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1.
Rev. Hosp. Ital. B. Aires (2004) ; 40(1): 34-38, mar. 2020. tab
Artigo em Espanhol | LILACS | ID: biblio-1102292

RESUMO

Las mujeres han sido tratadas por décadas con testosterona intentando aliviar una gran variedad de síntomas con riesgos y beneficios inciertos. En la mayoría de los países, la testosterona se prescribe "off-label", de modo que las mujeres están utilizando compuestos y dosis ideadas para tratamientos en hombres. En este sentido, varias sociedades médicas de distintos continentes adoptaron recientemente por consenso una toma de posición sobre los beneficios y potenciales riesgos de la terapia con testosterona en la mujer, explorar las áreas de incertidumbre e identificar prácticas de prescripción con potencial de causar daño. Las recomendaciones con respecto a los beneficios y riesgos de la terapia con testosterona se basan en los resultados de ensayos clínicos controlados con placebo de al menos 12 semanas de duración. A continuación se comentan las recomendaciones. (AU)


There are currently no clear established indications for testosterone replacement therapy for women. Nonetheless, clinicians have been treating women with testosterone to alleviate a variety of symptoms for decades with uncertainty regarding its benefits and risks. In most countries, testosterone therapy is prescribed off-label, which means that women are using testosterone formulations or compounds approved for men with a modified dose for women. Due to these issues, there was a need for a global Consensus Position Statement on testosterone therapy for women based on the available evidence from placebo randomized controlled trials (RCTs). This Position Statement was developed to inform health care professionals about the benefits and potential risks of testosterone therapy intended for women. The aim of the Consensus was to provide clear guidance as to which women might benefit from testosterone therapy; to identify symptoms, signs, and certain conditions for which the evidence does not support the prescription of testosterone; to explore areas of uncertainty, and to identify any prescribing practices that have the potential to cause harm. (AU)


Assuntos
Humanos , Feminino , Idoso , Testosterona/uso terapêutico , Pós-Menopausa/efeitos dos fármacos , Depressores do Apetite/efeitos adversos , Fenitoína/efeitos adversos , Placebos/administração & dosagem , Psicotrópicos/efeitos adversos , Tamoxifeno/efeitos adversos , Testosterona/administração & dosagem , Testosterona/análise , Testosterona/efeitos adversos , Testosterona/farmacologia , Fármacos Cardiovasculares/efeitos adversos , Indometacina/efeitos adversos , Hormônio Liberador de Gonadotropina/efeitos adversos , Pós-Menopausa/fisiologia , Ensaios Clínicos Controlados como Assunto , Antagonistas Colinérgicos/efeitos adversos , Anticoncepcionais Orais/efeitos adversos , Disfunções Sexuais Psicogênicas/etiologia , Disfunções Sexuais Psicogênicas/terapia , Danazol/efeitos adversos , Consenso , Inibidores da Aromatase/efeitos adversos , Uso Off-Label , Inibidores do Fator Xa/efeitos adversos , Anfetaminas/efeitos adversos , Antagonistas dos Receptores Histamínicos/efeitos adversos , Antagonistas de Androgênios/efeitos adversos , Androgênios/fisiologia , Cetoconazol/efeitos adversos , Entorpecentes/efeitos adversos
2.
J Pharmacol Sci ; 142(4): 172-175, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31982331

RESUMO

It has been difficult to experimentally reproduce synergistic effects of ketoconazole on terfenadine-induced torsade de pointes. We assessed proarrhythmic effects of terfenadine (30 mg/kg, p.o.) with/without ketoconazole (100 mg/kg, p.o.) pretreatment using the chronic atrioventricular block cynomolgus monkeys with repeated-measured design (n = 4). Terfenadine with ketoconazole pretreatment repeatedly induced non-sustained torsade de pointes in each animal, although terfenadine alone did not induce it at all. Thus, the chronic atrioventricular block cynomolgus monkeys can be used for studying drug interaction-associated torsade de pointes, providing a non-clinical strategy to circumvent untoward drug interactions in patients specially under polypharmacy.


Assuntos
Bloqueio Atrioventricular , Modelos Animais de Doenças , Sinergismo Farmacológico , Cetoconazol/efeitos adversos , Terfenadina/efeitos adversos , Torsades de Pointes/induzido quimicamente , Animais , Doença Crônica , Cetoconazol/administração & dosagem , Macaca fascicularis , Polimedicação , Terfenadina/administração & dosagem
3.
Lancet Diabetes Endocrinol ; 7(11): 855-865, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542384

RESUMO

BACKGROUND: Levoketoconazole is a ketoconazole stereoisomer in development for treatment of Cushing's syndrome and has not been assessed previously in a clinical trial in patients with Cushing's syndrome. We aimed to investigate the efficacy and safety of levoketoconazole in patients with endogenous Cushing's syndrome. METHODS: SONICS is a phase 3, multicentre, open-label, non-randomised, single-arm study in which we recruited adults (≥18 years) with confirmed Cushing's syndrome and a mean 24-h urinary free cortisol (mUFC) of at least 1·5 times the upper limit of normal from 60 hospital and community sites in 19 countries (15 countries in Europe, and Canada, Israel, Turkey, and the USA). Patients were treated with oral levoketoconazole in a 2-21 week incremental dose-titration phase starting at 150 mg twice daily (150 mg increments until mUFC normalisation, maximum 600 mg twice daily) and a 6-month maintenance phase. The primary outcome was the proportion of patients with mUFC normalisation at end of maintenance, without dose increase during the maintenance phase (in the intention-to-treat population). Prespecified adverse events of special interest were potential liver toxicity, corrected QT prolongation, and adrenal insufficiency. This trial is registered with ClinicalTrials.gov, NCT01838551. FINDINGS: Between July 30, 2014, and June 30, 2017, 201 individuals were screened and 94 patients were enrolled and received at least one dose of study medication. Of the 94 patients, 80 (85%) had pituitary Cushing's syndrome. Mean mUFC at baseline was 671·4 nmol/24 h (243·3 µg/24 h), which is 4·9 times the upper limit of normal. Of the 77 patients who advanced to the maintenance phase, 62 (81%) had mUFC normalisation by end-of-dose titration. At the end of the 6-month maintenance phase, 29 (31%) of 94 patients were responders; the least-squares mean estimate of the proportion of responders was 0·30 (95% CI 0·21-0·40; p=0·0154 vs null hypothesis of ≤0·20). The most common adverse events in the 94 patients were nausea (30 [32%]) and headache (26 [28%]). Adverse events led to study discontinuation in 12 (13%) of 94 patients. Two patients had a QT interval (Fridericia corrected) of more than 500 ms, and three patients had suspected adrenal insufficiency. Alanine aminotransferase reversibly increased to more than three times the upper limit of normal in ten (11%) patients. Four patients had serious adverse events that were considered probably or definitely related to the study drug: abnormal liver function test results (n=1), prolonged QT interval (n=2), and adrenal insufficiency (n=1). One person died from colon carcinoma unrelated to study medication. INTERPRETATION: Twice-daily oral levoketoconazole treatment led to sustained improvements in urinary free cortisol, with an acceptable safety and tolerability profile. Levoketoconazole might represent a useful therapeutic option for the medical treatment of Cushing's syndrome. FUNDING: Strongbridge Biopharma.


Assuntos
Síndrome de Cushing/tratamento farmacológico , Cetoconazol/uso terapêutico , Adolescente , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/epidemiologia , Adulto , Idoso , Alanina Transaminase/sangue , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Síndrome de Cushing/urina , Feminino , Humanos , Hidrocortisona/análise , Hidrocortisona/urina , Cetoconazol/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/epidemiologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
4.
Biol Pharm Bull ; 42(8): 1366-1375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366871

RESUMO

Drug-induced liver injury (DILI) is a common side effect of several medications and is considered a major factor responsible for the discontinuation of drugs during their development. Cholestasis is a DILI that results from impairment of bile acid transporters, such as the bile salt export pump (BSEP), leading to accumulation of bile acids. Both in vitro and in vivo studies are required to predict the risk of drug-induced cholestasis. In the present study, we used chimeric mice with humanized liver as a model to study drug-induced cholestasis. Administration of a single dose of ketoconazole or rifampicin, known to potentially cause cholestasis by inhibiting BSEP, did not result in elevated levels of alkaline phosphatase (ALP), which are known hepatic biomarkers. The concentration of taurodeoxycholic acid increased in the liver after ketoconazole administration, whereas rifampicin resulted in increased tauromuricholic acid and taurocholic acid (TCA) levels in the liver and plasma. Furthermore, rifampicin resulted in an increase in the uniform distribution of a compound with m/z 514.3, presumed as TCA through imaging mass spectrometry. The mRNA levels of bile acid-related genes were also altered after treatment with ketoconazole or rifampicin. We believe these observations to be a part of a feedback mechanism to decrease bile acid concentrations. The changes in bile acid concentrations results may reflect the initial responses of the human body to cholestasis. Furthermore, these findings may contribute to the screening of drug candidates, thereby avoiding drug-induced cholestasis during clinical trials and drug development.


Assuntos
Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Colestase/metabolismo , Cetoconazol/efeitos adversos , Fígado/efeitos dos fármacos , Rifampina/efeitos adversos , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Ácidos e Sais Biliares/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Colestase/sangue , Colestase/induzido quimicamente , Humanos , Cetoconazol/sangue , Cetoconazol/farmacocinética , Fígado/metabolismo , Masculino , Camundongos , Rifampina/sangue , Rifampina/farmacocinética
5.
J Vet Intern Med ; 33(5): 2235-2238, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31448839

RESUMO

A 11-year-old male neutered Shih Tzu was referred to a tertiary facility with a history of weight loss, decreased appetite, polydipsia, and lethargy. The dog had a 10-year history of nonspecific allergic dermatitis and was being treated with 16 mg/kg of ketoconazole q12h for Malassezia dermatitis. Vague gastrointestinal signs, hypocholesterolemia, and lack of a stress leukogram increased suspicion for hypoadrenocorticism (HA). An adrenocorticotropic hormone (ACTH) stimulation test identified hypocortisolemia on pre- and post-ACTH samples and ketoconazole was discontinued. After a short course of corticosteroid treatment, an ACTH stimulation test was repeated and pre-ACTH cortisol concentration was within the reference range, and the post-ACTH cortisol concentration was mildly increased. The temporal association between return of adequate adrenocortical cortisol production and discontinuation of ketoconazole led to the conclusion that the dog had developed iatrogenic HA secondary to ketoconazole treatment.


Assuntos
Insuficiência Adrenal/veterinária , Doenças do Cão/induzido quimicamente , Doença Iatrogênica/veterinária , Cetoconazol/efeitos adversos , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/diagnóstico , Hormônio Adrenocorticotrópico/administração & dosagem , Hormônio Adrenocorticotrópico/farmacologia , Animais , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Dermatomicoses/tratamento farmacológico , Dermatomicoses/veterinária , Doenças do Cão/diagnóstico , Cães , Hidrocortisona/sangue , Cetoconazol/administração & dosagem , Cetoconazol/uso terapêutico , Malassezia , Masculino
7.
J Dermatolog Treat ; 30(8): 760-771, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30668185

RESUMO

Introduction: Although labeling changes and market withdrawal have been implemented for oral ketoconazole (KTZ) due to serious adverse effects (AEs), topical KTZ is generally thought to be effective and safe for the treatment of superficial fungal infections. New dermatologic indications for the use of topical KTZ have arisen such as onychomycosis, blepharitis, and hair loss. This article aims to review the literature on topical KTZ's efficacy and AEs, as well as provide an overview on current insights regarding its mechanism of action and upcoming developments. Methods: A PubMed search was done to include randomized controlled trials (RCTs) focusing on the use of topical KTZ in human subjects. Results: Forty studies with 4566 patients were included in this review. Topical KTZ is clinically effective for the treatment of Malassezia-related conditions such as seborrheic dermatitis (SD) and pityriasis versicolor (PV) with a reported efficacy of 63-90% and 71-89%, respectively. Conclusions: Topical KTZ demonstrates high clinical efficacy for Malassezia-related conditions. More efficacious alternatives are now available for Tinea and Candida. Although topical KTZ is safe, clinicians should be aware that allergic contact dermatitis may occur. Further studies should be completed to investigate the use of topical KTZ for hair loss and inflammatory dermatoses.


Assuntos
Antifúngicos/uso terapêutico , Dermatite Seborreica/tratamento farmacológico , Cetoconazol/uso terapêutico , Tinha Versicolor/tratamento farmacológico , Administração Tópica , Alopecia/diagnóstico , Alopecia/etiologia , Antifúngicos/efeitos adversos , Humanos , Cetoconazol/efeitos adversos , Malassezia/fisiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Tinha Versicolor/microbiologia , Resultado do Tratamento
8.
Clin Pharmacol Drug Dev ; 8(3): 290-303, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30052328

RESUMO

Alicapistat is an orally active selective inhibitor of calpain 1 and 2 whose overactivation has been linked to Alzheimer disease (AD). Three studies were conducted in healthy subjects (18-55 years), 1 in healthy elderly subjects (≥65 years), and 1 in patients with mild to moderate AD. Four studies assessed pharmacokinetics, 1 study in healthy subjects assessed pharmacodynamics (sleep parameters, particularly rapid eye movement [REM], as a measure of central nervous system [CNS] penetration and activity), and all studies assessed safety. Participants received single doses or multiple twice-daily doses of alicapistat for up to 14 days. Maximum alicapistat plasma concentrations were reached in 2 to 5 hours; half-life was 7 to 12 hours postdose. Alicapistat exposure was dose proportional in the alicapistat 50- to 1000-mg dose range. Exposure of the alicapistat R,S diastereomer was approximately 2-fold greater than exposure of the R,R diastereomer in healthy young and elderly subjects and patients with AD. Alicapistat at 400- or 800-mg twice-daily doses had no effect on REM sleep parameters, whereas the active control, donepezil at 10 mg twice daily, affected sleep parameters. Across all trials, the incidence of treatment-emergent adverse events was similar in the placebo and alicapistat groups. There were no clinically significant changes in vital signs and laboratory measurements. The lack of an effect of alicapistat on sleep suggests that concentrations in the CNS were inadequate or that preclinical studies do not predict alicapistat effects in humans.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Calpaína/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Cetoconazol/farmacologia , Pirrolidinas/farmacologia , Doença de Alzheimer/enzimologia , Ensaios Clínicos Fase I como Assunto , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/sangue , Voluntários Saudáveis , Humanos , Cetoconazol/efeitos adversos , Cetoconazol/farmacocinética , Pirrolidinas/efeitos adversos , Pirrolidinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Sono/efeitos dos fármacos
9.
Eur J Endocrinol ; 179(5): L1-L2, 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30320504

RESUMO

We read with interest the paper of Young et al. in which the authors recommend avoiding ketoconazole in the treatment of Cushing's syndrome when patients display increased liver enzymes (>2-fold the upper limit of normal (ULN)). We found in a small series of patients that We read with interest the paper of Young et al. in which the authors recommend avoiding ketoconazole in the treatment of Cushing's syndrome when patients display increased liver enzymes (>2-fold the upper limit of normal (ULN)). Although limited, our experience suggests that liver function tests may improve during ketoconazole treatment and that, in a life-threatening situation such as severe Cushing's syndrome, increased liver enzymes should not preclude ketoconazole prescription.


Assuntos
Síndrome de Cushing/tratamento farmacológico , Cetoconazol/uso terapêutico , Fígado/enzimologia , Adulto , Síndrome de Cushing/enzimologia , Quimioterapia Combinada , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Cetoconazol/efeitos adversos , Masculino , Metirapona/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento
10.
Invest New Drugs ; 36(6): 1085-1092, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30191523

RESUMO

Introduction Ketoconazole is CYP-17 inhibitor with demonstrated activity in men with castration-resistant prostate cancer (CRPC). Lenalidomide is an antiangiogenic and immunomodulatory agent with broad antitumor activity. We hypothesized that the modulation of the cellular immune response to apoptosis caused by ketoconazole may be increased with the addition of lenalidomide. Methods This is an open-label, non-randomized, single-arm phase II study evaluating the efficacy and safety of the combination of ketoconazole and lenalidomide in patients with CRPC. Treatment schema included standard ketoconazole 400 mg orally three times daily plus hydrocortisone orally (20 mg in the morning and 10 mg at night) in combination with lenalidomide 25 mg orally daily for 21 days in a 28-day cycle and aspirin 75 mg daily. The primary endpoint of this study was response (either by ≥ 50% PSA decline or objective disease assessed by RECIST v1.0). Exploratory endpoints included changes in T cell, dendritic cell (DC) marker counts, and their correlation with PSA response to treatment. Results A total of 34 CRPC patients, median age 69 years, 76% ECOG 0 and 76% with metastases participated in the study. Patients received a median of 2 cycles (range 1-35); nine patients (26%) received >10 cycles of treatment. PSA responses were observed in 17 patients (50%) with 11 patients (32%) achieving a PSA decline of >90%. Among the 9 patients with measurable disease, 2 patients (22%) had PR and 2 other (22%) had SD as best response. Median time to failure (TTF) was 2.7 months (range 0.2-32.8); and 8 patients were treated for ≥ 15 months. Most common adverse events included fatigue (76%), skin reactions (62%), lymphopenia (44%) and anemia (44%). One possible treatment-related death was noted. For 16 patients with available serial correlative data, there was a significant increase in the dendritic cells subsets BDCA-1 (+146.7, -20.1 to +501.1%, p = 0.018) and BDCA-3 (39.8%, -100 to 282.6%, p = 0.001) after 8 weeks of treatment. No association between immune cell counts and PSA response at 8 weeks was observed. Conclusion The combination of ketoconazole and lenalidomide was well tolerated but did not meet the primary endpoint of response, despite durable responses were observed in a selected group of patients. Although ketoconazole has now been replaced with more active novel agents, the combination of novel CYP-17 inhibitors with agents capable of modulating the immune system warrants further prospective investigation. NCT00460031.


Assuntos
Cetoconazol/uso terapêutico , Lenalidomida/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Humanos , Cetoconazol/administração & dosagem , Cetoconazol/efeitos adversos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/metabolismo , Tempo para o Tratamento , Resultado do Tratamento
11.
J Pak Med Assoc ; 68(5): 715-720, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29885168

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of myrtus communis L. solution in the treatment of dandruff and to compare it with ketoconazole. METHODS: This double-blind randomised clinical trial was conducted at Shiraz University of Medical Sciences, Shiraz, Iran, from December 2015 to August 2016, and comprised patients with dandruff aged 18-60 years visiting the dermatology out-patient clinic. The subjects were randomised into two equal groups. The treatment group received myrtus communis L. solution and a placebo shampoo, while the control group received ketoconazole shampoo and a placebo solution. The total duration of the study for each subject was one month and subjects in both groups used their respective interventions 8 times during that period. The parameters studied were pruritus, erythema, severity of scaling, and the extent of scalp involvement. All subjects underwent scalp scaling tests at the beginning, after 10 days and at the end of the 30th day. SPSS 21 was used for data analysis. RESULTS: Of the 90 individuals, there were 45(50%) in each of the two groups. However, 74(82%) subjects completed the third visit and, of them, there were 37(50%) in each group. Both groups showed significant improvement in all outcome measures (p<0.001). There were no significant differences between the groups in terms of efficacy, satisfaction rate and side effects (p>0.05 for each outcome). CONCLUSIONS: Myrtus solution was found to be effective in the treatment of dandruff.


Assuntos
Antifúngicos/uso terapêutico , Caspa/tratamento farmacológico , Cetoconazol/uso terapêutico , Myrtus , Fitoterapia , Preparações de Plantas/uso terapêutico , Adulto , Antifúngicos/efeitos adversos , Caspa/complicações , Método Duplo-Cego , Eritema/etiologia , Feminino , Preparações para Cabelo/uso terapêutico , Humanos , Cetoconazol/efeitos adversos , Masculino , Satisfação do Paciente , Fitoterapia/efeitos adversos , Preparações de Plantas/efeitos adversos , Prurido/etiologia , Índice de Gravidade de Doença , Adulto Jovem
12.
Eur J Drug Metab Pharmacokinet ; 43(5): 533-541, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29500603

RESUMO

BACKGROUND: Nintedanib is a substrate for p-glycoprotein which can impact bioavailability. We investigated the effects of ketoconazole, a p-glycoprotein inhibitor, and rifampicin, a p-glycoprotein inducer, on the pharmacokinetics of nintedanib. METHODS: In the ketoconazole study, 34 healthy subjects received nintedanib 50 mg orally alone and 1 h after the last dose of ketoconazole given orally at a dose of 400 mg once daily for 3 days in 1 of 2 randomized sequences. In the rifampicin study, 26 subjects received nintedanib 150 mg orally alone and the morning after the last dose of rifampicin given orally at a dose of 600 mg once daily for 7 days. The primary objective was to determine the relative bioavailability of nintedanib administered following multiple doses of ketoconazole or rifampicin versus alone, based on AUC from time 0 extrapolated to infinity (AUC0-∞) and maximum concentration (Cmax) calculated using an analysis of variance. Geometric mean ratios and 2-sided 90% CIs were calculated. RESULTS: Exposure to nintedanib increased when it was administered following ketoconazole versus alone (AUC0-∞: geometric mean ratio, 160.5% [90% CI, 148.2-173.7]; Cmax: geometric mean ratio, 179.6% [90% CI, 157.6-204.8]) and decreased when it was administered following rifampicin versus alone (AUC0-∞: geometric mean ratio, 50.1% [90% CI, 47.2-53.3]; Cmax: geometric mean ratio, 59.8% [90% CI, 53.8-66.4]). The time to reach Cmax (tmax) and half-life (t½) of nintedanib were unaffected by co-administration of ketoconazole or rifampicin. CONCLUSIONS: Exposure to nintedanib is increased by co-administration of ketoconazole and decreased by co-administration of rifampicin, likely due to effects on bioavailability of the absorbed fraction. ClinicalTrials.govidentifiers:NCT01679613, NCT01770392.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Indóis/administração & dosagem , Indóis/farmacocinética , Cetoconazol/administração & dosagem , Rifampina/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/agonistas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Esquema de Medicação , Interações Medicamentosas , Alemanha , Voluntários Saudáveis , Humanos , Indóis/efeitos adversos , Absorção Intestinal , Cetoconazol/efeitos adversos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Rifampina/efeitos adversos , Medição de Risco , Adulto Jovem
13.
Eur J Endocrinol ; 178(5): 447-458, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29472378

RESUMO

OBJECTIVE: Ketoconazole (KTZ) is one of few available treatments for Cushing's syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ. DESIGN: An observational prospective French cohort study (Compassionate Use Programme (CUP)). METHODS: Enrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury. RESULTS: Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes. CONCLUSIONS: These findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Ensaios de Uso Compassivo/métodos , Síndrome de Cushing/tratamento farmacológico , Síndrome de Cushing/epidemiologia , Cetoconazol/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Criança , Estudos de Coortes , Ensaios de Uso Compassivo/efeitos adversos , Síndrome de Cushing/metabolismo , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Feminino , França/epidemiologia , Humanos , Cetoconazol/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
15.
J Appl Toxicol ; 38(4): 450-458, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29143966

RESUMO

Drugs carry a proarrhythmic risk, which gets even greater when they are used in combination. In vitro assessment of the proarrhythmic potential of drugs is limited to one compound and thus neglects the potential of drug-drug interactions, including those involving active metabolites. Here we present the results of an in vitro study of potential drug-drug interactions at the level of the hERG channel for the combination of up to three compounds: loratadine, desloratadine and ketoconazole. Experiments were performed at room temperature on an automated patch-clamp device CytoPatch 2, with the use of heterogeneously, stably transfected HEK cells. Single drugs, pairs and triplets were used. The results provided as the inhibition of the IKr current for pairs were compared against the calculated theoretical interaction. Models applied to calculate the combined effect of inhibitory actions of simultaneously given drugs include: (1) simple additive model with a maximal inhibition limit of 1 (all channels blocked in 100%); (2) Bliss independence; and (3) Loewe additivity. The observed IC50 values for loratadine, desloratadine and ketoconazole were 5.15, 1.95 and 0.74 µm respectively. For the combination of drugs tested in pairs, the effect was concentration dependent. In lower concentrations, the synergistic effect was observed, while for the highest tested concentrations it was subadditive. To triple the effect, it was subadditive regardless of concentrations. The square root of sum of squares of differences between the observed and predicted total inhibition was calculated to assess the theoretical interaction models. For most of the drugs, the allotopic model offered the best fit.


Assuntos
Interações Medicamentosas , Canal de Potássio ERG1/efeitos dos fármacos , Cetoconazol/efeitos adversos , Loratadina/análogos & derivados , Loratadina/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Combinação de Medicamentos , Eletrofisiologia , Células HEK293 , Humanos , Técnicas In Vitro , Cetoconazol/administração & dosagem , Loratadina/administração & dosagem , Modelos Teóricos , Técnicas de Patch-Clamp
16.
Exp Anim ; 67(1): 71-82, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29129847

RESUMO

Cyclophosphamide (CP) is widely used in anticancer therapy regimens and 2-dechloroethylcyclophosphamide (DECP) is its side-chain dechloroethylated metabolite. N-dechloroethylation of CP mediated by the enzyme CYP3A4 yields nephrotoxic and neurotoxic chloroacetaldehyde (CAA) in equimolar amount to DECP. This study aimed to evaluate the inhibitory effect of ketoconazole (KTZ) on CP metabolism through in vitro and in vivo drug-drug interaction (DDI) research. Long-term treatment of KTZ induces hepatic injury; thus single doses of KTZ at low, middle, and high levels (10, 20, and 40 mg/kg) were investigated for pharmacokinetic DDI with CP. Our in vitro human liver microsome modeling approach suggested that KTZ inhibited CYP3A4 activity and then decreased DECP exposure. In addition, an UHPLC-MS/MS method for quantifying CP, DECP, and KTZ in rat plasma was developed and fully validated with a 4 min analysis coupled with a simple and reproducible one-step protein precipitation. A further in vivo pharmacokinetic study demonstrated that combination use of CP (10 mg/kg) and KTZ (10, 20, and 40 mg/kg) in rats caused a KTZ dose-dependent decrease in main parameters of DECP (Cmax, Tmax, and AUC0-∞) and provided magnitude exposure of DECP (more than a 50% AUC decrease) as a consequence of CYP3A inhibition but had only a small effect on the CP plasma concentration. Our results suggested that combination usage of a CYP3A4 inhibitor like KTZ may decrease CAA exposure and thus intervene against CAA-induced adverse effects in CP clinical treatment.


Assuntos
Ciclofosfamida/metabolismo , Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A/fisiologia , Cetoconazol/efeitos adversos , Cetoconazol/farmacologia , Microssomos Hepáticos/metabolismo , Acetaldeído/efeitos adversos , Acetaldeído/análogos & derivados , Animais , Cromatografia Líquida de Alta Pressão , Ciclofosfamida/análogos & derivados , Interações Medicamentosas , Humanos , Técnicas In Vitro , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
17.
J Prosthodont ; 27(2): 177-181, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29135059

RESUMO

PURPOSE: To investigate the ultimate tensile strength of temporary soft denture liners modified by minimum inhibitory concentrations (MICs) of antifungal agents for Candida albicans biofilm (SC5314) determined in previous microbiological research. MATERIALS AND METHODS: Dumbbell-shaped specimens (n = 7) with a central cross-sectional area of 6 × 3 × 33 mm were produced by Softone and Trusoft, without (control) or with incorporation of drugs in powder form at MICs for C. albicans biofilm (per g of material powder): nystatin (0.032 g), chlorhexidine diacetate (0.064 g), ketoconazole (0.128 g), miconazole (0.256 g), and itraconazole (0.256 g). After plasticization, specimens were immersed in distilled water at 37°C for 24 hours, 7 or 14 days, and then tested in tension in a universal testing machine at 40 mm/min. Data of tensile strength (MPa) and elongation percentage (%) were submitted to 3-way ANOVA and Tukey's test (α = 0.05). RESULTS: At the end of 14 days, the tensile strength for both materials was significantly lower in the groups modified by miconazole and itraconazole compared to the other groups (p < 0.0001), which showed no significant difference between them (p > 0.05). After 7 and 14 days in water, miconazole and itraconazole added into both materials resulted in significantly lower elongation percentages compared to the other antifungal agents and control (p < 0.0001), which were similar to each other (p > 0.05). CONCLUSIONS: The addition of the nystatin, chlorhexidine, and ketoconazole at MICs for C. albicans biofilm resulted in no harmful effects on the tensile strength and elongation percentage of the temporary soft denture liner materials up to 14 days.


Assuntos
Antifúngicos/efeitos adversos , Reembasadores de Dentadura , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Clorexidina/administração & dosagem , Clorexidina/efeitos adversos , Clorexidina/farmacologia , Humanos , Itraconazol/administração & dosagem , Itraconazol/efeitos adversos , Itraconazol/farmacologia , Cetoconazol/administração & dosagem , Cetoconazol/efeitos adversos , Cetoconazol/farmacologia , Miconazol/administração & dosagem , Miconazol/efeitos adversos , Miconazol/farmacologia , Testes de Sensibilidade Microbiana , Nistatina/administração & dosagem , Nistatina/efeitos adversos , Nistatina/farmacologia , Resistência à Tração/efeitos dos fármacos
18.
PLoS One ; 12(10): e0186117, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29016694

RESUMO

BACKGROUND: Several controlled and uncontrolled studies addressing azole antifungal drugs for cutaneous and mucosal leishmaniasis have been published with inconclusive results. We conducted a systematic literature review of studies evaluating the efficacy and toxicity associated with azole therapy for tegumentary leishmaniasis. METHODOLOGY: PRISMA guidelines for systematic reviews and the Cochrane manual were followed, and the review methodology was registered (PROSPERO; CRD42016048668). Sources included the EMBASE, Web of Science, MEDLINE, LILACS, and IBECS databases along with a manual search of references from evaluated studies. Additional resources such as Google Scholar and clinicaltrials.gov were also searched. We included all studies reporting cure rate after cutaneous or mucosal leishmaniasis treatment with systemic azole drugs, regardless of their design. R software was used to estimate global rates of success and adverse events with each drug. The main outcome of interest was clinical cure, defined as complete re-epithelialization of all lesions. RESULTS: A total of 37 studies involving 1259 patients that reported outcomes after fluconazole (9), ketoconazole (14) and itraconazole (15) treatments were included. Only 14 (38%) were randomized controlled trials (RCT). The pooled azole final efficacy rate was 64% (CI95%: 57-70%) for all studies and 60% (CI95%: 50-70%) (p = 0.41) if only RCTs studies were considered. Twenty-four studies were conducted in the Old World and 13 studies in the Americas. The final efficacy rate according to New and Old World were 62% (CI95%: 43-77%) and 66% (CI95%: 58-73%), respectively. The final efficacy rate of azoles according to species were 89% (CI95%: 50-98%) for L. mexicana; 88% for L. infantum (CI95%: 27-99%); 80% for L. donovani; 53% (CI95%: 29-76%) for L. major; 49% for L. braziliensis (CI95%: 21-78%); and 15% (CI95%: 1-84%) for L. tropica. The cure rates were similar among the fluconazole, ketoconazole and itraconazole group arms (p = 0.89), specifically 61% (CI95%: 48-72%), 64% (CI95%: 44-80%) 65% (CI95%: 56-72%), respectively. Adverse events during fluconazole, itraconazole and ketoconazole therapy were reported in 7% (CI95%: 3-14%), 12% (CI95% 8-19%) and 13% (CI95%: 6-29%) of treated patients, respectively, without difference among them (p = 0.35). This systematic review included studies with small samples and both non-comparative and non-randomized studies and the main limitation was the low quality of the available studies. CONCLUSIONS: Available evidence suggests that fluconazole, ketoconazole and itraconazole have similar and modest efficacy rates for tegumentary leishmaniasis treatment. There is insufficient evidence to support the exclusive use of azole therapy as a single agent for leishmaniasis treatment.


Assuntos
Antifúngicos/uso terapêutico , Azóis/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Mucocutânea/tratamento farmacológico , Administração Cutânea , Administração através da Mucosa , Antifúngicos/efeitos adversos , Azóis/efeitos adversos , Bases de Dados Factuais , Humanos , Itraconazol/efeitos adversos , Itraconazol/uso terapêutico , Cetoconazol/efeitos adversos , Cetoconazol/uso terapêutico , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Mucocutânea/epidemiologia , Leishmaniose Mucocutânea/parasitologia
19.
Can Vet J ; 58(9): 914-918, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28878412

RESUMO

A 10-year-old spayed female cocker spaniel dog was referred for an evaluation of acute-onset generalized pustular cutaneous lesions following application of ketoconazole shampoo. Cytologic and histopathologic examinations of the lesions revealed intra-epidermal pustules with predominantly neutrophils and acantholytic cells. This is the first description of putative contact ketoconazole shampoo-triggered pemphigus foliaceus in a dog.


Assuntos
Doenças do Cão/induzido quimicamente , Cetoconazol/efeitos adversos , Pênfigo/veterinária , Animais , Cães , Feminino , Pênfigo/induzido quimicamente
20.
Environ Toxicol Pharmacol ; 55: 14-19, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28802958

RESUMO

The presence of pharmaceuticals in the aquatic environment has received great attention due to their potential impacts on public health. The single, as well as the combined toxicities of erythromycin (ERY) and ketoconazole (KCZ) on the bioaccumulation, biochemical and behavioral responses, were examined in crucian carp. This study focused on the uptake of contaminants, acetylcholinesterase (AChE) activity in the brain, swimming and shoaling behavior of fish. After 14days of binary exposure, the addition of KCZ at nominal concentrations of 0.2, 2 and 20µg/L significantly increased the accumulation of ERY in the brain of the fish and the bioconcentration factor of 2.08 was 2.6-fold higher than that calculated from the ERY-alone exposure. The brain AChE activity was significantly inhibited by ERY and KCZ with a significant correlation with respect to the accumulative concentration of the contaminants. The inhibition rates of swimming activity to KCZ were increased with a corresponding increase in the exposure concentration of KCZ in the single exposure. However, this manner was altered by the combined exposure. In addition, shoaling was significantly enhanced by KCZ-alone exposure, which was significantly correlated with the swimming activity. This study indicates that the mixture of the contaminants may cause endocrine disrupting effects and behavior modification especially in fish with known ecological and evolutionary consequences.


Assuntos
Acetilcolinesterase/metabolismo , Carpas/fisiologia , Eritromicina/efeitos adversos , Cetoconazol/efeitos adversos , Poluentes Químicos da Água/efeitos adversos , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Química Encefálica , Carpas/crescimento & desenvolvimento , Carpas/metabolismo , Regulação para Baixo , Proteínas de Peixes/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Natação
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