RESUMO
BACKGROUND AND OBJECTIVE: Rare diseases place a significant burden on patients, families, the healthcare system, and society. Evidence on the socioeconomic burden of rare disease is limited and mostly reflects diseases where treatments are available. We developed a framework encompassing recommended cost elements for studies of the socioeconomic burden of rare diseases. METHODS: A scoping review, conducted in five databases (Cochrane Library, EconLit, Embase, MEDLINE, and APA PsycINFO), identified English language publications from 2000 to 2021 presenting frameworks developed for determining, measuring or valuing costs for rare or chronic diseases. Cost elements were extracted and used to develop a literature-informed framework. Structured feedback was gathered from experts in rare diseases, health economics/health services, and policy research to revise the framework. RESULTS: Of 2990 records identified, eight papers were included and informed our preliminary framework; three focused on rare disease and five on chronic disease. Following expert input, we developed a framework consisting of nine cost categories (inpatient, outpatient, community, healthcare products/goods, productivity/education, travel/accommodation, government benefits, family impacts, and other), with several cost elements within each category. Our framework includes unique costs, added from the expert feedback, including genetic testing to inform treatment, use of private laboratories or out-of-country testing, family involvement in foundations and organizations, and advocacy costs for special access programs. CONCLUSIONS: Our work is the first to identify a comprehensive list of cost elements for rare disease for use by researchers and policy makers to fully capture socioeconomic burden. Use of the framework will increase the quality and comparability of future studies. Future work should focus on measuring and valuing these costs through onset, diagnosis, and post-diagnosis.
Assuntos
Atenção à Saúde , Doenças Raras , Humanos , Doenças Raras/terapia , Doença Crônica , Fatores SocioeconômicosRESUMO
Genome-wide variation in SARS-CoV-2 reveals evolution and transmission dynamics which are critical considerations for disease control and prevention decisions. Here, we review estimates of the genome-wide viral mutation rates, summarize current COVID-19 case load in the province of Ontario, Canada (5 January 2021), and analyze published SARS-CoV-2 genomes from Ontario (collected prior to 24 November 2020) to test for more infectious genetic variants or lineages. The reported mutation rate (â¼10-6 nucleotide [nt]-1 cycle-1) for SARS-CoV-2 is typical for coronaviruses. Analysis of published SARS-CoV-2 genomes revealed that the G614 spike protein mutation has dominated infections in Ontario and that SARS-CoV-2 lineages present in Ontario have not differed significantly in their rate of spread. These results suggest that the SARS-CoV-2 population circulating in Ontario has not changed significantly to date. However, ongoing genome monitoring is essential for identification of new variants and lineages that may contribute to increased viral transmission.
Assuntos
Variação Genética/genética , Genoma Viral/genética , Taxa de Mutação , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Sequência de Bases , COVID-19/patologia , Humanos , Ontário , Filogenia , Análise de Sequência de RNARESUMO
OBJECTIVE: To evaluate the effects of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D), the angiotensinogen M235T and the angiotensin II type 1 receptor A1166C polymorphisms, and hormone therapy used on endothelial function in postmenopausal women without manifestation of coronary artery disease. DESIGN: Sixty-four postmenopausal women (42 hormone therapy users and 22 hormone therapy nonusers) without clinical manifestation of coronary artery disease were evaluated using external vascular ultrasonography to measure endothelium-dependent (hyperemic response, flow-mediated dilatation) and -independent (nitroglycerin) dilatation. Genotypes were determined by polymerase chain reaction amplification. RESULTS: Women with the ACE-DD genotype displayed a lower flow-mediated dilatation compared to those with the ACE-II genotype (8.4% +/- 3.9% vs 12.6% +/- 5.4%, P = 0.04). Endothelial function was not associated with the angiotensinogen M235T and anglotensin II type 1 receptor A1166C polymorphisms. ACE polymorphism seems to modulate endothelial function among postmenopausal women without hormone therapy (8.2% +/- 5.1% vs 18.4% +/- 5.9% for the DD and the II genotype, respectively, P = 0.02). However, in hormone therapy users, flow-mediated dilatation was similar according to the ACE genotypes. CONCLUSIONS: Our findings suggest that ACE-I/D polymorphism is related to endothelial dysfunction in postmenopausal women. Furthermore, a potential interaction between estrogen users and ACE polymorphism on endothelial function may be present.
Assuntos
Angiotensinogênio/genética , Endotélio Vascular/fisiologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Pós-Menopausa/genética , Receptor Tipo 1 de Angiotensina/genética , Alelos , Artéria Braquial/diagnóstico por imagem , Feminino , Deleção de Genes , Genótipo , Terapia de Reposição Hormonal , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/fisiologia , Sistema Renina-Angiotensina , UltrassonografiaRESUMO
PURPOSE: Troxacitabine is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Significant differences in troxacitabine toxicity between mice, rats, monkeys, and humans were observed during preclinical and clinical evaluations. To better understand the different toxicity and efficacy results observed between the human xenograft mouse tumor models used for preclinical assessment and the clinical study results, the pharmacodynamics and pharmacokinetics of troxacitabine were reassessed in murine and human models. EXPERIMENTAL DESIGN: Clonal and thymidine incorporation assays were used to investigate the in vitro antiproliferative activity of troxacitabine on a selected panel of mouse and human tumor cell lines and normal hemapoietic cells. Analysis of the intracellular metabolites of [14C]troxacitabine was determined in mouse and human T-lymphocytes obtained from peripheral blood. The antitumor efficacy of troxacitabine administered either as single or repeated high-dose bolus administrations or as low-dose continuous infusions was evaluated in the human colon HT-29 xenograft model. We also determined plasma concentrations of troxacitabine using the different administration schedules. RESULTS: Five to nine hundred-fold lower concentrations of troxacitabine were required to inhibit cell growth in human compared with murine tumor and normal hemapoietic cell lines. Furthermore, the sensitivity of cells of both species to troxacitabine was strongly time dependent, requiring >24 hours exposure for maximum activity. Analysis of the intracellular metabolites of [14C]troxacitabine in T-lymphocytes obtained from peripheral blood revealed subsequently higher levels of mono-, di-, and triphosphates in human compared with mouse. Antitumor efficacy studies revealed that prolonged exposure schedules (up to 6 days) showed equivalent efficacy to repeated high-dose bolus administrations. Five-day continuous infusion of 20 mg/mL troxacitabine via subcutaneous implanted mini-osmotic pump maintained systemic concentrations of 262 ng/mL (1.2 micromol/L) for the duration of administration, which are clinically achievable plasma concentrations, and led to significant antitumor activity [treated versus control (T/C) of 27% and tumor regression during treatment]. CONCLUSIONS: These studies support the hypothesis that troxacitabine infusions might be the administration regimen with the greatest likelihood of fully exploiting clinically the potent preclinical antitumor activity of troxacitabine.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Citosina/análogos & derivados , Citosina/farmacologia , Citosina/farmacocinética , Dioxolanos/farmacologia , Dioxolanos/farmacocinética , Neoplasias/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Proliferação de Células , Ensaio de Unidades Formadoras de Colônias , Relação Dose-Resposta a Droga , Feminino , Células-Tronco Hematopoéticas , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Transplante de Neoplasias , Especificidade da Espécie , Fatores de TempoRESUMO
The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE), the A1166C polymorphism in the angiotensin type 1 receptor (AT1R), and the M235T polymorphism of the angiotensinogen gene are associated with cardiovascular disease mostly in men. Few data are available on the effects of these genetic variations in postmenopausal women according to hormone replacement therapy (HRT) use. In this case-control study, we determine the frequency of mutant alleles in the ACE I/D, M235T and A1166C polymorphisms in postmenopausal Caucasian women with and without a diagnosis of acute coronary syndrome (ACS). Data from 198 women with ACS (63+/-10 years) and 149 controls (62+/-7 years) showed that ACE-DD genotype was more prevalent in women with ACS compared to controls (30% vs. 19%, P<0.05). There was no difference in genotype distributions for either the M235T or the A1166C polymorphisms between groups. The difference in ACE genotype distribution between ACS women and controls was driven by current HRT users with 30% of ACS and 15% of controls carrying the ACE-DD genotype (P<0.05). The oligenic combination of ACE-DD and M235T-TT genotypes was higher in ACS compared to controls. Among carriers of M235T-TT, 7% of ACS and 1% of controls also had the ACE-DD genotype, P<0.05. Thus, the ACE-DD genotype may be associated with ACS in postmenopausal women, particularly in HRT users.
Assuntos
Angina Instável/genética , Infarto do Miocárdio/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Doença Aguda , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Sistema Renina-Angiotensina/genética , SíndromeRESUMO
Nucleoside phosphonates are widely used therapeutic agents with a broad spectrum of antiviral activity. However, only a few of them are reported to have antitumor activity. In this study, we show that a tetrahydrofuran phosphonate analogue of guanosine, (-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-ylmethyl) tetrahydrofuran (BCH-1868), previously reported as having antiviral activity, also displays antitumor activity. In vitro, BCH-1868 inhibited the proliferation of several murine and human cancer cell lines with IC50s in the microM range independently of the tissue type or the presence of multidrug resistance protein MRP/gp190. In vivo, BCH-1868 was active against a variety of human tumor xenograft models (Caki-1, HT-29, DU 145, COLO 205, and CCRF-CEM). In all tumors tested, a significant tumor growth inhibition was noted at 40-50 mg/kg (daily x 5), but no tumor regression was observed in the settings used. To better understand these results, we partially characterized, at the cellular level, the mechanism of action of this new cyclic nucleoside phosphonate and investigated its pharmacokinetic characteristics in mice. We showed that BCH-1868 exerts its antitumor activity by an inhibitory mechanism at the level of DNA polymerase a, resulting in arrest of DNA synthesis and a block of cell division at the S phase of the cell cycle. Low-circulating plasma concentration (Cmax = 87 microM; area under the curve = 1138 micromol x min/liters; after a bolus i.v. injection of 10 mg/kg) and rapid clearance of the drug (terminal half-life, t1/2 = 16 min) may contribute to the modest antitumor efficacy observed in vivo.
Assuntos
Antineoplásicos/farmacocinética , Antivirais/farmacologia , Guanina/farmacocinética , Ácidos Fosfínicos/farmacocinética , Animais , Ciclo Celular , Divisão Celular , DNA Polimerase I/antagonistas & inibidores , Relação Dose-Resposta a Droga , Guanina/análogos & derivados , Humanos , Concentração Inibidora 50 , Fígado/metabolismo , Camundongos , Camundongos Nus , Camundongos SCID , Modelos Químicos , Transplante de Neoplasias , Fatores de Tempo , Células Tumorais CultivadasRESUMO
A novel series of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes was identified as potent apoptosis inducers through a cell-based high throughput screening assay. Six compounds from this series, MX-58151, MX-58276, MX-76747, MX-116214, MX-116407, and MX-126303, were further profiled and shown to have potent in vitro cytotoxic activity toward proliferating cells only and to interact with tubulin at the colchicine-binding site, thereby inhibiting tubulin polymerization and leading to cell cycle arrest and apoptosis. Furthermore, these compounds were shown to disrupt newly formed capillary tubes in vitro at low nanomolar concentrations. These data suggested that the compounds might have vascular targeting activity. In this study, we have evaluated the ability of these compounds to disrupt tumor vasculature and to induce tumor necrosis. We investigated the pharmacokinetic and toxicity profiles of all six compounds and examined their ability to induce tumor necrosis. We next examined the antitumor efficacy of a subset of compounds in three different human solid tumor xenografts. In the human lung tumor xenograft (Calu-6), MX-116407 was highly active, producing tumor regressions in all 10 animals. Moreover, MX-116407 significantly enhanced the antitumor activity of cisplatin, resulting in 40% tumor-free animals at time of sacrifice. Our results identify MX-116407 as the lead candidate and strongly support its continued development as a novel anticancer agent for human use.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Aminação , Inibidores da Angiogênese/sangue , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos/sangue , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzopiranos/sangue , Benzopiranos/química , Benzopiranos/farmacocinética , Bromo/química , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Necrose , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Transplante HeterólogoRESUMO
PURPOSE: Troxacitabine (BCH-4556, l-(-)-OddC, Troxatyl) is a novel beta- l-nucleoside analogue with potent antineoplastic activity both in vitro and in several tumor models in vivo, and is presently in phase II clinical trials. The combination of the cytosine analogues troxacitabine and araC (1-beta- d-arabinofuranosylcytosine, cytarabine) has shown promising activity in patients with acute myelogenous leukemia. To further examine the interactions between these two analogues, we investigated the in vitro and in vivo effects of their combination against a human leukemia cell line, CCRF-CEM. METHODS: . The in vitro cytotoxic effect of the combination of troxacitabine and araC on the survival of CCRF-CEM cells was measured using a standard MTT assay and combination indices were generated with the CalcuSyn software. For in vivo studies, we evaluated the effect of both drugs, alone and in combination, on survival of CCRF-CEM tumor-bearing animals. Mechanistic studies addressed recovery of DNA synthesis, intracellular levels of araC metabolites, feedback inhibition by triphosphate species and pharmacokinetics of both drugs. RESULTS: The combination of troxacitabine and araC in vitro was synergistic with combination indices between 0.1 and 0.7. This appeared to be related to the impact of the combination on DNA synthesis recovery, which was significantly delayed following exposure to the combination of troxacitabine and araC compared to either agent alone. Analysis of the effect of troxacitabine on the intracellular metabolites of araC revealed that troxacitabine did not inhibit araC deamination and caused a slight decrease in the overall intracellular accumulation of araCTP. The lower accumulation of araCTP could not be attributed to feedback inhibition caused by troxacitabine triphosphate on dCK. Furthermore, our in vivo experiments demonstrated that the combination of araC and troxacitabine was better at slowing down the progression of leukemia in SCID mice than either agent used alone without additive toxicities. Injections of 10 mg/kg troxacitabine i.p. daily for 5 days in combination with araC at 10 mg/kg led to an increase in median survival time of 58 days compared to 49.5 and 53.5 days for araC and troxacitabine, respectively, given as single agents. This represents an increase in life span of 17%, respectively when compared to araC alone. A pharmacokinetic study revealed that troxacitabine did not influence the disposition of araC when coadministered. CONCLUSIONS: Overall, our results show that the antileukemic activity of troxacitabine and araC is complementary when the two nucleoside analogues are combined in vivo. These effects appear to be related to their interaction at the level of DNA repair rather than to pharmacokinetic interactions. These results encourage the use of troxacitabine and araC in combination in patients with acute leukemia.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Citosina/análogos & derivados , Leucemia Experimental/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citarabina/administração & dosagem , Citarabina/farmacocinética , Citarabina/farmacologia , Citosina/administração & dosagem , Citosina/farmacocinética , Citosina/farmacologia , DNA de Neoplasias/biossíntese , DNA de Neoplasias/efeitos dos fármacos , Dioxolanos/administração & dosagem , Dioxolanos/farmacocinética , Dioxolanos/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Injeções Intraperitoneais , Leucemia Experimental/patologia , Camundongos , Camundongos SCID , Transplante de NeoplasiasRESUMO
BACKGROUND: Previous studies suggest that the clinical presentation of acute coronary syndromes (ACS) may differ between women and men. It is not known if different clinical presentations may be explained by hormonal status in women with ACS. Our objective was to compare the clinical presentation of ACS between premenopausal (PRE) women and post-menopausal women with hormone replacement therapy (HRT) and without (POST). METHODS: This was a prospective study of consecutive women admitted with a diagnosis of ACS (myocardial infarction [MI] or unstable angina). All women answered a detailed questionnaire that included a list of 27 clinical symptoms. Symptom results were adjusted for age and current coronary event diagnosis. RESULTS: Seventy-three Caucasian women were studied. No differences were found in terms of the frequency of reported typical symptoms of ACS between PRE (n = 23), HRT (n = 32), and POST (n = 18). However, PRE more often reported atypical chest symptoms than HRT and POST women (57% vs. 31% vs. 22%, PRE vs. HRT vs. POST, respectively, p = 0.05). HRT and POST women experienced substernal chest pain more frequently than PRE (44% vs. 78% vs. 83%, p = 0.03). In contrast, PRE more frequently tended to experience chest pressure (57% vs. 31% vs. 39%, p = 0.2) or chest pain in other locations (22% vs. 3% vs. 6%, p = 0.06). HRT and POST groups reported more frequent indigestion-like pain/discomfort (22% vs. 50% vs. 56%, p = 0.04) and midback pain (35% vs. 63% vs. 72%, p = 0.04) during ACS compared with PRE women. POST experienced sudden fatigue more frequently than PRE and HRT (61% vs. 53% vs. 89%, p = 0.03). CONCLUSIONS: Our results suggest that almost all women admitted with ACS experienced typical chest symptoms but frequently reported both typical and atypical symptoms. Independently of age, atypical chest symptoms occurred more frequently in premenopausal women than in postmenopausal women with or without HRT.
Assuntos
Angina Instável/diagnóstico , Dor no Peito/etiologia , Terapia de Reposição de Estrogênios , Infarto do Miocárdio/diagnóstico , Pós-Menopausa , Pré-Menopausa , Adulto , Fatores Etários , Angina Instável/complicações , Angina Instável/epidemiologia , Dor no Peito/epidemiologia , Tontura/etiologia , Dispneia/etiologia , Fadiga/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/epidemiologia , Prevalência , Estudos Prospectivos , Quebeque/epidemiologia , Fatores de Risco , Inquéritos e Questionários , Saúde da MulherRESUMO
Propafenone and its 5-hydroxy metabolite exhibit different electrophysiological properties. Objectives of the CAQ-PAF study were (1) to develop a strategy favoring propafenone instead of 5-hydroxypropafenone in plasma following oral administration of propafenone and (2) to evaluate the potential of low-dose quinidine to chronically inhibit CYP2D6. Patients (n = 102) with atrial fibrillation received propafenone 150 mg 3 times daily with either quinidine 100 mg twice daily or placebo. Throughout the study (follow-up, 199 ± 155 days), quinidine successfully inhibited CYP2D6: propafenone concentrations were 3 times higher in patients receiving quinidine (1033 ± 611 ng/mL vs 328 ± 229 ng/mL; P < .001). Moreover, 80% (n = 10) of patients with propafenone levels greater than 1500 ng/mL were in sinus rhythm at 1 year. In contrast, recurrence of atrial fibrillation occurred in 22 of 23 patients with propafenone levels less than 1000 ng/mL (P < .0001). Thus, chronic inhibition of CYP2D6 is achievable with low-dose quinidine in humans. Increased plasma levels of propafenone may be highly beneficial to prevent recurrence of atrial fibrillation.
Assuntos
Antiarrítmicos/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Propafenona/administração & dosagem , Quinidina/administração & dosagem , Idoso , Antiarrítmicos/efeitos adversos , Antiarrítmicos/sangue , Antiarrítmicos/farmacocinética , Fibrilação Atrial/sangue , Fibrilação Atrial/fisiopatologia , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Genótipo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Propafenona/efeitos adversos , Propafenona/sangue , Propafenona/farmacocinéticaAssuntos
Bacteriemia/epidemiologia , Bacteriemia/prevenção & controle , Meningite Pneumocócica/epidemiologia , Meningite Pneumocócica/prevenção & controle , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Feminino , Humanos , MasculinoRESUMO
The angiotensin-converting enzyme (ACE) gene is a candidate genetic locus for coronary artery disease (CAD). Studies investigating the relationship between the ACE-insertion/deletion (I/D) gene polymorphism and myocardial infarction (MI) have been inconsistent. The authors hypothesized that age may be an important modulating factor in this relationship. ACE-I/D allele and genotype distribution was determined in 3 groups: 104 men with a first MI at a young age (≤45 years old), 271 healthy young men (≤30 years old), and 28 healthy elderly men (>65 years old). All participants were French descendants from Quebec City, Canada. Frequency distribution of the ACE alleles and genotypes was similar among the healthy young, the healthy elderly, and the MI patients (P > .05). However, when considering the age at the time of the MI (≤40, ≤35, or ≤30 years old), a significant age-dependent effect with the prevalence of the ACE-DD genotype was found, as it increased by 22%, 61%, and 157%, respectively, compared with the healthy young group (P < .05). Similar observations were obtained versus the healthy elderly men (P < .05). The ACE-I/D polymorphism seems to be a genetic risk factor for MI in young men and becomes an important modulator of MI risk at a young age.
Assuntos
Envelhecimento/genética , Estudos de Associação Genética , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional/genética , Fatores de Risco , Deleção de Sequência/genética , Adulto JovemRESUMO
The objective of this study was to determine if sex influences the pharmacokinetics and hemodynamics of the CYP2D6 substrate metoprolol and its interaction with diphenhydramine (CYP2D6 inhibitor) in healthy young participants with high (extensive metabolizer [EM]) or low (poor metabolizer [PM]) CYP2D6 activities. A prespecified comparative analysis of data from 2 sequential clinical trials that included 16 EM and 4 PM women and 10 EM and 6 PM men was performed. The participants in the 2 trials were administered a single oral dose of 100 mg metoprolol in the presence of steady-state diphenhydramine or placebo. Serial plasma and urine samples were obtained for 48 hours, and hemodynamic data was obtained for 12 hours after metoprolol. In the placebo arm, EM and PM women had 62% and 59% higher S-metoprolol AUC(0-infinity) and 26% and 71% lower CL/F, respectively, compared to men with the same phenotype (all Ps < .05 women compared to men). These differences dissipated on body weight (WT) correction. Women (especially PMs) experienced greater negative chronotropic effects of metoprolol than men (P < .0001 women compared to men). Diphenhydramine coadministration increased S-metoprolol AUC by 84% in EM women and 45% in EM men (P < .009 women compared to men). In the diphenhydramine arm, sex differences in pharmacokinetics persisted even after WT correction, resulting in greater negative chronotropic effects in women (all Ps < .05 women compared to men). Metoprolol dose should be adjusted for body weight, particularly in women. Coadministration of a CYP2D6 inhibitor such as diphenhydramine, by a patient at similar doses in the 2 sexes, could result in a greater inhibition of clearance of CYP2D6 substrates with a resulting higher risk of pronounced pharmacological and adverse effects in women compared to men.
Assuntos
Citocromo P-450 CYP2D6/metabolismo , Difenidramina/farmacologia , Metoprolol/farmacocinética , Adulto , Antiarrítmicos/farmacocinética , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP2D6 , Método Duplo-Cego , Interações Medicamentosas , Feminino , Hemodinâmica/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Masculino , Farmacogenética , Fatores Sexuais , Adulto JovemRESUMO
The administration of xenobiotics may significantly alter the expression of cytochromes P450 (CYPs), thereby leading to potentially toxic cellular, physiologic, and pharmacologic responses. Indeed, an important task in the development of new therapeutic entities is to evaluate efficiently and quantitatively their potential effects on the expression level of different CYPs. In this report, reverse transcriptase polymerase chain reaction (RT-PCR) was used to measure basal and induced mRNA of a wide range of rat CYP isoforms. Rats (n=3 per treatment) were treated with five prototype inducers of CYP isoforms or with vehicle only. RT and PCR efficiencies were determined using appropriate RNA and DNA standards. Messenger RNA was quantified by PicoGreen standard curves and normalized to cyclophilin. Quantitative RT-PCR was used successfully to demonstrate that CYP isoforms were induced at the mRNA level following drug administration. Notably, phenobarbital resulted in significant induction of CYP2B1, CYP2B2, CYP2C6, CYP2C13, CYP2E1, CYP3A1, and CYP3A2. 3-Methylcholanthrene induced CYP1A1, CYP1A2, and CYP1B1. CYP2C11 expression was highly variable and suppressed by pyridine, whereas the expression of CYP2E1 was suppressed by dexamethasone. We demonstrated that quantitative RT-PCR can be used to evaluate efficiently the effect of compounds on the expression of a wide range of CYP isoforms. The technique is advantageous over others in that it is very sensitive, efficient and applicable to highly homologous CYP isoforms.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Isoenzimas/genética , Animais , Sequência de Bases , Ciclofilinas/genética , Sistema Enzimático do Citocromo P-450/biossíntese , Primers do DNA , DNA Complementar , Indução Enzimática , Isoenzimas/biossíntese , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Premenopausal women may be most vulnerable to acute coronary syndromes at a point in their menstrual cycle when their plasma estrogen levels are the lowest during and immediately after menstruation. Metoprolol is a first-line drug in the management of patients with acute coronary syndrome; however, when metoprolol was marketed in 1982, women were largely excluded from clinical trials. Furthermore, the over-the-counter antihistamine diphenhydramine inhibited the metabolism of the CYP2D6 substrate metoprolol in healthy, young men with pharmacokinetic and pharmacodynamic consequences. The pharmacokinetics and pharmacodynamics of metoprolol and its interaction with diphenhydramine were investigated in a randomized, double-blind, crossover, placebo-controlled manner in healthy, premenopausal extensive (EM; n = 16) and poor metabolizer (PM; n = 4) women immediately after menstruation. During the placebo phase, EMs had between 5.2- and 8.4-fold higher total clearance (CL/F) of R- and S-metoprolol compared with PMs, whereas the latter had a 35% greater area under the effect curve (AUEC) and 60% greater EC(50) value for heart rate reduction than EMs (all P < 0.05). Diphenhydramine coadmininstration caused a 2.2- to 3.2-fold decrease in CL/F of metoprolol enantiomers with a resulting 21% increase in AUEC and 29% increase in EC(50) value for heart rate reduction in EMs (all P < 0.05). This is the first study to report an in-depth elucidation of metoprolol's pharmacokinetics and hemodynamics in premenopausal EM and PM women at a point in their menstrual cycle when vulnerability for acute coronary events may be greatest. Caution is warranted when the over-the-counter antihistamine diphenhydramine is part of a chronic therapeutic regimen.
Assuntos
Difenidramina/farmacologia , Teste de Esforço , Metoprolol/farmacocinética , Pré-Menopausa/fisiologia , Adolescente , Adulto , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Citocromo P-450 CYP2D6/fisiologia , Método Duplo-Cego , Interações Medicamentosas , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Metoprolol/farmacologia , Fenótipo , Estereoisomerismo , Volume Sistólico/efeitos dos fármacosRESUMO
AIMS: To assess the feasibility of administering at the same time low doses of five probe drugs, metoprolol (25 mg), chlorzoxazone (250 mg), tolbutamide (250 mg), dapsone (100 mg) and caffeine (100 mg) to determine simultaneously the activities of CYP2D6, CYP2E1, CYP2C9, CYP3A4, CYP1A2, N-acetyltransferase-2 and xanthine oxidase. METHODS: Ten healthy young non-smoking males received the following drugs or combinations of drugs over a 5-week period: week 1) metoprolol; 2) tolbutamide; 3) caffeine, chlorzoxazone and dapsone; 4) caffeine, chlorzoxazone, dapsone and metoprolol; 5) caffeine, chlorzoxazone, dapsone, metoprolol and tolbutamide. The drugs were self-administered at bedtime and urine was collected for the following 8 h. RESULTS: Mean molar phenotypic ratios obtained after administering metoprolol (mean change of -11%) or tolbutamide (mean change of -0.3%) alone, were not significantly different from those obtained when other drugs were co-administered (P > 0.05). The mean within-subject coefficients of variation were 33%, 18%, 22%, 13%, 16%, 13% and 5% for CYP3A4, CYP2D6, CYP2C9, CYP2E1, CYP1A2, N-acetyltransferase 2 and xanthine oxidase metabolic ratios, respectively. No significant interactions (P > 0.5) were observed during the simultaneous administration of various combinations of the five probe drugs. CONCLUSIONS: We propose that this cocktail, composed of five widely available drugs, constitutes a promising means of simultaneously determining the activities of the major CYP enzymes in large populations.