RESUMO
This study presents the contents of α-methylenecyclopropylglycine, a potentially toxic amino acid, in the peel, pulp and seed fractions of two well-known litchi varieties, namely Shahi and China, over a span of three harvest-seasons. For analysing α-methylenecyclopropylglycine, an LC-MS/MS-based method was validated. The method-accuracies fell within 75-110 % (RSD, <15 %) at 0.1 mg/kg (LOQ) and higher levels. A comparative evaluation of the results in peel, pulp and seed at 30 days before harvest (DBH), 15-DBH, and edible-ripe stage revealed that α-methylenecyclopropylglycine content increased as the litchi seeds grew towards maturity, regardless of the cultivar. In arils, at maturity, the concentration of α-methylenecyclopropylglycine ranged from not-detected to 11.7 µg/g dry weight. The Shahi cultivar showed slightly higher α-methylenecyclopropylglycine content in comparison to China litchi. This paper presents the first known analysis of combined seasonal data on different fruit components at various growth stages for the two chosen litchi cultivars grown in India.
Assuntos
Frutas , Litchi , Sementes , Espectrometria de Massas em Tandem , Litchi/química , Litchi/crescimento & desenvolvimento , Litchi/metabolismo , Frutas/química , Frutas/crescimento & desenvolvimento , China , Sementes/química , Sementes/crescimento & desenvolvimento , Glicina/análogos & derivados , Glicina/análise , Cromatografia Líquida de Alta Pressão , Ciclopropanos/análiseRESUMO
BACKGROUND: Dyslipidemia is increasingly common in people living with HIV (PLHIV), thereby increasing the risk of cardiovascular events and diminishing the quality of life for these individuals. The study of blood lipid metabolism of PLHIV has great clinical significance in predicting the risk of cardiovascular disease. Therefore, this study aims to examine the blood lipid metabolism status of HIV-infected patients in Huzhou before and after receiving highly active antiretroviral therapy (HAART) and to explore the impact of different HAART regimens on dyslipidemia. METHOD: PLHIV confirmed in Huzhou from June 2010 to June 2022 was included. The baseline characteristics and clinical data during the follow-up period were collected, including some blood lipid indicators (total cholesterol and triglycerides) and HAART regimens. A multivariate logistic regression model and the generalized estimating equation model were used to analyze the independent effects of treatment regimens on the risk of dyslipidemia. RESULT: The overall prevalence of dyslipidemia among PLHIV after HAART was 70.11%. PLHIV receiving lamivudine (3TC) + efavirenz (EFV) + zidovudine (AZT) had a higher prevalence of dyslipidemia compared to those receiving 3TC+EFV+tenofovir disoproxil fumarate (TDF). In a logistic analysis adjusted for important covariates such as BMI, age, diabetes status, etc., we found that the risks of dyslipidemia were higher with 3TC+EFV+AZT (dyslipidemia: odds ratio [OR] = 2.09, 95% confidence interval [Cl]: 1.28-3.41; TG ≥1.7: OR = 2.40, 95%Cl:1.50-3.84) than with 3TC+EFV+TDF. Furthermore, on PLHIV that was matched 1:1 by the HAART regimens, the results of the generalized estimation equation again showed that 3TC+EFV+AZT (TG ≥1.7: OR = 1.84, 95%Cl: 1.10-3.07) is higher for the risk of marginal elevations of TG than 3TC+EFV+TDF. CONCLUSION: The prevalence of dyslipidemia varies according to different antiretroviral regimens. Using both horizontal and longitudinal data, we have repeatedly demonstrated that AZT has a more adverse effect on blood lipids than TDF from two perspectives. Therefore, we recommend caution in using the 3TC+EFV+AZT regimen for people at clinical risk of co-occurring cardiovascular disease.
Assuntos
Terapia Antirretroviral de Alta Atividade , Benzoxazinas , Dislipidemias , Infecções por HIV , Lamivudina , Humanos , Dislipidemias/epidemiologia , Dislipidemias/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Masculino , Feminino , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Pessoa de Meia-Idade , China/epidemiologia , Benzoxazinas/efeitos adversos , Benzoxazinas/uso terapêutico , Benzoxazinas/administração & dosagem , Lamivudina/uso terapêutico , Lamivudina/efeitos adversos , Ciclopropanos , Alcinos , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Zidovudina/efeitos adversos , Zidovudina/uso terapêutico , Fatores de Risco , Tenofovir/efeitos adversos , Tenofovir/uso terapêutico , PrevalênciaRESUMO
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
This research aims to produce orodispersible films (ODFs) and determine their potential use in the oral delivery of montelukast sodium for asthma treatment and allergic rhinitis. ODFs were successfully developed by Three-dimensional (3D) printing using propylene glycol (PG), and hydroxypropyl methylcellulose (HPMC), polyethylene glycol 400 (PEG). Finally, the amount of montelukast sodium in the ODFs was 5% (w/w). Drug-excipients compatibility with Fourier Transformed Infrared (FTIR) spectroscopy, mass uniformity, thickness, disintegration time, folding endurance, moisture absorption, pH, in vitro drug release (dissolution), drug content, moisture loss, moisture content, mechanical properties, and cytotoxicity studies were performed on the prepared films. All formulations disintegrated in approximately 40 s. Over 98% of drug release from all films within 2 min was confirmed. It was reported that Fm1-4 (8% HPMC and 1% PEG) and Fm2-4 (10% HPMC and 3% PEG) are more suitable for drug content, but Fm2-4 may be the ideal formulation considering its durability and transportability properties. Based on the characterization results and in vitro release values, the montelukast sodium ODF can be an option for other dosage forms. It was concluded that the formulations did not show toxic potential by in vitro cytotoxicity study with 3T3 cells. This new formulation can efficiently treat allergic rhinitis and asthma diseases.
Assuntos
Acetatos , Antiasmáticos , Asma , Ciclopropanos , Liberação Controlada de Fármacos , Polietilenoglicóis , Impressão Tridimensional , Quinolinas , Sulfetos , Ciclopropanos/administração & dosagem , Quinolinas/administração & dosagem , Quinolinas/química , Acetatos/química , Acetatos/administração & dosagem , Sulfetos/química , Asma/tratamento farmacológico , Polietilenoglicóis/química , Administração Oral , Antiasmáticos/administração & dosagem , Antiasmáticos/química , Antiasmáticos/farmacologia , Animais , Excipientes/química , Camundongos , Sistemas de Liberação de Medicamentos/métodos , Química Farmacêutica/métodos , Derivados da Hipromelose/química , Propilenoglicol/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , SolubilidadeAssuntos
Acetatos , Antiasmáticos , Asma , Ciclopropanos , Quinolinas , Sulfetos , Humanos , Asma/tratamento farmacológico , Sulfetos/efeitos adversos , Ciclopropanos/efeitos adversos , Acetatos/efeitos adversos , Acetatos/uso terapêutico , Antiasmáticos/efeitos adversos , Quinolinas/efeitos adversos , Criança , Masculino , Comportamento ProblemaRESUMO
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.
Assuntos
Alcinos , Benzoxazinas , Cognição , Ciclopropanos , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Adulto , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Benzoxazinas/uso terapêutico , Masculino , África do Sul/epidemiologia , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Cognição/efeitos dos fármacos , Adulto Jovem , Carga Viral , Fármacos Anti-HIV/uso terapêutico , Adolescente , RNA Viral/líquido cefalorraquidiano , Substituição de MedicamentosRESUMO
Background: Sigma-1 receptors are highly expressed in brain areas related to cognitive function and are a promising target for anti-amnesic treatments. We previously showed that activation of sigma-1 receptors by the selective agonist compound methyl(1âR,2âS/1âS,2âR)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropane carboxylate [(±)-PPCC] promotes a remarkable recovery in rat models of memory loss associated to cholinergic dysfunction. Objective: In this study, we sought to assess the role of (±)-PPCC on working memory deficits caused by noradrenergic depletion. Methods: Animals with a mild or severe working memory deficits associated to varying degrees of noradrenergic neuronal depletion were treated with the sigma-1 agonist just prior to the beginning of each behavioral testing session. Results: While (±)-PPCC alone at a dose of 1âmg/kg/day failed to affect working memory in lesioned animals, its association with the α2 adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (±)-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation. Conclusions: Future studies are thus necessary to address the effects of long-lasting (±)-PPCC treatment, with or without clonidine, on cognitive abilities and Alzheimer's disease-like histopathology. Considering the already established involvement of sigma-1 receptors in endogenous cell plasticity mechanisms, their activation by selective agonist compounds holds promises as possibly positive contributor to disease-modifying events in neurodegenerative diseases.
Assuntos
Modelos Animais de Doenças , Transtornos da Memória , Receptores sigma , Receptor Sigma-1 , Animais , Receptores sigma/agonistas , Receptores sigma/metabolismo , Transtornos da Memória/tratamento farmacológico , Ratos , Masculino , Ratos Wistar , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Piperidinas/farmacologia , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêuticoRESUMO
Cyclopropane and azacyclopropane, also known as aziridine, moieties are found in natural products. These moieties serve as pivotal components that lead to a broad spectrum of biological activities. While diverse strategies involving various classes of enzymes are utilized to catalyze formation of these strained three-membered rings, how non-heme iron and 2-oxoglutarate (Fe/2OG) dependent enzymes enable regio- and stereo-selective C-C and C-N ring closure has only been reported very recently. Herein, we present detailed experimental protocols for mechanistically studying Fe/2OG enzymes that catalyze cyclopropanation and aziridination reactions. These protocols include protein purification, in vitro assays, biophysical spectroscopies, and isotope-tracer experiments. We also report how to use in silico approaches to look for Fe/2OG aziridinases. Furthermore, our current mechanistic understanding of three-membered ring formation is discussed. These results not only shed light on the reaction mechanisms of Fe/2OG enzymes-catalyzed cyclopropanation and aziridination, but also open avenues for expanding the reaction repertoire of the Fe/2OG enzyme superfamily.
Assuntos
Aziridinas , Ciclopropanos , Ácidos Cetoglutáricos , Ciclopropanos/química , Ciclopropanos/metabolismo , Aziridinas/química , Aziridinas/metabolismo , Ácidos Cetoglutáricos/metabolismo , Ácidos Cetoglutáricos/química , Ferro/química , Ferro/metabolismo , Ferroproteínas não Heme/química , Ferroproteínas não Heme/metabolismo , Biocatálise , Ensaios Enzimáticos/métodos , CatáliseAssuntos
Aminopiridinas , Benzamidas , Ciclopropanos , Dermatite Atópica , Inibidores da Fosfodiesterase 4 , Humanos , Dermatite Atópica/tratamento farmacológico , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Aminopiridinas/administração & dosagem , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/administração & dosagem , Ciclopropanos/uso terapêutico , Ciclopropanos/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacologia , Ciclopropanos/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Creme para a Pele/administração & dosagem , Administração CutâneaRESUMO
PURPOSE: Montelukast is used extensively in children and adolescents for allergic rhinitis and asthma. However, concerns have been raised regarding the increased risk of neuropsychiatric adverse events (NPAEs) associated with montelukast use. Therefore, our case-crossover study was conducted to observe whether there is an increased risk of NPAEs associated with montelukast use in children and adolescents. MATERIALS AND METHODS: A population-based case-crossover study using the customised Health Insurance Review and Assessment (HIRA) dataset was conducted. Paediatric patients aged between 0 and 19 years diagnosed with allergic rhinitis and/or asthma with a history of at least one montelukast prescription between 1 January 2018 and 31 December 2021 were included. Exposure to montelukast was assessed during 3-, 7-, 14-, 28- and 56-day hazard periods prior to each patient's NPAE. Stratified analyses according to age group, gender and season for the risk of NPAEs associated with montelukast use in the previous 7 days and 14 days were performed, respectively. Conditional logistic regression analysis was used to calculate adjusted ORs (aORs) with their corresponding 95% CIs, adjusting for concomitant medications. RESULTS: A total of 161 386 paediatric patients was identified. An increased risk of NPAEs associated with montelukast was found in all time window periods, including 3-day (aOR 1.28, 95% CI 1.24 to 1.32), 7-day (aOR 1.29, 95% CI 1.26 to 1.33), 14-day (aOR 1.34, 95% CI 1.31 to 1.37), 28-day (aOR 1.38, 95% CI 1.36 to 1.41) and 56-day (aOR 1.21, 95% CI 1.19 to 1.22) preceding hazard periods compared with use in the four control periods. CONCLUSION: Children and adolescents with allergic rhinitis and/or asthma should be prescribed montelukast with caution considering clinical benefits.
Assuntos
Acetatos , Antiasmáticos , Asma , Estudos Cross-Over , Ciclopropanos , Quinolinas , Sulfetos , Humanos , Criança , Adolescente , Masculino , Feminino , Pré-Escolar , Acetatos/efeitos adversos , Acetatos/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Sulfetos/efeitos adversos , Asma/tratamento farmacológico , Asma/epidemiologia , Lactente , Antiasmáticos/efeitos adversos , Antiasmáticos/administração & dosagem , Antiasmáticos/uso terapêutico , Rinite Alérgica/epidemiologia , Recém-Nascido , Adulto JovemRESUMO
BACKGROUND: A dolutegravir (DTG)-based antiretroviral regimen has been rolled out for pregnant women in low- and middle-income countries since 2020. However, available safety data are limited to a few clinical trials and observational studies. Hence, we present real-world pregnancy and birth outcome safety data from a large sample multicenter cohort study in Ethiopia. METHODS: A retrospective cohort study was conducted in fourteen hospitals across Ethiopia from 2017 to 2022. HIV-infected pregnant women were followed from the date of prevention of mother-to-child transmission (PMTCT) care enrolment until the infant was 6-8 weeks old. The primary safety outcome was a composite of adverse pregnancy events comprising spontaneous abortion, intrauterine fetal death (IUFD) before onset of labor, preterm birth, and maternal death. Additionally, a composite adverse birth outcome was assessed, comprising intrapartum fetal demise, low birth weight, and neonatal death. Finally, a composite of adverse pregnancy or birth outcome was also investigated. The exposure of interest was the antiretroviral treatment (ART) regimen used during pregnancy for PMTCT of HIV. RESULTS: During the study period, 2643 women were enrolled in routine PMTCT care. However, 2490 (92.2%) participants were eligible for the study. A total of 136/1724 (7.9%, 95% CI: 6.7-9.3%) women experienced adverse pregnancy outcomes. Fewer women in the DTG-based group (5.4%, 95% CI: 3.7-7.5%) had adverse pregnancy outcomes than in the Efavirenz (EFV)-based group (8.3%, 95% CI: 6.6-10.3%), P = 0.004. After controlling for baseline differences, the DTG group had a 43% lower risk of adverse pregnancy outcomes (adjusted odd ratio (AOR), 0.57; 95% CI, 0.32-0.96%) and a 53% lower risk of preterm birth (AOR, 0.47; 95% CI, 0.22-0.98%) compared to the EFV group. A total of 103/1616 (6.4%, 95% CI: 5.2-7.7%) women had adverse birth outcomes. Although the difference was not statistically significant, fewer women in the DTG group (30/548; 5.5%, 95% CI: 3.7-7.7%) than in the EFV group (57/830; 6.9%, 95% CI: 5.2-8.8%) had adverse birth outcomes. CONCLUSIONS: In this study, we observed that DTG-based regimens were associated with better pregnancy and birth outcome safety profiles, reaffirming the WHO recommendation. However, a prospective study is recommended to assess uncaptured maternal and perinatal adverse outcomes, such as congenital abnormalities, and infant growth and neurocognitive development.
Assuntos
Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Transmissão Vertical de Doenças Infecciosas , Oxazinas , Piperazinas , Complicações Infecciosas na Gravidez , Resultado da Gravidez , Piridonas , Humanos , Gravidez , Feminino , Etiópia/epidemiologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Infecções por HIV/tratamento farmacológico , Adulto , Estudos Retrospectivos , Complicações Infecciosas na Gravidez/tratamento farmacológico , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Adulto Jovem , Ciclopropanos , Benzoxazinas/uso terapêutico , Benzoxazinas/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Alcinos , Estudos de Coortes , Nascimento Prematuro/epidemiologiaRESUMO
As an important small organic molecule, cyclopropane is widely used in drug design. In this paper, fifty-three amide derivatives containing cyclopropane were designed and synthesized by introducing amide groups and aryl groups into cyclopropane through the active splicing method, and their antibacterial and antifungal activities were evaluated in vitro. Among them, thirty-five compounds were new compounds, and eighteen compounds were known compounds (F14, F15, F18, F20-F26, F36, and F38-F44). Bioassay results disclosed that four, three, and nine of the compounds showed moderate activity against Staphylococcus aureus, Escherichia coli, and Candida albicans, respectively. Three compounds were sensitive to Candida albicans, with excellent antifungal activity (MIC80 = 16 µg/mL). The molecular docking results show that compounds F8, F24, and F42 have good affinity with the potential antifungal drug target CYP51 protein.
Assuntos
Amidas , Antifúngicos , Candida albicans , Ciclopropanos , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Staphylococcus aureus , Ciclopropanos/farmacologia , Ciclopropanos/química , Ciclopropanos/síntese química , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Candida albicans/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Escherichia coli/efeitos dos fármacos , Relação Estrutura-Atividade , Anti-Infecciosos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Estrutura MolecularRESUMO
BACKGROUND: Chronic inflammatory skin diseases are of great social and medical importance and require effective drug therapy. Phosphodiesterase 4 (PDE4) inhibitors represent a possible therapeutic option by regulating inflammatory processes. PDEs cause the release of proinflammatory cytokines by interfering with signaling pathways. The PDE4 inhibitors apremilast (treatment of psoriasis and Behçet's disease), roflumilast (treatment of chronic obstructive pulmonary disease), and crisaborole (treatment of atopic dermatitis) are currently approved in Europe. PSORIASIS: Apremilast is used for second-line treatment of plaque psoriasis and psoriatic arthritis and has a favorable side effect profile. Topical PDE4 inhibitors are currently being researched and have not yet been approved by the European Medicines Agency (EMA). ATOPIC DERMATITIS: The topical PDE4 inhibitor crisaborole was approved by the EMA in 2020 as a topical treatment alternative to glucocorticoids and calcineurin inhibitors. Although the substance has shown good tolerability in studies and also alleviates the accompanying itching, it did not find its way onto the German market. BEHçET'S DISEASE: Apremilast is approved for the treatment of Behçet's disease in adults with refractory, severe oral ulcers. OUTLOOK: Case studies have also demonstrated the efficacy of systemic PDE4 inhibition in other skin diseases (including blistering autoimmune dermatoses, lichen planus, and acantholytic genodermatoses). The substances are also being researched and used to treat extracutaneous inflammatory diseases.
Assuntos
Inibidores da Fosfodiesterase 4 , Psoríase , Talidomida , Humanos , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/farmacologia , Talidomida/efeitos adversos , Psoríase/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Aminopiridinas/uso terapêutico , Aminopiridinas/efeitos adversos , Compostos de Boro/uso terapêutico , Compostos de Boro/farmacologia , Síndrome de Behçet/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Ciclopropanos , Compostos Bicíclicos Heterocíclicos com PontesRESUMO
BACKGROUND: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens. OBJECTIVE: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens. METHODS: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019. The first LOT during the study period was included in the analysis. We examined all-cause HCRU and costs and HIV-related HCRU and combined costs to the health plan and direct patient costs by site of service and compared between INSTI-based regimens: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (single tablet) vs dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single tablet), dolutegravir + emtricitabine/tenofovir alafenamide (DTG+FTC/TAF) (multitablet), and dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+FTC/TDF) (multitablet). Analysis of HCRU by site of service was conducted following inverse probability treatment weighting. Multivariable regression was conducted using a generalized linear model with stepwise covariate selection to estimate HIV-related medical costs and control for remaining differences after inverse probability treatment weighting. RESULTS: 4,251 PWH were identified: B/F/TAF (n = 2,727; 64.2%), DTG/ABC/3TC (n = 898; 21.1%), DTG+FTC/TAF (n = 539; 12.7%), and DTG+FTC/TDF (n = 87; 2.1%). PWH treated with DTG+FTC/TAF had a significantly higher mean of all-cause ambulatory visits than PWH treated with B/F/TAF (1.8 vs 1.6, P < 0.001). A significantly smaller proportion of PWH treated with DTG/ABC/3TC had an all-cause ambulatory visit vs PWH treated with B/F/TAF (90.6% vs 93.9%, P < 0.001). All-cause total costs were not significantly different between regimens. Mean (SD) medical HIV-related costs per month during the LOT were not significantly different between B/F/TAF $699 (3,602), DTG/ABC/3TC $770 (3,469), DTG+FTC/TAF $817 (3,128), and DTG+FTC/TDF $3,570 (17,691). After further controlling for unbalanced measures, HIV-related medical costs during the LOT were higher (20%) but did not reach statistical significance for DTG/ABC/3TC (cost ratio = 1.20, 95% CI = 0.851-1.694; P = 0.299), 49% higher for DTG+FTC/TAF (cost ratio = 1.489, 95% CI = 1.018-2.179; P = 0.040), and almost 11 times greater for DTG+FTC/TDF (cost ratio = 10.759, 95% CI = 2.182-53.048; P = 0.004) compared with B/F/TAF. CONCLUSIONS: HIV-related medical costs during the LOT were lowest for PWH treated with INSTI-based single-tablet regimens. Simplifying treatment regimens may help PWH maintain lower health care costs.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Piridonas , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/economia , Estudos Retrospectivos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Piridonas/economia , Piridonas/uso terapêutico , Fármacos Anti-HIV/economia , Fármacos Anti-HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/economia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Tenofovir/uso terapêutico , Tenofovir/economia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Custos de Cuidados de Saúde/estatística & dados numéricos , Combinação de Medicamentos , Oxazinas/uso terapêutico , Oxazinas/economia , Emtricitabina/uso terapêutico , Emtricitabina/economia , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/economia , Piperazinas/economia , Piperazinas/uso terapêutico , Lamivudina/economia , Lamivudina/uso terapêutico , Inibidores de Integrase de HIV/economia , Inibidores de Integrase de HIV/uso terapêutico , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Substituição de Medicamentos/economia , Amidas , Ciclopropanos , Didesoxiadenosina/análogos & derivadosRESUMO
The application of coatings is a strategy for maintaining the freshness of highly perishable fruits. This research aimed to evaluate the quality indices of strawberries (Amaou) coated with new coatings based on the sodium carboxymethyl cellulose (CMC) and cellulose nanofibres (CNF) with incorporated mandarin peel extract (ME) or 1-methylcyclopropene (1-MCP) during storage at 20days at 5 °C and 85% relative humidity (RH). Dissolving the coating solution containing ME in 1-MCP maintained its colour for up to 50 days. Coatings enhanced with ME and/or 1-MCP maintained fresh strawberries more effectively than the control, reducing weight loss and maintaining firmness, total soluble solids (TSS), citric acid, colour, and total phenolic content. The CCM2-2 coating solution showed superior effects on the weight loss and relative percentages of strawberry metabolites compared to the other coatings, as confirmed by the different components.
Assuntos
Citrus , Ciclopropanos , Conservação de Alimentos , Armazenamento de Alimentos , Fragaria , Frutas , Extratos Vegetais , Frutas/química , Fragaria/química , Fragaria/metabolismo , Conservação de Alimentos/métodos , Ciclopropanos/química , Ciclopropanos/farmacologia , Extratos Vegetais/química , Citrus/química , Metaboloma , Temperatura BaixaRESUMO
TMEM16A, a member of the Transmembrane protein 16 family, serves as the molecular basis for calcium activated chloride channels (CaCCs). We use RT-PCR to demonstrate the expression of TMEM16A in the neurons of Helicoverpa armigera, and record the CaCCs current of acute isolated neurons of H. armigera for the first time using patch clamp technology. In order to screen effective inhibitors of calcium-activated chloride channels, the inhibitory effects of four chloride channel inhibitors, CaCCinh-A01, NPPB, DIDS, and SITS, on CaCCs were compared. The inhibitory effects of the four inhibitors on the outward current of CaCCs were CaCCinh-A01 (10 µM, 56.31 %), NPPB (200 µM, 43.69 %), SITS (1 mM, 12.41 %) and DIDS (1 mM, 13.29 %). Among these inhibitors, CaCCinh-A01 demonstrated the highest efficacy as a blocker. To further explore whether calcium channel proteins can serve as potential targets of pyrethroids, we compared the effects of (type I) tefluthrin and (type II) deltamethrin on CaCCs. 10 µM and 100 µM tefluthrin can stimulate a large tail current in CaCCs, prolonging their deactivation time by 10.44 ms and 31.49 ms, and the V0.5 shifted in the hyperpolarization by 2-8 mV. Then, deltamethrin had no obvious effect on the deactivation and activation of CaCCs. Therefore, CaCCs of H. armigera can be used as a potential target of pyrethroids, but type I and type II pyrethroids have different effects on CaCCs.
Assuntos
Canais de Cloreto , Inseticidas , Mariposas , Neurônios , Piretrinas , Animais , Inseticidas/toxicidade , Inseticidas/farmacologia , Piretrinas/toxicidade , Piretrinas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Canais de Cloreto/metabolismo , Canais de Cloreto/antagonistas & inibidores , Mariposas/efeitos dos fármacos , Anoctamina-1/metabolismo , Anoctamina-1/antagonistas & inibidores , Proteínas de Insetos/metabolismo , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/genética , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Nitrobenzoatos/farmacologia , Helicoverpa armigera , Ciclopropanos , Hidrocarbonetos FluoradosRESUMO
This study investigates the pharmacokinetics (PK) of montelukast (MTK), a cysteinyl leukotriene receptor antagonist increasingly being considered in veterinary medicine. In dogs, MTK has found indications mainly for treating atopic dermatitis as an off-label use. Six male Labrador dogs underwent a single oral administration of MTK (40â¯mg/dog) in both fasted and fed conditions according to an open, single-dose, two-treatment, two-phase, cross-over design, with a washout period of one week. Blood was withdrawn to heparinized tubes at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, and 24â¯hr. MTK plasma concentrations were quantified using a validated HPLC method, and the data were analysed using PKanalix™ software with a non-compartmental approach. Concentrations remained quantifiable at 24â¯hr after administration, under both conditions. No significant differences were observed in the PK parameters between the fasted and fed states. MTK was relatively eliminated slowly, with t1/2 values of 8.10 and 7.68â¯hr after fasted and fed states, respectively. The attainment of maximum concentration (Cmax) occurred at a Tmax of 4â¯hr, with mean values of 1.98⯵g/mL and 2.80⯵g/mL under fasted and fed conditions, respectively. Given the unknown therapeutic range of MTK in dogs and the absence of controlled studies proving its efficacy in this species, further dosing adjustments and refinements should be considered based on both the current PK data and the need to establish an effective therapeutic range, if present. Future research should focus on efficacy studies, multiple-dose investigations, and pharmacodynamic assessments to evaluate the suitability of MTK use in dogs.
Assuntos
Acetatos , Estudos Cross-Over , Ciclopropanos , Jejum , Antagonistas de Leucotrienos , Quinolinas , Sulfetos , Animais , Cães , Sulfetos/farmacocinética , Sulfetos/administração & dosagem , Masculino , Quinolinas/farmacocinética , Quinolinas/administração & dosagem , Ciclopropanos/farmacocinética , Ciclopropanos/administração & dosagem , Acetatos/farmacocinética , Acetatos/administração & dosagem , Administração Oral , Antagonistas de Leucotrienos/farmacocinética , Antagonistas de Leucotrienos/administração & dosagem , Área Sob a Curva , Meia-VidaRESUMO
Introduction: VESTED (NCT03048422) compared the safety and efficacy of three antiretroviral treatment (ART) regimens in pregnant and postpartum women: dolutegravir+emtricitabine/tenofovir alafenamide fumarate; dolutegravir+emtricitabine/tenofovir disoproxil fumarate (TDF); efavirenz/emtricitabine/TDF. Vertical HIV transmission (VT) occurred to 4/617 (0.60%) live-born infants, who were evaluated for HIV drug resistance (HIVDR) and other risk factors. Setting: In 2018-2020, pregnant (weeks-14-28) women living with HIV and ≤14 days of ART were enrolled at 22 international sites and followed with their infants through 50 weeks postpartum. Methods: HIV sequences derived by single genome amplification (SGA) from longitudinally collected specimens were assessed from VT Cases for HIVDR in protease, reverse transcriptase, integrase, and the nef 3'polypurine tract (3'PPT). Results: The four Case mothers were prescribed efavirenz-based-ART for 1-7 days prior to randomization to study ART. Their infants received postnatal nevirapine+/-zidovudine prophylaxis and were breastfed. A total of 833 SGA sequences were derived. The "major" (Stanford HIVDR Score ≥60) non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation (K103N) was detected persistently in one viremic mother, and likely contributed to VT of HIVDR. Major NNRTI HIVDR mutations were detected in all three surviving infants. No integrase, nor high frequencies of 3'PPT mutations conferring dolutegravir HIVDR were detected. The timing of HIV infant diagnosis, plasma HIV RNA levels and HIVDR suggests one in utero, one peripartum, one early, and one late breastfeeding transmission. Conclusions: VT was rare. New-onset NNRTI HIVDR in Case mothers was likely from efavirenz-ART prescribed prior to study dolutegravir-ART, and in one case appeared transmitted to the infant despite nevirapine prophylaxis.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , Transmissão Vertical de Doenças Infecciosas , Humanos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Infecções por HIV/virologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Farmacorresistência Viral/genética , Gravidez , Fármacos Anti-HIV/uso terapêutico , Adulto , Recém-Nascido , Piperazinas/uso terapêutico , Ciclopropanos , HIV-1/genética , HIV-1/efeitos dos fármacos , Tenofovir/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Alcinos , Piridonas/uso terapêutico , Emtricitabina/uso terapêutico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Benzoxazinas/uso terapêutico , Oxazinas/uso terapêuticoRESUMO
Irreversible cardiotoxicity limits the clinical application of doxorubicin (DOX). DOX-induced cardiotoxicity has been associated with induction of senescence and activation of the p38 MAPK pathway. Losmapimod (LOSM), an orally active p38 MAPK inhibitor, is an anti-inflammatory agent with cardioprotective effects. Nevertheless, the effect of LOSM against DOX-induced cardiotoxicity has not been reported. In this study, we determined the effects of LOSM on DOX-induced chronic cardiotoxicity in C57BL/6â¯N mice. Five-week-old C57BL/6â¯N mice were fed diet containing LOSM (estimated daily intake 12â¯mg/kg/day) or a control diet for four days. Thereafter, mice were randomized to receive six weekly intraperitoneal injections of either DOX (4â¯mg/kg) or saline. Three days after the last injection, cardiac function was assessed by trans-thoracic echocardiography. Activation of p38, JNK, and ERK1/2 MAPKs were assessed by immunoblotting in the heart and liver. Gene expressions of senescence, inflammatory, oxidative stress, and mitochondrial function markers were quantified using real-time PCR and serum inflammatory markers were assessed by Luminex. Our results demonstrated that LOSM attenuated p38 MAPK activation, ameliorated DOX-induced cardiac dysfunction, and abrogated DOX-induced expression of the senescence marker p21Cip1. Additionally, LOSM demonstrated anti-inflammatory effects, with reduced cardiac Il-1α and Il-6 gene expression in DOX-treated mice. Systemic inflammation, assessed by serum cytokine levels, showed decreased IL-6 and CXCL1 in both DOX-treated mice and mice on LOSM diet. LOSM significantly increased mitofusin2 gene expression, which may enhance mitochondrial fusion. These findings underscore the potential therapeutic efficacy of p38 MAPK inhibition, exemplified by LOSM, in ameliorating DOX-induced cardiotoxicity, senescence, and inflammation.
Assuntos
Cardiotoxicidade , Doxorrubicina , Inflamação , Camundongos Endogâmicos C57BL , Animais , Doxorrubicina/toxicidade , Doxorrubicina/efeitos adversos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Masculino , Piridinas/farmacologia , Senescência Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Anti-Inflamatórios/farmacologia , CiclopropanosRESUMO
Cyclization provides a general strategy for improving the proteolytic stability, cell membrane permeability and target binding affinity of peptides. Insertion of a stable, non-reducible linker into a disulphide bond is a commonly used approach for cyclizing phage-displayed peptides. However, among the vast collection of cysteine reactive linkers available, few provide the selectivity required to target specific cysteine residues within the peptide in the phage display system, whilst sparing those on the phage capsid. Here, we report the development of a cyclopropenone-based proximity-driven chemical linker that can efficiently cyclize synthetic peptides and peptides fused to a phage-coat protein, and cyclize phage-displayed peptides in a site-specific manner, with no disruption to phage infectivity. Our cyclization strategy enables the construction of stable, highly diverse phage display libraries. These libraries can be used for the selection of high-affinity cyclic peptide binders, as exemplified through model selections on streptavidin and the therapeutic target αvß3.