapêutico , Rivaroxabana/administração & dosagem , Varfarina/uso terapêutico , Varfarina/administração & dosagem , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagem , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Pirazóis/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Inibidores do Fator Xa/uso terapêuticoAssuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , Adulto , Humanos , Adenina/análogos & derivados , Adenina/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Negro ou Afro-Americano , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Combinação de Medicamentos , Emtricitabina/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Adesão à Medicação/estatística & dados numéricos , Piperazinas/uso terapêutico , Piridonas/uso terapêutico , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Preclinical models of pancreatic cancer (PDAC) suggest a synergistic role for combined MEK and autophagy signaling inhibition, as well as MEK and CDK4/6 pathway targeting. Several case reports implicate clinical activity of the combination of either trametinib and hydroxychloroquine (HCQ) in patients with KRAS-mutant PDAC or trametinib with CDK4/6 inhibitors in patients with KRAS and CDKN2A/B alterations. However, prospective data from clinical trials is lacking. Here, we aim to provide clinical evidence regarding the use of these experimental regimens in the setting of dedicated precision oncology programs. METHODS: In this retrospective case series, PDAC patients who received either trametinib/HCQ (THCQ) or trametinib/palbociclib (TP) were retrospectively identified across 11 participating cancer centers in Germany. RESULTS: Overall, 34 patients were identified. 19 patients received THCQ, and 15 received TP, respectively. In patients treated with THCQ, the median duration of treatment was 46 days, median progression-free survival (PFS) was 52 days and median overall survival (OS) was 68 days. In the THCQ subgroup, all patients evaluable for response (13/19) had progressive disease (PD) within 100 days. In the TP subgroup, the median duration of treatment was 60 days, median PFS was 56 days and median OS was 195 days. In the TP subgroup, 9/15 patients were evaluable for response, of which 1/9 showed a partial response (PR) while 8/9 had PD. One patient achieved a clinical benefit despite progression under TP. CONCLUSION: THCQ and TP are not effective in patients with advanced PDAC harboring KRAS mutations or alterations in MAPK/CDKN2A/B.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Hidroxicloroquina , Neoplasias Pancreáticas , Piperazinas , Piridinas , Piridonas , Pirimidinonas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Feminino , Idoso , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/uso terapêutico , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Hidroxicloroquina/uso terapêutico , Hidroxicloroquina/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/administração & dosagem , Adulto , Idoso de 80 Anos ou maisRESUMO
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy with a high relapse rate and a poor prognosis hallmarked by RAS pathway mutations. Stieglitz and colleagues conducted a phase II clinical trial using the MEK inhibitor trametinib to treat patients with relapsed and refractory juvenile myelomonocytic leukemia and observed an objective response rate of 50% and an overall survival of 80% after 4 years. See related article by Stieglitz et al., p. 1590 (4) .
Assuntos
Leucemia Mielomonocítica Juvenil , Piridonas , Pirimidinonas , Humanos , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Leucemia Mielomonocítica Juvenil/tratamento farmacológico , Leucemia Mielomonocítica Juvenil/genética , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/uso terapêutico , Resultado do Tratamento , Doenças Raras/tratamento farmacológico , Ensaios Clínicos como AssuntoRESUMO
This systematic review and meta-analysis evaluates the effects of dabrafenib and/or trametinib in treating BRAF V600-mutant gliomas. The study analyzed eight trials involving both high-grade and low-grade glioma patients, assessing outcomes such as progression-free survival (PFS), overall survival (OS), adverse events (AEs), and disease response. The pooled results showed a median PFS of 6.10 months and OS of 22.73 months, with notable improvement in disease response rates when using combination therapy. However, the high incidence of AEs (50%) and death events (43%) necessitates caution in interpreting these results. The study's limitations include a lack of randomized controlled trials and high heterogeneity in AE data. Future research should focus on larger, controlled studies, standardized AE assessments, and exploration of neurocognitive outcomes to better understand and optimize treatment strategies for BRAF V600-mutant gliomas.
Assuntos
Neoplasias Encefálicas , Glioma , Imidazóis , Mutação , Oximas , Proteínas Proto-Oncogênicas B-raf , Piridonas , Pirimidinonas , Humanos , Oximas/uso terapêutico , Pirimidinonas/uso terapêutico , Glioma/tratamento farmacológico , Glioma/genética , Piridonas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Imidazóis/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Resultado do TratamentoRESUMO
BACKGROUND: The first purpose of this study was to determine whether a measurement of the level of direct oral anticoagulants (DOACs) was possible with heparin-calibrated chromogenic anti-factor Xa activity (AXA). The second purpose of this study was to evaluate whether the antidote treatment decision level (30 or 50 ng/mL of DOAC) can be determined by unfractionated heparin (UHF)/low molecular weight heparin (LMWH)-calibrated AXA. METHODS: AXA was measured by using two reagents and dedicated analyzers (Sysmex CS-5100 analyzer and STA R Max3). Four types of calibrators were used: 1) Stago DOAC (rivaroxaban, edoxaban, and apixaban)-specific calibrator, 2) Stago LMWH calibrator, 3) Sysmex UHF calibrator, and 4) Sysmex LMWH calibrator. Regression analysis was used between assays. Receiver operating characteristic (ROC) curves were performed, and the concordance rate was calculated. RESULTS: The correlation coefficients were in the range of 0.75 - 0.91 for rivaroxaban and 0.81 - 0.94 for apixaban. The correlation coefficient between edoxaban-calibrated AXA and Sysmex LMWH/Sysmex UHF calibrator-calibrated AXA was low (r = 0.47). Overall correlation between DOAC-calibrated AXA and Stago LMWH-calibrated AXA was linear, at only low concentration in all three DOACs. The concordance rate (89.3 - 100%) is good for de-termining the antidote management level by UFH/LMWH-calibrated AXA, compared with those of DOAC-calibrated AXA in rivaroxaban and apixaban. The concordance rate ranged from 63% to 67% between Sysmex UFH/ LMWH-calibrated AXA and edoxaban-calibrated AXA. CONCLUSIONS: The findings of our study suggest limitations in calculating accurate concentrations, when using UFH/LMWH-calibrated AXA to measure DOAC. This study demonstrates that UFH/LMWH-calibrated AXA may be useful in determining the presence of DOACs at the cutoff level for the antidote treatment in rivarovaban and apixaban. However, in edoxaban, UFH/LMWH-calibrated AXA could not accurately measure the presence of DOACs at the cutoff for antidote treatment.
Assuntos
Inibidores do Fator Xa , Heparina , Pirazóis , Piridinas , Piridonas , Rivaroxabana , Tiazóis , Piridonas/análise , Humanos , Pirazóis/análise , Rivaroxabana/sangue , Rivaroxabana/análise , Inibidores do Fator Xa/farmacologia , Calibragem , Heparina/análise , Anticoagulantes/farmacologia , Anticoagulantes/análise , Curva ROC , Reprodutibilidade dos Testes , Testes de Coagulação Sanguínea/métodos , Testes de Coagulação Sanguínea/instrumentação , Testes de Coagulação Sanguínea/normas , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/instrumentaçãoRESUMO
Monkeypox (MPXV) is one of the infectious viruses which caused morbidity and mortality problems in these years. Despite its danger to public health, there is no approved drug to stand and handle MPXV. On the other hand, drug repurposing is a promising screening method for the low-cost introduction of approved drugs for emerging diseases and viruses which utilizes computational methods. Therefore, drug repurposing is a promising approach to suggesting approved drugs for the MPXV. This paper proposes a computational framework for MPXV antiviral prediction. To do this, we have generated a new virus-antiviral dataset. Moreover, we applied several machine learning and one deep learning method for virus-antiviral prediction. The suggested drugs by the learning methods have been investigated using docking studies. The target protein structure is modeled using homology modeling and, then, refined and validated. To the best of our knowledge, this work is the first work to study deep learning methods for the prediction of MPXV antivirals. The screening results confirm that Tilorone, Valacyclovir, Ribavirin, Favipiravir, and Baloxavir marboxil are effective drugs for MPXV treatment.
Assuntos
Antivirais , Aprendizado Profundo , Reposicionamento de Medicamentos , Monkeypox virus , Antivirais/farmacologia , Monkeypox virus/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Pirazinas/farmacologia , Simulação de Acoplamento Molecular , Dibenzotiepinas , Amidas/farmacologia , Ribavirina/farmacologia , Triazinas/farmacologia , Mpox/tratamento farmacológico , Mpox/virologia , Humanos , Aprendizado de Máquina , Morfolinas , PiridonasRESUMO
BACKGROUND: An increase in the prevalence of HIV drug resistance (HIVDR) has been reported in recent years, especially in persons on non-nucleoside reverse transcriptase inhibitors (NNRTIs) due to their low genetic barrier to mutations. However, there is a paucity of epidemiological data quantifying HIVDR in the era of new drugs like dolutegravir (DTG) in sub-Saharan Africa. We, therefore, sought to determine the prevalence and correlates of viral load (VL) suppression in adult people with HIV (PWH) on a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) or tenofovir alafenamide/emtricitabine/dolutegravir (TAFED) and describe patterns of mutations in individuals failing treatment. METHODS: We conducted a cross-sectional study among 384 adults living with HIV aged ≥15 years between 5th June 2023 and 10th August 2023. Demographic, laboratory and clinical data were collected from electronic health records using a data collection form. Viral load suppression was defined as plasma HIV-1 RNA VL of <1000 copies/ml after being on ART for ≥ 6 months. SPSS version 22 to analyze the data. Descriptive statistics and logistic regression were the statistical methods used. RESULTS: The median (interquartile range (IQR)) age was 22 (IQR 18, 38) years, and 66.1% (n = 254) were females. VL suppression was 90.4% (n = 347); (95% confidence interval (CI) 87.6%-93.6%) after switching to TLD/TAFED. Among the virally suppressed, the majority (67.1%, n = 233) were female. Those who missed ≥2 doses in the last 30 days prior to the most recent review were less likely to attain viral suppression compared to those who did not miss any dose (adjusted odds ratio (AOR) 0.047; 95% CI 0.016-0.136; p<0.001). Four participants had resistance mutations to lamivudine and tenofovir. The most common NRTI mutations were M184MV and K65R while K101E was the most common NNRTI mutation. CONCLUSION: Our findings show that viral suppression was high after switching to TLD/TAFED; but lower than the last 95% target of the UNAIDS. Adherence to antiretroviral therapy was a significant correlate of VL suppression. We, therefore, recommend prompt switching of PWH to TLD/TAFED regimen and close monitoring to enhance adherence to therapy.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Lamivudina , Mutação , Piperazinas , Piridonas , Tenofovir , Carga Viral , Humanos , Feminino , Adulto , HIV-1/genética , HIV-1/efeitos dos fármacos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Farmacorresistência Viral/genética , Carga Viral/efeitos dos fármacos , Zâmbia/epidemiologia , Estudos Transversais , Tenofovir/uso terapêutico , Tenofovir/farmacologia , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/farmacologia , Piperazinas/uso terapêutico , Lamivudina/uso terapêutico , Lamivudina/farmacologia , Piridonas/uso terapêutico , Oxazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Emtricitabina/uso terapêutico , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Combinação de MedicamentosRESUMO
The authors report a case of bilateral cataract in a 9-year-old girl after being treated with a combination of the targeted therapy drugs dabrafenib and trametinib. Although adverse effects have been reported with this treatment, this report is the first documented case of cataract as a complication. [J Pediatr Ophthalmol Strabismus. 2024;61(5):e47-e49.].
Assuntos
Catarata , Imidazóis , Oximas , Piridonas , Pirimidinonas , Humanos , Pirimidinonas/efeitos adversos , Feminino , Oximas/efeitos adversos , Criança , Piridonas/efeitos adversos , Imidazóis/efeitos adversos , Catarata/induzido quimicamente , Catarata/diagnóstico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidoresRESUMO
The systematic review and meta-analysis titled "The Effects of Dabrafenib and/or Trametinib Treatment in BRAF V600-Mutant Glioma" provides a critical evaluation of these targeted therapies for a challenging subset of gliomas. This review is notable for its comprehensive data integration, offering a robust assessment of the efficacy and safety of dabrafenib and trametinib. By focusing on BRAF V600 mutations, it contributes valuable insights into personalized treatment strategies. However, limitations include study heterogeneity and a lack of long-term follow-up data, which hinder the generalizability and complete understanding of treatment effects. Additionally, while the review emphasizes therapeutic potential, it requires a thorough evaluation of adverse effects. Future research should address these limitations by providing more consistent data, longer follow-up, and a balanced view of treatment risks and benefits.
Assuntos
Neoplasias Encefálicas , Glioma , Imidazóis , Oximas , Piridonas , Pirimidinonas , Humanos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Glioma/tratamento farmacológico , Glioma/genética , Imidazóis/uso terapêutico , Mutação , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Metanálise como Assunto , Revisões Sistemáticas como AssuntoRESUMO
Understanding the current situation and risk of environmental contamination by anti-influenza drugs in aquatic environments is key to prevent the unexpected emergence and spread of drug-resistant viruses. However, few reports have been focused on newer drugs that have recently been introduced in clinical settings. In this study, the behaviour of the prodrug baloxavir marboxil (BALM)-the active ingredient of Xofluza, an increasingly popular anti-influenza drug-and its pharmacologically active metabolite baloxavir (BAL) in the aquatic environment was evaluated. Additionally, their presence in urban rivers and a wastewater treatment plant (WWTP) in the Yodo River basin was investigated and compared with those of the major anti-influenza drugs used to date (favipiravir (FAV), peramivir (PER), laninamivir (LAN), and its active metabolite, laninamivir octanoate (LANO), oseltamivir (OSE), and its active metabolite, oseltamivir carboxylate (OSEC), and zanamivir (ZAN)) to comprehensively assess their environmental fate in the aquatic environment. The results clearly showed that BALM, FAV, and BAL were rapidly degraded through photolysis (2-h, 0.6-h, and 0.4-h half-lives, respectively), followed by LAN, which was gradually biodegraded (7-h half-life). In addition, BALM and BAL decreased by up to 47 % after 4 days and 34 % after 2 days of biodegradation in river water. However, the remaining conventional drugs, except for LANO (<1 % after 10 days), were persistent, being transported from the upstream to downstream sites. The LogKd values for the rates of sorption of BALM (0.5-1.6) and BAL (1.8-3.1) on river sediment were higher than those of conventional drugs (-0.5 to 1.7). Notably, all anti-influenza drugs were effectively removed by ozonation (>90-99.9 % removal) after biological treatment at a WWTP. Thus, these findings suggest the importance of introducing ozonation to reduce pollution loads in rivers and the environmental risks associated with drug-resistant viruses in aquatic environments, thereby promoting safe river environments.
Assuntos
Antivirais , Monitoramento Ambiental , Rios , Triazinas , Poluentes Químicos da Água , Antivirais/análise , Japão , Poluentes Químicos da Água/análise , Rios/química , Triazinas/análise , Morfolinas/análise , Piridonas/análise , Piridinas/análise , Dibenzotiepinas , Oseltamivir/análise , Piranos/análise , Águas Residuárias/química , Pirazinas/análiseRESUMO
Antiretroviral therapy (ART) has reduced the mortality and morbidity associated with HIV. However, irrespective of treatment, people living with HIV remain at a higher risk of developing non-AIDS-associated diseases. In 2019, the World Health Organization recommended the transition from efavirenz (EFV)- to dolutegravir (DTG)-based ART. Data on the impact of this transition are still limited. The current study therefore investigated the metabolic profiles, cytokine inflammatory responses, and platelet activation before and after the treatment transition. Plasma samples from nine virally suppressed adults living with HIV and sixteen healthy, HIV-uninfected individuals residing in Gauteng, South Africa were compared. Metabolite and cytokine profiles, and markers associated with platelet activation, were investigated with untargeted proton magnetic resonance metabolomics, multiplex suspension bead array immunoassays, and sandwich enzyme-linked immunosorbent assays, respectively. In those individuals with normal C-reactive protein levels, the transition to a DTG-based ART regimen resulted in decreased concentrations of acetoacetic acid, creatinine, adenosine monophosphate, 1,7-dimethylxanthine, glycolic acid, 3-hydroxybutyric acid, urea, and lysine. Moreover, increased levels of formic acid, glucose, lactic acid, myo-inositol, valine, glycolic acid, and 3-hydroxybutyric acid were observed. Notably, levels of interleukin-6, platelet-derived growth factor-BB, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, soluble cluster of differentiation 40 ligand, as well as regulated on activation, normal T-cell expressed and secreted (RANTES) reached levels close to those observed in the healthy control participants. The elevated concentration of macrophage inflammatory protein-1 alpha was the only marker indicative of elevated levels of inflammation associated with DTG-based treatment. The transition from EFV- to DTG-based regimens therefore appears to be of potential benefit with metabolic and inflammatory markers, as well as those associated with cardiovascular disease and other chronic non-AIDS-related diseases, reaching levels similar to those observed in individuals not living with HIV.
Assuntos
Alcinos , Benzoxazinas , Ciclopropanos , Citocinas , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Ativação Plaquetária , Piridonas , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/sangue , Projetos Piloto , Ativação Plaquetária/efeitos dos fármacos , Benzoxazinas/uso terapêutico , Masculino , Adulto , Feminino , Piperazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Oxazinas/uso terapêutico , Pessoa de Meia-Idade , Citocinas/sangue , Metabolômica , Inflamação , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/sangue , África do Sul , Metaboloma/efeitos dos fármacosRESUMO
Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza.
Assuntos
Antivirais , Dibenzotiepinas , Farmacorresistência Viral , Sinergismo Farmacológico , Inibidores Enzimáticos , Morfolinas , Neuraminidase , Piridonas , Triazinas , Dibenzotiepinas/farmacologia , Antivirais/farmacologia , Triazinas/farmacologia , Morfolinas/farmacologia , Piridonas/farmacologia , Neuraminidase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Humanos , Vírus da Influenza B/efeitos dos fármacos , Animais , Piridinas/farmacologia , Tiazóis/farmacologia , Guanidinas/farmacologia , Orthomyxoviridae/efeitos dos fármacos , Cães , Células Madin Darby de Rim Canino , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Ácidos Siálicos , Vírus da Influenza A/efeitos dos fármacos , Tiepinas/farmacologia , Triazóis/farmacologia , Benzimidazóis/farmacologia , PiranosRESUMO
Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with efficacy against some NNRTI-resistant mutants. Although DOR resistance mutations are established for HIV-1 subtype B, it is less clear for non-B subtypes. This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions. These mutations are frequently observed in patients failing efavirenz- or nevirapine-based first-line regimens. However, they are also observed in those failing a protease inhibitor-based second-line regimen, as we have observed in our database. Genotypic drug resistance testing is therefore vital prior to the initiation of DOR-based treatment for those previously exposed to efavirenz or nevirapine.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Genótipo , Infecções por HIV , HIV-1 , Mutação , Piridonas , Triazóis , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Farmacorresistência Viral/genética , Piridonas/farmacologia , Fármacos Anti-HIV/farmacologia , Infecções por HIV/virologia , Infecções por HIV/tratamento farmacológico , Triazóis/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fenótipo , Testes de Sensibilidade Microbiana , África do SulRESUMO
The Caf1/CNOT7 nuclease is a catalytic component of the Ccr4-Not deadenylase complex, which is a key regulator of post-transcriptional gene regulation. In addition to providing catalytic activity, Caf1/CNOT7 and its paralogue Caf1/CNOT8 also contribute a structural function by mediating interactions between the large, non-catalytic subunit CNOT1, which forms the backbone of the Ccr4-Not complex and the second nuclease subunit Ccr4 (CNOT6/CNOT6L). To facilitate investigations into the role of Caf1/CNOT7 in gene regulation, we aimed to discover and develop non-nucleoside inhibitors of the enzyme. Here, we disclose that the tri-substituted 2-pyridone compound 5-(5-bromo-2-hydroxy-benzoyl)-1-(4-chloro-2-methoxy-5-methyl-phenyl)-2-oxo-pyridine-3-carbonitrile is an inhibitor of the Caf1/CNOT7 nuclease. Using a fluorescence-based nuclease assay, the activity of 16 structural analogues was determined, which predominantly explored substituents on the 1-phenyl group. While no compound with higher potency was identified among this set of structural analogues, the lowest potency was observed with the analogue lacking substituents on the 1-phenyl group. This indicates that substituents on the 1-phenyl group contribute significantly to binding. To identify possible binding modes of the inhibitors, molecular docking was carried out. This analysis suggested that the binding modes of the five most potent inhibitors may display similar conformations upon binding active site residues. Possible interactions include π-π interactions with His225, hydrogen bonding with the backbone of Phe43 and Van der Waals interactions with His225, Leu209, Leu112 and Leu115.
Assuntos
Piridonas , Humanos , Piridonas/química , Piridonas/farmacologia , Simulação de Acoplamento Molecular , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Fatores de Transcrição/química , Ribonucleases/química , Ribonucleases/antagonistas & inibidores , Ribonucleases/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Relação Estrutura-Atividade , Exorribonucleases , Proteínas RepressorasRESUMO
Organophosphate pesticides have potent endocrine disrupting effects, hence banned in many countries. However, many organophosphates like chlorpyrifos, malathion et cetera continue to be used in some countries (Wolejko et al., 2022; Wolejko et al., 2022)including India. Fodder mediated ingestion of these substances may be harmful for livestock fertility. We have investigated the effect of the widely used organophosphate pesticide chlorpyrifos (CPF) and its metabolite, 3,5,6-trichloropyridinol (TCPy) on the expression of genes essential for spermatogenesis in goat testicular tissue. The testicular Sertoli cells (Sc) regulate germ cell division and differentiation under the influence of follicle stimulating hormone (FSH) and testosterone (T). Impaired FSH and T mediated signalling in Sc can compromise spermatogenesis leading to sub-fertility/infertility. As Sc express receptors (R) for FSH and T, they are highly susceptible to the endocrine disrupting effects of pesticides affecting fertility by dysregulating the functioning of Sc. Our results indicated that exposure to different concentrations of CPF and TCPy can compromise Sc function by downregulating the expression of FSHR and AR which was associated with a concomitant decline in the expression of genes essential for germ cell division and differentiation, like KITLG, INHBB, CLDN11 and GJA1. CPF also induced a significant reduction in the activity of acetylcholinesterase in the testes and increased the total testicular antioxidant capacity. Our results suggested that CPF and its metabolite TCPy may induce reproductive toxicity by dysregulating the expression of Sc specific genes essential for spermatogenesis.
Assuntos
Clorpirifos , Cabras , Espermatogênese , Testículo , Animais , Masculino , Espermatogênese/efeitos dos fármacos , Clorpirifos/toxicidade , Testículo/efeitos dos fármacos , Testículo/metabolismo , Regulação para Baixo/efeitos dos fármacos , Inseticidas/toxicidade , Piridinas/farmacologia , Piridinas/toxicidade , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Receptores do FSH/genética , Receptores do FSH/metabolismo , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , PiridonasAssuntos
Anticonvulsivantes , Epilepsia , Hematoma , Nitrilas , Piridonas , Humanos , Masculino , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Nitrilas/administração & dosagem , Hematoma/etiologia , Epilepsia/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Doenças Cerebelares/induzido quimicamente , Idoso , Idoso de 80 Anos ou maisRESUMO
BACKGROUND AND OBJECTIVE: Prospective sequential analyses after a new drug approval allow proactive surveillance of new drugs. In the current study, we demonstrate feasibility of frailty-specific sequential analyses for dabigatran, rivaroxaban, and apixaban versus warfarin. METHODS: We partitioned Medicare data from 2011 to 2020 into datasets based on calendar year following the date of drug approval. Each calendar year of data was added sequentially for analysis. We used a new-user, active comparative design by comparing the initiators of dabigatran versus warfarin, rivaroxaban versus warfarin, and apixaban versus warfarin. Patients aged ≥ 65 years with atrial fibrillation without contraindication to the anticoagulants were included. Claims-based frailty index ≥ 0.25 was used to define frailty. The initiators of each direct oral anticoagulant were propensity-score matched to the initiators of warfarin within each frailty status. The effectiveness outcome was ischemic stroke or systemic thromboembolism, and the safety outcome was major bleeding. For each calendar year, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazards models using all data available up to that year. RESULTS: As an example of the results, in the 2020 dataset, compared with warfarin, apixaban was associated with a reduced risk of ischemic stroke or systemic thromboembolism (frail: HR 0.73, 95% CI 0.63-0.85; non-frail: HR 0.65, 95% CI 0.59-0.72) and major bleeding (frail: HR 0.63, 95% CI 0.57-0.69; non-frail: HR 0.59, 95% CI 0.56-0.63) in both frail and non-frail patients. We found evidence for apixaban's effectiveness and safety within 1-2 years after the drug approval in frail older patients. CONCLUSION: Our frailty-specific sequential analyses can be applied to future near-real-time monitoring of newly approved drugs.
Assuntos
Anticoagulantes , Fragilidade , Medicare , Humanos , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagem , Estados Unidos , Masculino , Feminino , Medicare/estatística & dados numéricos , Idoso de 80 Anos ou mais , Administração Oral , Estudos Prospectivos , Fragilidade/tratamento farmacológico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Varfarina/uso terapêutico , Varfarina/efeitos adversos , Rivaroxabana/uso terapêutico , Rivaroxabana/efeitos adversos , Rivaroxabana/administração & dosagem , Dabigatrana/uso terapêutico , Dabigatrana/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Piridonas/uso terapêutico , Piridonas/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Idoso FragilizadoRESUMO
BACKGROUND: Both efavirenz and dolutegravir have been associated with neuropsychiatric side-effects and cognitive impairment. Furthermore, cerebrospinal fluid (CSF) HIV RNA escape has not been comprehensively studied in African populations. We aimed to examine changes in cognition, neuropsychiatric symptoms, and CSF viral control associated with the widespread switch from efavirenz-based to dolutegravir-based antiretroviral therapy (ART). METHODS: This prospective cohort study of people with HIV and people without HIV recruited adults with HIV (aged 18-55 years) from the Gugulethu Community Health Centre in a low-income periurban area of Cape Town, South Africa. Eligible participants had been receiving efavirenz-based ART for at least 1 year and were identified by the clinic to switch to dolutegravir-based ART as part of the national programmatic switch. Participants were studied at baseline and followed up at 1 year after switch to dolutegravir. People without HIV were recruited from the same area, matched for age and gender, and followed up at the same time interval. People with HIV and people without HIV underwent comprehensive cognitive testing over seven domains and measures of functioning, mood, anxiety, and sleep. People with HIV had CSF sampling for HIV RNA quantification. FINDINGS: Between Aug 12, 2019, and Sept 16, 2022, we recruited 178 people with HIV and 95 people without HIV. 145 (81%) of 178 people with HIV and 40 (66%) of 60 people without HIV who were offered underwent follow-up. Global cognitive performance was 2·57 T score points lower in people with HIV than in people without HIV at baseline (p=0·0008). At follow-up, cognition in people with HIV improved more than practice effects observed in people without HIV (coefficient 1·40, 95% CI 0·48-2·32, p=0·0028) and no significant difference in cognitive performance between groups was apparent (51·43 vs 52·73; p=0·22). Sleep quality improved following the switch (risk ratio 0·90, 95% CI 0·84-0·95; p=0·0002), driven mainly by indicators of disturbed sleep. There were nine incident cases of depression, although baseline differences were present. There was one case (1%) of CSF escape at baseline and three cases (4%) at follow-up; all were at low levels or resolved with repeated sampling. INTERPRETATION: Improvements in cognition and sleep are probably related to switching from efavirenz. However, the possible increase in depression warrants further examination. Cognitive performance in virally supressed African people with HIV receiving dolutegravir-based therapy is similar to people without HIV. CSF escape is uncommon on both efavirenz-based and dolutegravir-based therapy. FUNDING: South African Medical Research Council and UK Medical Research Council, Newton Fund.