RESUMO
BACKGROUND: This real-world analysis evaluated drug utilization focusing on wastage and healthcare costs for treatment of patients with advanced breast cancer (aBC) hormone receptor-positive (HR+)/human epidermal growth factor receptor-2 negative (HER2-) in Italy. METHODS: A retrospective analysis was conducted on administrative data covering about 13.3 million health-assisted individuals. Across January/2017-June/2021, all patients with HR+/HER2-aBC were identified by ≥ 1 prescription for cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). Cost analysis was performed and updated referring to the prices of November 2021. RESULTS: Overall, 3,647 HR+/HER2-aBC patients were included (2,627 palbociclib treated, 729 ribociclib treated, and 291 abemaciclib treated). After 12 months of follow-up, 35% of palbociclib patients had a dose reduction (on average 8.9 wasted pills/patient), 44.7% of abemaciclib patients had a dose reduction (on average 6.7 wasted pills/patient), 22.1% of ribociclib patients had a dose reduction (no wasted pills). Therapy wastage added up to 528,716 for palbociclib-treated patients (524/patient) and 5,738 in abemaciclib-treated patients (151/patient). No wastage was attributed to ribociclib. CONCLUSIONS: Dose reduction was associated with drug wastage in palbociclib and abemaciclib-treated patients, but not in ribociclib-treated ones. These findings might be helpful to policy decision-makers who, for healthcare strategies implementation, among several variables should consider the possible restraining of drug wastage.
Assuntos
Benzimidazóis , Neoplasias da Mama , Purinas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores de Proteínas Quinases/farmacologiaRESUMO
A new and suitable multicomponent one-pot reaction was developed for the synthesis of 2-amino-3-cyanopyridine derivatives. BACKGROUND: This synthesis was demonstrated by the efficient and easy access to a variety of substituted 2-aminopyridines using enaminones as key precursors under solvent-free conditions. METHODS: A range of spectroscopic techniques was used to determine and confirm the chemical structures (FTIR, 1H NMR, 13C NMR). The antimicrobial potency of synthesized compounds (2a-d) was tested using disk diffusion assays, and the Minimum Inhibitory Concentration (MIC) for the active compounds was determined against a panel of microorganisms, including Gram-positive and Gram-negative bacteria and yeasts. Moreover, a docking analysis was conducted by Molecular Operating Environment (MOE) software to provide supplementary information about the potential, as well as an ADME-T prediction to describe the pharmacokinetic properties of the best compound and its toxicity. RESULTS: The results of the antimicrobial activity indicated that compound 2c showed the highest activity against Gram-positive bacteria, particularly S. aureus and B. subtilis whose MIC values were 0.039 ± 0.000 µg·mL-1. The results of the theoretical study of compound 2c were in line with the experimental data and exhibited excellent antibacterial potential. CONCLUSIONS: On the basis of the obtained results, compound 2c can be used as an antibacterial agent model with high antibacterial potency.
Assuntos
Antibacterianos , Anti-Infecciosos , Aminopiridinas/farmacologia , Antibacterianos/química , Anti-Infecciosos/farmacologia , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Staphylococcus aureus , Relação Estrutura-AtividadeAssuntos
Aminopiridinas/farmacologia , Antibacterianos/farmacologia , Quinolonas/farmacologia , Administração Tópica , Aminopiridinas/química , Aminopiridinas/economia , Antibacterianos/química , Antibacterianos/economia , Contraindicações de Medicamentos , Interações Medicamentosas , Farmacorresistência Bacteriana , Humanos , Estrutura Molecular , Pomadas , Quinolonas/química , Quinolonas/economiaRESUMO
Sclerotinia homoeocarpa causes dollar spot disease on turfgrass and is a serious problem on many species worldwide. Fludioxonil, a phenylpyrrole fungicide, is not currently registered for dollar spot control in China. In this study, the baseline sensitivity to fludioxonil was established using an in vitro assay for 105 isolates of S. homoeocarpa collected from 10 locations in different regions of China. Results indicate that the frequency distribution of effective concentration for 50% inhibition of mycelial growth (EC50) values of the S. homoeocarpa isolates was unimodal (Wâ¯=â¯0.9847, Pâ¯=â¯.2730). The mean EC50 value was 0.0020⯱â¯0.0006⯵g/ml with a range from 0.0003 to 0.0035⯵g/ml. A total of 7 fludioxonil-resistant mutants were obtained in laboratory, the mutants were stable in fludioxonil sensitivity after the 10th transfer, with resistance factor (RF) ranging from 4.320 to >13,901.4. The mutants showed a positive cross-resistance between fludioxonil and the dicarboximide fungicide iprodione, but not propiconazole, fluazinam, and thiophanate-methyl. When mycelial growth rate, pathogenicity and osmotic sensitivity were assessed, the mutants decreased in the fitness compared with their parental isolates. Sequence alignment of the histidine kinase gene Shos1 revealed a 13-bp fragment deletion only in one mutant, no mutations were observed on Shos1 in the rest resistant mutants.
Assuntos
Ascomicetos/efeitos dos fármacos , Ascomicetos/metabolismo , Dioxóis/farmacologia , Fungicidas Industriais/farmacologia , Pirróis/farmacologia , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Aminopiridinas/farmacologia , Ascomicetos/genética , China , Farmacorresistência Fúngica/genética , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Regulação Fúngica da Expressão Gênica/genética , Hidantoínas/farmacologia , Mutação/genética , Tiofanato/farmacologia , Triazóis/farmacologiaRESUMO
Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a number of biological processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With a majority of the members of our lead series (e.g., 1) suffering from time-dependent inhibition (TDI) of CYP3A4, we sought design avenues that would eliminate this risk. One such approach arose from the observation that carboxylic acid-based intermediates employed in our discovery efforts retained high MAP4K4 inhibitory potency and were devoid of the TDI risk. The medicinal chemistry effort that led to the discovery of this central nervous system-impaired inhibitor together with its preclinical safety profile is described.
Assuntos
Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Aminopiridinas/efeitos adversos , Animais , Disponibilidade Biológica , Ácidos Carboxílicos/química , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/farmacologia , Descoberta de Drogas , Meia-Vida , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Molecular , Inibidores de Proteínas Quinases/efeitos adversos , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/sangueRESUMO
In the current study, sensitivity distribution of Sclerotinia sclerotiorum populations to fluazinam was determined using 103 strains collected from the fields of Jiangsu Province of China in 2016-2017 and the resistance risk of fluazinam was assessed. The average EC50 (50% effective concentration) values and MIC (minimum inhibitory concentration) values of 103 S. sclerotiorum strains against fluazinam were 0.0073±0.0045µg/ml and <0.3µg/ml for mycelial growth, respectively. Nine mutants with low resistance level were obtained from wild type sensitive strains exposed on PDA medium amended with fluazinam and the resistance was stable after their ten transfers on PDA without the fungicide. Compared with the parental strains, the nine fluazinam-resistant mutants decreased in mycelial growth, sclerotial production, pathogenicity and were more sensitive to 0.7M NaCl. In addition, cell membrane permeability of resistant mutants was higher than that of their parental strains. Cross resistance assay showed that there was no cross-resistance between fluazinam and fludioxonil, dimetachlone, prochloraz, tebuconazole, azoxystrobin, or procymidone in S. sclerotiorum. The above results indicated that there was a low resistance risk for fluazinam in S. sclerotiorum. However, the sensitivity of all fluazinam-resistant mutants to fludioxonil decreased. Sequencing alignment results showed that there were no mutations in the two-component histidine kinase gene (Shk1) of the resistant mutants and the expression levels of Shk1 of three resistant mutants were significantly up-regulated while others were almost the same as their parental strains. These results will contribute to evaluating the resistance risk of fluazinam for management of diseases caused by S. sclerotiorum and further increase our understanding about the mode of action of fluazinam.
Assuntos
Aminopiridinas/farmacologia , Ascomicetos/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Fungicidas Industriais/farmacologia , Ascomicetos/genética , Ascomicetos/crescimento & desenvolvimento , Ascomicetos/patogenicidade , Permeabilidade da Membrana Celular/efeitos dos fármacos , Farmacorresistência Fúngica/genética , Histidina Quinase/genética , Testes de Sensibilidade Microbiana , Mutação , Medição de Risco , Regulação para CimaRESUMO
Immaturity in impulse control among adolescents could result in substance abuse, criminal involvement, and suicide. The brains of adolescents and adults are anatomically, neurophysiologically, and pharmacologically different. Therefore, preclinical models of adolescent impulsivity are required to screen drugs for adolescents and elucidate the neural mechanisms underlying age-related differences in impulsivity. The conventional 3- or 5-choice serial reaction time task, which is a widely used task to assess impulsivity in adult rodents, cannot be used for young mice because of two technical problems: impaired growth caused by food restriction and the very long training duration. To overcome these problems, we altered the conventional training process, optimizing the degree of food restriction for young animals and shortening the training duration. We found that almost all basal performance levels were similar between the novel and conventional procedures. We also confirmed the pharmacological validity of our results: the 5-hydroxytryptamine 2C (5-HT2C) receptor agonist Ro60-0175 (0.6â¯mg/kg, subcutaneous) reduced the occurrence of premature responses, whereas the 5-HT2C receptor antagonist SB242084 (0.5â¯mg/kg intraperitoneal) increased their occurrence, consistent with results of previous studies using conventional procedures. Furthermore, we detected age-related differences in impulsivity using the novel procedure: adolescent mice were found to be more impulsive than adult mice, congruent with the results of human studies. Thus, the new procedure enables the assessment of impulsivity in adolescent mice and facilitates a better understanding of the neurophysiological/pharmacological properties of adolescents.
Assuntos
Comportamento Impulsivo , Camundongos Endogâmicos C57BL/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL/psicologia , Modelos Animais , Testes Neuropsicológicos , Envelhecimento/psicologia , Aminopiridinas/farmacologia , Animais , Etilaminas/farmacologia , Função Executiva/efeitos dos fármacos , Função Executiva/fisiologia , Privação de Alimentos/fisiologia , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Indóis/farmacologia , Inibição Psicológica , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Camundongos Endogâmicos C57BL/fisiologia , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Fatores de TempoAssuntos
Aminopiridinas/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Purinas/uso terapêutico , Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Aprovação de Drogas , Indústria Farmacêutica , Feminino , Humanos , Purinas/farmacologia , Estados Unidos , United States Food and Drug AdministrationRESUMO
AIMS: To investigate the metabolic effects of the phosphodiesterase-4 (PDE4) inhibitor roflumilast, a clinically approved anti-inflammatory drug used for the treatment of chronic obstructive pulmonary disease. MATERIALS AND METHODS: The metabolic effects of roflumilast were investigated in C57BL/6J mice, fed a high-fat Western-type diet and treated with or without roflumilast for a period of 12 weeks. RESULTS: Roflumilast led to a marked reduction in body weight gain, which became apparent in the second week after treatment initiation and was attributable to a pronounced increase in energy expenditure. Furthermore, roflumilast improved glucose tolerance, reduced insulin resistance and diminished steatohepatitis in mice. Mechanistically, this was associated with hepatic protein kinase A (PKA) and cAMP response element binding protein (CREB) activation, leading to peroxisome proliferator-activated receptor gamma coactivator-1α (PCG-1α)-dependent induction of mitochondrial biogenesis. Consistently, roflumilast increased the cellular respiratory capacity of hepatocytes in a PKA-dependent manner. CONCLUSION: Roflumilast-dependent PDE4 inhibition is a new target for weight loss strategies, especially in conditions of associated comorbidities such as insulin resistance and non-alcoholic steatohepatitis.
Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Aumento de Peso/efeitos dos fármacos , Animais , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Ciclopropanos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Transdução de Sinais/efeitos dos fármacosAssuntos
Fibrose Cística , Quimioterapia Combinada , Mutação/genética , Aminofenóis/farmacologia , Aminofenóis/uso terapêutico , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Pesquisa Biomédica , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Indústria Farmacêutica , Quimioterapia Combinada/economia , Quimioterapia Combinada/tendências , Humanos , Quinolonas/farmacologia , Quinolonas/uso terapêuticoRESUMO
BACKGROUND: When faced with uncertainties about the effects of medical interventions regulatory agencies, guideline developers, clinicians, and researchers commonly ask for more research, and in particular for more randomized trials. The conduct of additional randomized trials is, however, sometimes not the most efficient way to reduce uncertainty. Instead, approaches such as value of information analysis or other approaches should be used to prioritize research that will most likely reduce uncertainty and inform decisions. DISCUSSION: In situations where additional research for specific interventions needs to be prioritized, we propose the use of quantitative benefit-harm assessments that illustrate how the benefit-harm balance may change as a consequence of additional research. The example of roflumilast for patients with chronic obstructive pulmonary disease shows that additional research on patient preferences (e.g., how important are exacerbations relative to psychiatric harms?) or outcome risks (e.g., what is the incidence of psychiatric outcomes in patients with chronic obstructive pulmonary disease without treatment?) is sometimes more valuable than additional randomized trials. We propose that quantitative benefit-harm assessments have the potential to explore the impact of additional research and to identify research priorities Our approach may be seen as another type of value of information analysis and as a useful approach to stimulate specific new research that has the potential to change current estimates of the benefit-harm balance and decision making.
Assuntos
Aminopiridinas/farmacologia , Benzamidas/farmacologia , Coleta de Dados , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pesquisa , Ciclopropanos/farmacologia , Humanos , Inibidores da Fosfodiesterase 4/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Medição de RiscoRESUMO
PURPOSE: The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker. METHODS: Twenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg × 3 days followed by 40 mg × 7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at -2, -1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3-7. RESULTS: The geometric mean ratio and 90% confidence interval of Cmax and AUC of acetaminophen were within 80-125% suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food. CONCLUSION: In the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the Tmax of acetaminophen was delayed by â¼1.25 h without affecting Cmax or AUC.
Assuntos
Acetaminofen/farmacocinética , Acetatos/farmacologia , Aminopiridinas/farmacologia , Interações Medicamentosas/fisiologia , Adulto , Área Sob a Curva , Estudos Cross-Over , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Feminino , Esvaziamento Gástrico/fisiologia , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
INTRODUCTION: At last, after many years of research, roflumilast has become the first oral phosphodiesterase-4 inhibitor to be approved by the medical agencies as an add-on therapy for chronic obstructive pulmonary disease. A second compound, apremilast is targeted for submission of new drug application for the treatment of psoriasis in the second half of 2013. These compounds represent a breakthrough and a reward in the field after the many failures to date in clinical development. AREAS COVERED: This review summarizes the clinical development of PDE4 inhibitors from 2010 - 2012 and the associated patent literature with a focus on strategies to overcome the common pitfalls of oral PDE4 inhibitors. EXPERT OPINION: In the last few years, influenced by the body of published clinical data, many companies have lost interest in PDE4 as a target. Many of those that have persevered have opted to realign their research programs either toward compounds specifically designed for inhaled delivery or in search of an increase in clinical efficacy by combining two mechanisms in a single compound. This change is reflected by the continued disclosure of novel and chemically diverse molecules, indicating for some in the pharmaceutical industry that all is not yet lost.
Assuntos
Desenho de Fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Administração Oral , Aminopiridinas/administração & dosagem , Aminopiridinas/farmacologia , Animais , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacologia , Aprovação de Drogas , Sistemas de Liberação de Medicamentos , Indústria Farmacêutica , Humanos , Patentes como Assunto , Inibidores da Fosfodiesterase 4/administração & dosagem , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Talidomida/farmacologiaRESUMO
The synthesis, molecular modeling, and pharmacological analysis of new multipotent simple, and readily available 2-aminopyridine-3,5-dicarbonitriles (3-20), and 2-chloropyridine-3,5-dicarbonitriles (21-28), prepared from 2-amino-6-chloropyridine-3,5-dicarbonitrile (1) and 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (2) is described. The biological evaluation showed that some of these molecules were modest inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in the micromolar range. The 2-amino (3, 4), and 2-chloro derivatives 21-23, 25, 26 were AChE selective inhibitors, whereas 2-amino derivatives 5, 14 proved to be selective for BuChE. Only inhibitor 24 was equipotent for both cholinesterases. Kinetic studies on compound 23 showed that this compound is a mixed-type inhibitor of AChE showing a K(i) of 6.33 microM. No clear SAR can be obtained form these data, but apparently, compounds bearing small groups such as the N,N'-dimethylamino or the pyrrolidino, regardless of the presence of a 2-amino, or 6-chloro substituent in the pyridine ring, preferentially inhibit AChE. Molecular modeling on inhibitors 4, 5, 22, and 23 has been carried out to give a better insight into the binding mode on the catalytic active site (CAS), and peripheral anionic site (PAS) of AChE. The most important differences in the observed binding relay on the modifications of the group at C2, as the amino group forms two hydrogen bonds that direct the binding mode, while in the case of compounds with a chlorine atom, this is not possible. The neuroprotective profile of these molecules has been investigated. In the LDH test, only compounds 26, 3, 22, and 24 showed neuroprotection with values in the range 37.8-31.6% in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone, but in the MTT test only compound 17 (32.9%) showed a similar profile. Consequently, these compounds can be considered as attractive multipotent therapeutic molecules on two key pharmacological receptors playing key roles in the progress of Alzheimer, that is, cholinergic dysfunction and oxidative stress, and neuronal vascular diseases.
Assuntos
Aminopiridinas/química , Aminopiridinas/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Piridinas/química , Piridinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Aminopiridinas/síntese química , Animais , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Colinérgicos/síntese química , Colinérgicos/química , Colinérgicos/farmacologia , Inibidores da Colinesterase/síntese química , Electrophorus , Cavalos , Humanos , Modelos Moleculares , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/síntese química , Nitrilas/síntese química , Piridinas/síntese química , Doenças Vasculares/tratamento farmacológicoRESUMO
OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of roflumilast in the treatment of asthma and chronic obstructive pulmonary disease (COPD). DATA SOURCES: Studies, review articles, and meeting abstracts evaluating roflumilast were obtained from MEDLINE (1966-May 16, 2006), EMBASE (1980-May 16, 2006), and International Pharmaceutical Abstracts (1970-May 16, 2006) databases. Key terms used in all of the database searches were roflumilast, phosphodiesterase-4 inhibitor, asthma, chronic obstructive pulmonary disease, and COPD. Company Web sites were reviewed, and bibliographies of selected articles were evaluated for pertinent articles. STUDY SELECTION AND DATA EXTRACTION: In vitro, in vivo, and animal studies were selected, as were published human studies on the efficacy and safety of roflumilast. Due to limited published data on its safety, efficacy, pharmacokinetics, and drug interactions, meeting abstracts were also selected. Data retrieved from abstracts only is indicated in the references. DATA SYNTHESIS: Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor which, due to its selective inhibition of the PDE 4 isoenzyme, has potential antiinflammatory and antimodulatory effects in the pulmonary system. It has been studied as an oral tablet in doses of 250 or 500 microg/day. Animal data and clinical trials have demonstrated roflumilast's efficacy and safety as an antiinflammatory and antimodulatory agent for use in asthma and COPD, with no documented drug interactions and a favorable adverse effect profile. CONCLUSIONS: Roflumilast may be an additional option in the treatment of asthma and COPD due to its ease of administration and a seemingly favorable adverse event profile. However, more research is needed to solidify roflumilast's place in therapy.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Aminopiridinas/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Benzamidas/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Aminopiridinas/toxicidade , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacocinética , Antiasmáticos/farmacologia , Antiasmáticos/toxicidade , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Benzamidas/farmacologia , Benzamidas/toxicidade , Ensaios Clínicos como Assunto , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Ciclopropanos/efeitos adversos , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Ciclopropanos/toxicidade , Custos de Medicamentos , Interações Medicamentosas , Humanos , Inibidores de Fosfodiesterase/efeitos adversos , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/toxicidadeRESUMO
Radiolabeled dopamine D4 receptor-selective agents ([3H]1-benzyl-4-[ N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine maleate; [3 H]PNU-101958. and [125I]1-[4-iodobenzyl]-4-[ N-(3-isopropoxy-2-pyridinyl)-N-methyl]-aminopiperidine; [125I]RBI-257) were prepared and characterized. With D4.2- and D2L receptor-transfected cell membranes, [3H]PNU-101958 showed high dopamine D4 receptor affinity and selectivity, and potent inhibition by dopamine D4 receptor-selective compounds. However, its binding with rat brain homogenates showed little regional selectivity, and pharmacology inconsistent with selective dopamine D4 receptor labeling. Autoradiography indicated partial displacement of [3H]PNU-101958 by unlabeled dopamine D4 receptor ligands without regional selectivity, and lack of selective labeling with [125I]RBI-257. The results encourage further efforts to develop better dopamine D4 receptor-selective radioligands.
Assuntos
Aminopiridinas/farmacologia , Piperidinas/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Aminopiridinas/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cricetinae , Dopaminérgicos/metabolismo , Dopaminérgicos/farmacologia , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Humanos , Técnicas In Vitro , Ligantes , Masculino , Piperidinas/metabolismo , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismo , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Espiperona/farmacologia , TrítioRESUMO
The hemodynamic effects of graded-dose infusions of amrinone (maximal dose 30 micrograms/kg/min) (10 patients) and isoproterenol (maximum dose 4 micrograms/min) (11 patients) were assessed in patients with a range of left ventricular (LV) function. LV ejection fraction ranged from 0.13 to 0.77 (mean +/- standard deviation 0.47 +/- 0.23) among the patients who received amrinone and from 0.24 to 0.77 (mean 0.52 +/- 0.18) among those who received isoproterenol. Peak-dose amrinone produced a reduction in LV filling pressure (from 15 +/- 10 to 10 +/- 7 mm Hg, p less than 0.001), but no significant change in heart rate, cardiac output, mean aortic pressure, total systemic vascular resistance (TSVR) or LV dP/dt max. In contrast, peak-dose isoproterenol produced a similar reduction in LV filling pressure (from 17 +/- 12 to 13 +/- 13 mm Hg, p less than 0.05), but also caused increases in heart rate, cardiac output and LV dP/dt max and decreases in mean aortic pressure and TSVR (p less than 0.001). The absolute change in cardiac output and stroke volume correlated closely with the change in TSVR in response to amrinone (r = -0.90, p less than 0.001 and r = -0.84, p = 0.002, respectively), but not in response to isoproterenol. Although isoproterenol produced a marked increase in cardiac output and LV dP/dt max (not explained by heart rate changes alone) in all patients, amrinone produced an increase in cardiac output only in those with markedly elevated LV filling pressures (who had a reduction in TSVR), and an increase in LV dP/dt in a minority.