RESUMO
AIMS: This study evaluated the use of machine learning to leverage drug absorption, distribution, metabolism and excretion (ADME) data together with physicochemical and pharmacological data to develop a novel anticholinergic burden scale and compare its performance to previously published scales. METHODS: Experimental and in silico ADME, physicochemical and pharmacological data were collected for antimuscarinic activity, blood-brain barrier penetration, bioavailability, chemical structure and P-glycoprotein (P-gp) substrate profile. These five drug properties were used to train an unsupervised model to assign anticholinergic burden scores to drugs. The model performance was evaluated through 10-fold cross-validation and compared with the clinical Anticholinergic Cognitive Burden (ACB) scale and nonclinical Anticholinergic Toxicity Scores (ATS) scale, which is based primarily on muscarinic binding affinity. RESULTS: In silico software (ADMET Predictor) used for screening drugs for their blood-brain barrier (BBB) penetration correctly identified some drugs that do not cross the BBB. The mean area under the curve for the unsupervised and ACB scale based on the five selected variables was 0.76 and 0.64, respectively. The unsupervised model agreed with the ACB scale on the classification of more than half of the drugs (49 of 88) agreed on the classification of less than half the drugs in the ATS scale (12 of 25). CONCLUSIONS: Our findings suggest that the commonly used ACB scale may misclassify certain drugs due to their inability to cross the BBB. By contrast, the ATS scale would misclassify drugs solely depending on muscarinic binding affinity without considering other drug properties. Machine learning models can be trained on these features to build classification models that are easy to update and have greater generalizability.
Assuntos
Barreira Hematoencefálica , Antagonistas Colinérgicos , Simulação por Computador , Aprendizado de Máquina , Humanos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Antagonistas Colinérgicos/efeitos adversos , Antagonistas Colinérgicos/farmacocinética , Cognição/efeitos dos fármacos , Disponibilidade Biológica , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/efeitos adversos , Modelos Biológicos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismoRESUMO
There is evidence that use of drugs with anticholinergic properties increases the risk of cognitive impairment, and increased exposure to these drugs potentiates this risk. Anticholinergic drugs are commonly used even with associated risk of adverse events. Aging, sex, and genetic polymorphisms of cytochrome P450 (CYP) enzymes are associated with alterations in pharmacokinetic processes, which increase drug exposure and may further increase the risk of adverse drug events. Due to the increasing burden of cognitive impairment in our aging population and the future of personalized medicine, the objective of this review was to provide a critical clinical perspective on age, sex, and CYP genetic polymorphisms and their role in the metabolism and exposure to anticholinergic drugs. Age-related changes that may increase anticholinergic drug exposure include pseudocapillarization of liver sinusoidal endothelial cells, an approximate 3.5% decline in CYP content for each decade of life, and a reduction in kidney function. Sex-related differences that may be influenced by anticholinergic drug exposure include women having delayed gastric and colonic emptying, higher gastric pH, reduced catechol-O-methyl transferase activity, reduced glucuronidation, and reduced renal clearance and men having larger stomachs which may affect medication absorption. The overlay of poor metabolism phenotypes for CYP2D6 and CYP2C19 may further modify anticholinergic drug exposure in a significant proportion of the population. These factors help explain findings of clinical trials that show older adults and specifically older women achieve higher plasma concentrations of anticholinergic drugs and that poor metabolizers of CYP2D6 experience increased drug exposure. Despite this knowledge neither age, sex nor CYP phenotype are routinely considered when making decisions about the use or dosing of anticholinergic medications. Future study of anticholinergic medication needs to account for age, sex and CYP polymorphisms so that we may better approach personalized medicine for optimal outcomes and avoidance of medication-related cognitive impairment.
Assuntos
Envelhecimento/genética , Envelhecimento/metabolismo , Antagonistas Colinérgicos/farmacocinética , Sistema Enzimático do Citocromo P-450/genética , Caracteres Sexuais , Animais , Feminino , Humanos , Masculino , Polimorfismo Genético , Receptores Muscarínicos/metabolismoRESUMO
Oxybutynin is a racemic anticholinergic drug used for the symptomatic treatment of detrusor overactivity. The formation of active metabolites related to tolerability problems depends on the route of administration. The objective of this evaluation was to develop a pharmacokinetic model for oral/intravesical administration as the basis for simulations with different dosages. Data from a published changeover clinical study with 18 healthy adults receiving a single oral dose of 5 mg immediate-release oxybutynin and single and multiple intravesical doses of 10 mg oxybutynin solution was evaluated. Enantioselective plasma concentrations of oxybutynin and N-desethyloxybutynin (NDO) were used to establish a population pharmacokinetic model using nonlinear mixed-effects modeling with NONMEM 7.4.1. For both enantiomers, the data were described well by a 2-compartment model for oxybutynin with an additional compartment for NDO. Oxybutynin absorption was modeled by transit compartments for oral and first-order absorption for intravesical application. Bioavailability of the more active (R)-enantiomer was 7% for oral and 10%-22% for intravesical administration. In simulations, intravesical doses of 5 to 15 mg (R)-oxybutynin administered 2 to 3 times daily decreased peak-trough fluctuations of NDO to 8% compared with 24% after oral administration. The NDO/oxybutynin ratio was reduced from 17 after oral administration to unity. Chronic intravesical versus oral administration of (R)-oxybutynin generates distinctly lower and less variable concentrations of (R)-NDO. Pharmacokinetic simulations suggest that exposure for 12.5 mg (R)-oxybutynin administered twice daily might not compromise efficacy and tolerability compared with exposure for standard thrice-daily administrations. This assumption needs to be assessed in clinical studies.
Assuntos
Antagonistas Colinérgicos/química , Antagonistas Colinérgicos/farmacocinética , Ácidos Mandélicos/química , Ácidos Mandélicos/farmacocinética , Administração Intravesical , Administração Oral , Área Sob a Curva , Antagonistas Colinérgicos/administração & dosagem , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Ácidos Mandélicos/administração & dosagem , Ácidos Mandélicos/metabolismo , Taxa de Depuração Metabólica , Modelos BiológicosRESUMO
BACKGROUND: Hyperhidrosis is a condition characterized by excessive sweating beyond what is required for normal thermal regulation. It can involve multiple body areas including the axillae, palms, soles, or craniofacial regions. Glycopyrronium tosylate (GT) is a topical anticholinergic approved by the FDA (2018) for treatment of primary axillary hyperhidrosis in patients 9 years and older. OBJECTIVE: Gain insight into variables (anatomical sites, occlusion, exposure time) affecting GT delivery into human skin. METHODS: Human skin from different anatomical regions (palmar, plantar, axillary, and abdominal skin) was mounted into flow-through diffusion cells (MedFlux-HT®). GT solution (2.4%) was applied at 10 mg/cm2 and the receiving fluid was collected every 2 hours, for 24 hours. GT penetration was determined using LC/MS/MS. The effect of occlusion was assessed by covering the skin with either parafilm or saran wrap, and the effect of exposure time was assessed by incubating the skin for 5, 15, or 60 minutes before washing off the GT from the surface. RESULTS: GT delivery through palmar and plantar skin was up to 40-fold lower compared to delivery through axillary or abdominal skin. Occlusion increased GT delivery up to 10-fold. Reducing exposure time from 24 hours to either 5, 15, or 60 minutes, decreased GT flux by 90%. However, occlusion during these varied exposure times was able to restore GT delivery to levels found in the 24-hour exposed, non-occluded control group. CONCLUSION: These in vitro skin penetration studies showed that skin thickness, exposure time, and occlusion substantially influenced GT delivery, potentially impacting clinical trial design. J Drugs Dermatol. 2020;19(11): doi:10.36849/JDD.2020.5062.
Assuntos
Antagonistas Colinérgicos/farmacocinética , Glicopirrolato/farmacocinética , Hiperidrose/tratamento farmacológico , Pele/metabolismo , Parede Abdominal , Administração Cutânea , Axila , Antagonistas Colinérgicos/administração & dosagem , Antagonistas Colinérgicos/análise , Cromatografia Líquida de Alta Pressão/métodos , Pé , Glicopirrolato/administração & dosagem , Glicopirrolato/análise , Mãos , Humanos , Absorção Cutânea , Espectrometria de Massas em Tandem/métodos , Fatores de TempoRESUMO
OBJECTIVES: The association between anticholinergic load-based Anticholinergic Risk Scale scores and nutritional status is unclear in Japanese patients. The aim of this study was to establish whether anticholinergic load affects the nutritional status of geriatric patients in convalescent stages. DESIGN: Retrospective longitudinal cohort study. SETTING: Convalescent rehabilitation wards. PARTICIPANTS: Of the 1490 patients aged ≥65 years who were discharged from convalescent rehabilitation wards between July 2010 and October 2018, 908 patients met the eligibility criteria. They were categorized according to the presence or absence of increased anticholinergic load from admission to discharge. MEASUREMENTS: Demographic data, laboratory data, the Functional Independence Measure were analyzed between the groups. The primary outcome was Geriatric Nutritional Risk Index (GNRI) at discharge. Multiple linear regression analysis was performed to analyze the relationship between anticholinergic load and GNRI at discharge. RESULTS: Multiple linear regression analysis after adjusting for confounding factors revealed that anticholinergic load was independently and negatively correlated with GNRI at discharge. Particularly, the use of chlorpromazine, hydroxyzine, haloperidol, metoclopramide, risperidone, etc. increased significantly from admission to discharge. CONCLUSION: Increased anticholinergic load during hospitalization may be a predictor of nutritional status in geriatric patients.
Assuntos
Antagonistas Colinérgicos/sangue , Antagonistas Colinérgicos/farmacocinética , Desnutrição/epidemiologia , Estado Nutricional/fisiologia , Idoso , Idoso de 80 Anos ou mais , Clorpromazina/farmacocinética , Antagonistas Colinérgicos/uso terapêutico , Feminino , Avaliação Geriátrica , Haloperidol/farmacocinética , Hospitalização , Humanos , Hidroxizina/farmacocinética , Japão/epidemiologia , Modelos Lineares , Estudos Longitudinais , Masculino , Metoclopramida/farmacocinética , Análise Multivariada , Avaliação Nutricional , Alta do Paciente , Análise de Regressão , Estudos Retrospectivos , Risperidona/farmacocinéticaRESUMO
OBJECTIVE: This study aimed to determine whether levels of choline (Ch) and acetylcholine (Ach) differ between responders and nonresponders to anticholinergic therapy. METHODS: Patients prescribed an anticholinergic were evaluated using the Overactive Bladder Symptom Score; Medical, Epidemiologic and Social Aspects of Aging and Incontinence Questionnaire; and Incontinence Impact Questionnaire-7. A 1-day voiding diary and a urine sample were collected. After treatment for 12 weeks, the questionnaires were administered and 1-day voiding diary was completed. Levels of Ach and Ch were measured by liquid chromatography with tandem mass spectrometry. Subjects were divided into responders and nonresponders. Wilcoxon rank sum test and Fisher exact test were used to express differences between groups. Spearman ρ correlation coefficient was used to determine the relationship between Ach and Ch and symptom severity, patient demographics, and questionnaire scores. RESULTS: Thirty-one women were included in the analysis. The treatment response rate was 48.8%. The median age was 67 years (interquartile range, 50-76 years), and median body mass index was 32.3 kg/m2 (27.5-40.6 kg/m2), with 41.2% having an additional complaint of stress incontinence. There were no significant differences in symptom severity or questionnaire scores between groups.The median Ch and Ach levels were higher in responders (28.6 vs 9.2 µL, P = 0.04) and (83.1 vs 18.7 nL, P = 0.02), respectively. Levels of both Ch and Ach had moderate positive correlations with the Medical, Epidemiologic and Social Aspects of Aging and Incontinence Questionnaire urgency urinary incontinence score (ρ = 0.533 [P = 0.002] and ρ = 0.453 [P = 0.01], respectively). CONCLUSION: In women with overactive bladder, urinary Ach and Ch levels are higher in responders to anticholinergic therapy compared with nonresponders.
Assuntos
Acetilcolina/sangue , Envelhecimento , Colina/sangue , Antagonistas Colinérgicos , Qualidade de Vida , Incontinência Urinária , Idoso , Envelhecimento/fisiologia , Envelhecimento/psicologia , Biomarcadores Farmacológicos/sangue , Antagonistas Colinérgicos/administração & dosagem , Antagonistas Colinérgicos/farmacocinética , Correlação de Dados , Feminino , Avaliação Geriátrica/métodos , Humanos , Inquéritos e Questionários , Avaliação de Sintomas/métodos , Bexiga Urinária Hiperativa/sangue , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/fisiopatologia , Incontinência Urinária/diagnóstico , Incontinência Urinária/etiologia , Incontinência Urinária/psicologiaRESUMO
Many observational studies published during the past 15 years have found an association between anticholinergic drug exposure and the risk of incident dementia. Animal data suggest plausible causal mechanisms for this finding. The results of a recent, large, and well-conducted study on the subject were widely disseminated by the lay and scientific media. This study addressed protopathic bias by examining anticholinergic drug exposure in time windows 1-11, 3-13, and 5-20 years before the identification of dementia. In brief, the study found that, pooling anticholinergic drug exposure across 11 drug categories, exposure in smallest to largest cumulative dosing groups was significantly associated with incident dementia risk, with an apparently dose-dependent relationship in unadjusted as well as adjusted analyses in all time windows prior to dementia identification. Whereas these findings appear compelling, there are at least 4 elephants in the room. First, only 3 of 11 anticholinergic drug categories were consistently associated with an increased risk of dementia; this suggests that anticholinergic activity may be an irrelevant common denominator. Second, for 2 of these 3 categories (antidepressant and antipsychotic drugs), confounding by indication seemed a distinct possibility. Third, in many analyses it seemed that exposure for as little as the equivalent of 1-90 days sufficed to increase the risk of dementia at a time interval of up to 20 years later; a causal mechanism here would need to have strong neurotoxic effects to result in the widespread brain changes that characterize dementia. Finally, the associations were almost uniformly stronger for vascular dementia than for Alzheimer's disease, making the identification of a causal mechanism even more challenging. Deprescribing anticholinergics to reduce state-dependent cognitive impairment, or to reduce the risk of delirium in vulnerable demographic and medical populations, is reasonable. Deprescribing anticholinergics to reduce the risk of future dementia is presently unwarranted.
Assuntos
Antagonistas Colinérgicos , Delírio , Demência , Causalidade , Antagonistas Colinérgicos/efeitos adversos , Antagonistas Colinérgicos/farmacocinética , Antagonistas Colinérgicos/uso terapêutico , Correlação de Dados , Delírio/induzido quimicamente , Delírio/epidemiologia , Demência/diagnóstico , Demência/epidemiologia , Demência/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Medição de RiscoAssuntos
Axila , Antagonistas Colinérgicos/administração & dosagem , Glicopirrolato/administração & dosagem , Hiperidrose/tratamento farmacológico , Administração Tópica , Antagonistas Colinérgicos/farmacocinética , Glicopirrolato/farmacocinética , Humanos , Hiperidrose/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
Starting from vanillin, known four benzyl bromides with Br were synthesized. The first synthesis of natural product 3,4-dibromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (2) and 3,4,6-tribromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (3) and derivatives were carried out by demethylation, acetylatilation, oxidation and hydrolysis reactions of the benzyl bromides. Also, these compounds were tested against some important enzymes like acetylcholinesterase and butyrylcholinesterase enzymes, carbonic anhydrase I, and II isoenzymes. The novel bromophenols showed Ki values of in range of 53.75⯱â¯12.54-234.68⯱â¯46.76â¯nM against hCA I, 42.84⯱â¯9.36 and 200.54⯱â¯57.25â¯nM against hCA II, 0.84⯱â¯0.12-14.63⯱â¯3.06â¯nM against AChE and 0.93⯱â¯0.20-18.53⯱â¯5.06â¯nM against BChE. Induced fit docking process performed on the compounds inhibiting hCA I, hCA II, AChE, and BChE receptors. Hydroxyl group should exist at the aromatic ring of the compounds for inhibition of the enzymes. The moieties reported in this study will be useful for design of more potent and selective inhibitors against the enzymes.
Assuntos
Produtos Biológicos/síntese química , Bromobenzenos/síntese química , Inibidores da Anidrase Carbônica/síntese química , Antagonistas Colinérgicos/síntese química , Fenóis/síntese química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacocinética , Bromobenzenos/metabolismo , Bromobenzenos/farmacocinética , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Anidrase Carbônica I/química , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/química , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/farmacocinética , Antagonistas Colinérgicos/metabolismo , Antagonistas Colinérgicos/farmacocinética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacocinética , Humanos , Simulação de Acoplamento Molecular , Fenóis/metabolismo , Fenóis/farmacocinética , Ligação ProteicaRESUMO
BACKGROUND: When characterizing inhalation products, a comprehensive assessment including in vitro, pharmacokinetic (PK), and clinical data is required. We conducted a characterization of tiotropium Respimat® when administered with AeroChamber Plus® Flow-Vu® anti-static valved holding chamber (test VHC) with face mask in 1-5-year-olds with persistent asthmatic symptoms. METHODS: In vitro tiotropium dose and particle size distribution delivered into a cascade impactor were evaluated under fixed paediatric and adult flow rates between actuation and samplings. The tiotropium mass likely to reach children's lungs was assessed by tidal breathing simulations and an ADAM-III Child Model. PK exposure to tiotropium in preschool children with persistent asthmatic symptoms (using test VHC) was compared with pooled data from nine Phase 2/3 trials in older children, adolescents, and adults with symptomatic persistent asthma not using test VHC. RESULTS: At fixed inspiratory flow rates, emitted mass and fine particle dose decreased under lower flow conditions; dose reduction was observed when Respimat® was administered by test VHC at paediatric flow rates. In <5-year-old children, such a dose reduction is appropriate. In terms of dose per kg/body weight, in vitro-delivered dosing in children was comparable with adults. Transmission and aerosol holding properties of Respimat® when administered with test VHC were fully sufficient for aerosol delivery to patients. At zero delay, particles <5⯵m (most relevant fraction) exhibited a transfer efficacy of ≥60%. The half-time was>10â¯s, allowing multiple breaths. Standardized tidal inhalation resulted in an emitted mass from the test VHC of approximately one-third of labelled dose, independent of coordination and face mask use, indicating predictable tiotropium administration by test VHC with Respimat®. Tiotropium exposure in 1-5-year-old patients using the test VHC, when adjusted by height or body surface, was comparable with that in older age groups without VHCs; no overexposure was observed. Adverse events were less frequent with tiotropium (2.5⯵g, nâ¯=â¯20 [55.6%]; 5⯵g, nâ¯=â¯18 [58.1%]) than placebo (nâ¯=â¯25 [73.5%]). CONCLUSIONS: Our findings provide good initial evidence to suggest that tiotropium Respimat® may be administered with AeroChamber Plus® Flow-Vu® VHC in 1-5-year-old patients with persistent asthmatic symptoms. To confirm the clinical efficacy and safety in these patients, additional trials are required. CLINICAL TRIALS REGISTRY NUMBER: The trial was registered under NCT01634113 at http://www.clinicaltrials.gov.
Assuntos
Combinação Albuterol e Ipratrópio/farmacocinética , Asma/tratamento farmacológico , Desenho de Equipamento/instrumentação , Espaçadores de Inalação/normas , Brometo de Tiotrópio/farmacocinética , Administração por Inalação , Combinação Albuterol e Ipratrópio/administração & dosagem , Pré-Escolar , Antagonistas Colinérgicos/farmacocinética , Cromatografia Líquida/métodos , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Lactente , Masculino , Inaladores Dosimetrados/estatística & dados numéricos , Inaladores Dosimetrados/tendências , Tamanho da Partícula , Brometo de Tiotrópio/administração & dosagemRESUMO
INTRODUCTION AND HYPOTHESIS: Anticholinergic medication is the medical treatment for overactive bladder (OAB). These drugs can act on the central nervous system and can lead to cognitive decline, dementia, and potentially death. Patients taking drugs with anticholinergic effects increase their anticholinergic burden-defined as the cumulative effect of taking one or more drugs that can have adverse effects. When prescribing anticholinergic medication for the elderly, we must choose the right drug. We aimed to discover the level of understanding on this subject and its application to real clinical practice amongst our healthcare professionals (HCPs). METHODS: An 18-point questionnaire was distributed to urogynaecologists, general gynaecologists, urologists, geriatricians, general practitioners (GPs), and nurse specialists to assess knowledge on the subject. RESULTS: A total of 96 HCPs completed the questionnaire. The nurse specialists had the highest score in identifying that oxybutynin was the drug most likely to cross the blood-brain barrier (BBB). The urogynaecologists had the highest score in identifying that trospium chloride was least likely to cross the BBB, whereas the GPs had the lowest score. Solifenacin was the most popular anticholinergic drug prescribed in the elderly without dementia. Trospium chloride was the most popular drug prescribed in the elderly with dementia. CONCLUSIONS: We have found that knowledge is lacking amongst all our HCPs, but especially amongst our first-line doctors, our GPs. Education is key in developing knowledge and safe prescribing, to improve the care we give to our patients.
Assuntos
Antagonistas Colinérgicos/efeitos adversos , Disfunção Cognitiva/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde/psicologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Adulto , Atitude do Pessoal de Saúde , Barreira Hematoencefálica/efeitos dos fármacos , Antagonistas Colinérgicos/farmacocinética , Disfunção Cognitiva/induzido quimicamente , Contraindicações de Medicamentos , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Clínicos Gerais/psicologia , Geriatras/psicologia , Ginecologia , Humanos , Masculino , Pessoa de Meia-Idade , Especialidades de Enfermagem , Bexiga Urinária Hiperativa/psicologia , Urologistas/psicologiaRESUMO
A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C8 column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r2 > 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.
Assuntos
Compostos Aza/sangue , Compostos Aza/farmacocinética , Cromatografia Líquida/métodos , Glicolatos/sangue , Glicolatos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Compostos Aza/administração & dosagem , Disponibilidade Biológica , Antagonistas Colinérgicos/administração & dosagem , Antagonistas Colinérgicos/sangue , Antagonistas Colinérgicos/farmacocinética , Cães , Glicolatos/administração & dosagem , Masculino , Técnica de Diluição de Radioisótopos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
PURPOSE: The Drug Burden Index (DBI) is a non-invasive method to quantify patients' anticholinergic and sedative drug burden from their prescriptions. This systematic review aimed to summarise the evidence on the associations between the DBI and clinical outcomes and methodological quality of studies. METHODS: A search in PubMed and Embase (search terms: 'drug', 'burden', and 'index') was performed and experts were contacted. We excluded publications that did not report empirical results or clinical outcomes. Methodological quality was assessed using the Newcastle-Ottawa Scale. Potential omissions of relevant clinical outcomes and populations were studied. RESULTS: Of the 2998 identified publications, 21 were eligible. Overall, methodological quality of studies was good. In all but one study, adjustment was made for prevalent co-morbidity. The DBI was examined in diverse older individuals, i.e. both males and females from different settings and countries. However, no studies were conducted in other relevant patient groups, e.g. psychiatric patients. Exposure to anticholinergic and sedative drugs was thoroughly ascertained, though the specific calculation of the DBI differed across studies. Outcomes were assessed from medical records, record linkage or validated objective tests or questionnaires. Many studies found associations between the DBI and outcomes including hospitalisation, physical and cognitive function. Cognitive function and quality of life were understudied and the number and scope of longitudinal studies was limited. CONCLUSIONS: An accumulating body of evidence supports the validity of the DBI. Longitudinal studies of cognitive function and quality of life and in other patient groups, e.g. psychiatric patients, are warranted.
Assuntos
Antagonistas Colinérgicos/farmacologia , Hipnóticos e Sedativos/farmacologia , Idoso , Antagonistas Colinérgicos/farmacocinética , Feminino , Humanos , Hipnóticos e Sedativos/farmacocinética , Masculino , Registro Médico Coordenado , PolimedicaçãoRESUMO
INTRODUCTION: The aim of this study was to assess the degree of adherence for two standard regimens for administrating anticholinergic drugs (12 and 24 hours) in patients with chronic obstruction of the airflow and to establish whether the use of a once-daily dose improves the level of treatment adherence. METHODS: We used long-acting anticholinergics (LAMAs) as a study variable, and included the entire health area of Castile-La Mancha, numbering 2,100,998 inhabitants, as the study population. We analyzed a total of 16,446 patients who had been prescribed a LAMA between January 1, 2013 and December 31, 2013. The follow-up period, based on a centralized system of electronic prescription management, was extended until December 2014. RESULTS: During 2013, the medication collected was 7.4%-10.7% higher than indicated by labeling. This was very similar for all LAMAs, irrespective of the patient's sex, the molecule, the device, and the drug dosage. We did not observe seasonal variations in the consumption of LAMAs, nor did we detect differences between prescription drugs for once-daily (every 24 hours) versus twice-daily (every 12 hours) administration, between the different molecules, or between different types of inhalers for the same molecule. The results were similar in 2014. CONCLUSION: The principal conclusion of this study is that, in an area with a centralized management system of pharmacological prescriptions, adherence to treatment with LAMAs is very high, irrespective of the molecules or inhalation device. We did not find that patients who used twice-daily medication had a lower adherence.
Assuntos
Antagonistas Colinérgicos , Adesão à Medicação/estatística & dados numéricos , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Idoso , Idoso de 80 Anos ou mais , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacocinética , Antagonistas Colinérgicos/administração & dosagem , Antagonistas Colinérgicos/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Prescrição Eletrônica/estatística & dados numéricos , Feminino , Humanos , Masculino , Conduta do Tratamento Medicamentoso/organização & administração , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Espanha/epidemiologiaRESUMO
Chronic obstructive pulmonary disease (COPD), a respiratory disease characterized by a progressive decline in lung function, is considered to be a leading cause of morbidity and mortality. Long-acting inhaled bronchodilators, such as long-acting ß2 agonists (LABAs) or long-acting muscarinic antagonists (LAMAs), are the cornerstone of maintenance therapy for patients with moderate-to-very-severe COPD. For patients not sufficiently controlled on a single long-acting bronchodilator, a combination of different bronchodilators has shown a significant increase in lung function. Tiotropium, a once-daily dosing LAMA, demonstrated sustained improvements in lung function as well as improved health-related quality of life, reduced exacerbations, and increased survival without altering the rate of decline in the mean forced expiratory volume in 1 second (FEV1) with fairly tolerable side effects. Olodaterol is a once-daily dosing LABA that has proven to be effective in improving lung function, reducing rescue medication use, and improving dyspnea and health-related quality of life, as well as improving exercise endurance with an acceptable safety profile. The combination of olodaterol and tiotropium provided additional improvements in lung function greater than monotherapy with each drug alone. Several well-designed randomized trials confirmed that the synergistic effect of both drugs in combination was able to improve lung function and health-related quality of life without a significant increase in adverse effects. The objective of this paper is to review available evidence on the clinical efficacy and safety of tiotropium, olodaterol, and their combination in patients with COPD.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Benzoxazinas/administração & dosagem , Broncodilatadores/administração & dosagem , Antagonistas Colinérgicos/administração & dosagem , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/economia , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Benzoxazinas/efeitos adversos , Benzoxazinas/economia , Benzoxazinas/farmacocinética , Broncodilatadores/efeitos adversos , Broncodilatadores/economia , Broncodilatadores/farmacocinética , Antagonistas Colinérgicos/efeitos adversos , Antagonistas Colinérgicos/economia , Antagonistas Colinérgicos/farmacocinética , Análise Custo-Benefício , Esquema de Medicação , Combinação de Medicamentos , Custos de Medicamentos , Sinergismo Farmacológico , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/economia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de Vida , Recuperação de Função Fisiológica , Brometo de Tiotrópio/efeitos adversos , Brometo de Tiotrópio/economia , Brometo de Tiotrópio/farmacocinética , Resultado do TratamentoRESUMO
BACKGROUND: People with cystic fibrosis (CF) suffer from chronic lung disease that is often treated with a bronchodilator. This trial evaluated the pharmacokinetics, safety, and tolerability of single and multiple doses of tiotropium inhaled via the Respimat® Soft Mist™ Inhaler in patients with CF. METHODS: Patients received a single dose (placebo, 2.5 µg, 5 µg, or 10 µg) and/or multiple doses (placebo, 2.5 µg, or 5 µg) of tiotropium daily for 28 days. RESULTS: Ninety-two patients, aged 5-57 years, were treated. All doses showed a satisfactory safety profile for adverse events, vital signs, laboratory evaluations, and physical examination. At steady-state, peak exposure to tiotropium was comparable between adult patients with CF and patients with chronic obstructive pulmonary disease. CONCLUSIONS: Tiotropium 2.5 µg or 5 µg inhaled via the Respimat® Soft Mist™ Inhaler once daily was well tolerated in patients with CF.
Assuntos
Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Antagonistas Colinérgicos/administração & dosagem , Antagonistas Colinérgicos/sangue , Fibrose Cística/tratamento farmacológico , Brometo de Tiotrópio/administração & dosagem , Brometo de Tiotrópio/sangue , Administração por Inalação , Adolescente , Adulto , Fatores Etários , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacocinética , Criança , Pré-Escolar , Antagonistas Colinérgicos/efeitos adversos , Antagonistas Colinérgicos/farmacocinética , Fibrose Cística/sangue , Fibrose Cística/diagnóstico , Método Duplo-Cego , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Brometo de Tiotrópio/efeitos adversos , Brometo de Tiotrópio/farmacocinética , Estados Unidos , Adulto JovemRESUMO
The compound series of traditional anticholinergics [atropine (Atr), anisodamine (Ani), anisodine (AT3), and scopolamine (Sco)], naturally occurring belladonna alkaloid, have been approved for numerous therapeutic uses since 1970s. Tiotropium, a novel M receptor antagonist for the treatment of chronic obstructive pulmonary disease, was structurally modified based on atropine-like drugs. Clinical phenomena suggested that the changes of substituent group were related to the pharmacokinetic and pharmacodynamic characteristics of the agents. In an attempt to compare the pharmacokinetics of the series of anticholinergics and investigate the subsets motivating selective anticholinergic potencies, a sensitive LC-MS/MS method was established to analyze the differences of pharmacokinetic parameters. In this paper, we determined the pharmacokinetics of atropine, anisodamine, anisodine, scopolamine, and tiotropium after i.v. and i.g. single dose administration. After i.v. administration, the maximum drug plasma concentrations (C max) of Atr, Ani, AT3, and Sco were 274.25 ± 53.66, 267.50 ± 33.16, 340.50 ± 44.52, and 483.75 ± 78.13 ng/mL. Tiotropium had a slightly higher area under the curve with a significant increase of C max value. Because of their partial solubility, Atr, Ani, AT3, and Sco had different bioavailability in rats of 21.62, 10.78, 80.45 and 2.52 %, respectively. Following i.g. administration of tiotropium, the C max value below 20 ng/mL revealed the very low oral absorption. The urinary excretion rates of Atr, Ani, AT3, Sco and tiotropium were 11.33, 54.86, 32.67, 8.69 and 73.91 %. This work provided relatively comprehensive preclinical data on the series of anticholinergics, which may be used to explain the clinical adverse effects and applications.
Assuntos
Atropina/farmacocinética , Antagonistas Colinérgicos/farmacocinética , Derivados da Escopolamina/farmacocinética , Escopolamina/farmacocinética , Alcaloides de Solanáceas/farmacocinética , Brometo de Tiotrópio/farmacocinética , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em TandemAssuntos
Álcoois Benzílicos/administração & dosagem , Clorobenzenos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/administração & dosagem , Administração por Inalação , Animais , Álcoois Benzílicos/farmacocinética , Clorobenzenos/farmacocinética , Antagonistas Colinérgicos/administração & dosagem , Antagonistas Colinérgicos/farmacocinética , Combinação de Medicamentos , Humanos , Doença Pulmonar Obstrutiva Crônica/metabolismo , Quinuclidinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
PURPOSE: The safety and efficacy of the second U.S.-approved long-acting inhaled anticholinergic for controlling bronchospasm in patients with chronic obstructive pulmonary disease (COPD) are reviewed. SUMMARY: Aclidinium bromide (Tudorza, Forest Pharmaceuticals) is indicated for long-term maintenance therapy for COPD-associated bronchospasm. It is marketed as a 60-dose metered-dose inhaler to be used twice daily. In Phase II and III clinical trials involving a total of more than 3000 patients, daily use of aclidinium bromide was found to significantly improve selected key indicators of lung function (trough values for forced expiratory volume at one second [FEV1] and other FEV1 outcome measures) compared with placebo use. Other benefits of aclidinium bromide therapy, including a significant reduction in nighttime COPD symptoms, were demonstrated for up to one year. However, aclidinium bromide has not been consistently demonstrated to be more effective than the other currently available long-acting inhaled anticholinergic, tiotropium bromide. Furthermore, the clinical trials indicated no significant difference between aclidinium bromide and tiotropium bromide with regard to rates of systemic adverse effects. For some patients, aclidinium bromide may offer advantages over tiotropium bromide (e.g., a faster time to peak FEV1, lower cost of therapy). CONCLUSION: Aclidinium bromide is an inhaled anticholinergic that improves lung function measures in patients with COPD. The most common adverse effects during clinical trials of the drug were headache, nasopharyngitis, and cough, none of which occurred at significantly higher rates than were seen with placebo use.