Uso de testosterona en mujeres: un comentario sobre el consenso global sobre el uso de la terapia de testosterona para mujeres / Global consensus position statement on the use of testosterone therapy for women

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)

Desenvolvimento e avaliação de nova preparação de anfotericina B e/ou cetoconazol em dispersão de bixina, pullulan e trealose / Development and evaluation of novel preparation of amphotericin B and/or ketoconazole in dispersion of bixin, pullulan and trehalose

Muitos pacientes acometidos por infecções fúngicas sucumbem devido a não eficácia dos antibióticos ou por toxicidade dos mesmos. Anfotericina B é um dos antifúngicos mais eficientes do mercado apesar de sua alta toxicidade, tem estrutura poliênica e é um composto insolúvel em água, sendo necessário o uso de adjuvantes e novas tecnologias para preparo de formulações eficazes. Cetoconazol é um composto imidazólico, também com ação antifúngica de grande espectro de ação e difícil solubilização em meio aquouso, porém solúvel somente em baixos valores de pH. Estudos têm demonstrado a utilização de bixina na preparação de dispersões aquosas de compostos insolúveis ou pouco solúveis em água. Bixina é o principal composto das cascas de semente de Bixa orellana (urucum), sendo um carotenoide insolúvel em água, porém, permite preparações na forma de nanodispersões aquosas com incorporação de fármacos apolares ou lipofílicos. O objetivo deste trabalho foi preparar anfotericina B e cetoconazol na forma de nanodispersões a partir de bixina, utilizando pullulan e trealose como adjuvantes e avaliar estabilidade e eficácia antimicrobiana por ensaios físico-químicos e microbiológicos. Pullulan é um polissacarídeo constituído por unidades de maltotriose, com propriedades adesivas e capacidade de formar biofilmes, enquanto trealose é um composto com duas unidades de glicose, com boa estabilidade em faixas de pH de 3 a 10 e capaz de suportar altas temperaturas, como processos de esterilização por calor úmido. Ensaios físico-químicos demonstraram boa manutenção das características das preparações propostas neste projeto, como, por exemplo, diâmetro hidrodinâmico e potencial zeta das estruturas das nanodispersões de bixina e antifúngicos e também eficácia antimicrobiana frente a Candida albicans ATCC 10231. Os resultados apresentam perspectivas para aprimoramentos de formulações com fármacos pouco solúveis ou insolúveis em água, pesquisa de novos biomateriais e outras aplicações nas áreas farmacêutica e cosmética

Many patients with fungal infections succumb due to ineffectiveness or toxicity of antibiotics. Amphotericin B is one of the most efficient antifungals on the market despite its high toxicity. It presents polyenic structure and is a water-insoluble compound. In this case, it is necessary to use adjuvants and new technologies to prepare effective formulations. Ketoconazole is an imidazolic compound, also with broad spectrum antifungal action and difficult solubilization in aqueous medium but it is soluble at low pH values. Studies have demonstrated the use of bixin in the preparation of aqueous dispersions of insoluble or poorly soluble compounds in water. Bixin is the main compound of Bixa orellana (annatto) seed husks, being a water-insoluble carotenoid, but it allows preparations in the form of aqueous nanodispersions with incorporation of apolar or lipophilic drugs. The objective of this work was to prepare amphotericin B and ketoconazole as nanodispersions from bixin, using pullulan and trehalose as adjuvants and to evaluate them under aspects of stability and efficacy by physicochemical and microbiological assays. Pullulan is a polysaccharide consisting of maltotriose units with adhesive properties and ability to form biofilms, while trehalose is a compound with two glucose units with good stability at pH ranges from 3 to 10 and capable of withstanding high temperatures such as processes of sterilization by moist heat. Physicochemical tests demonstrated good maintenance of the characteristics of the preparations proposed in this project, such as hydrodynamic diameter and zeta potential of bixin and antifungal nanodispersions and also antimicrobial efficacy against Candida albicans ATCC 10231. The results present prospects for improvement. of poorly soluble or water-insoluble drug formulations, research on new biomaterials and other applications in the pharmaceutical and cosmetic fields

Tratamiento farmacológico del síndrome de Cushing / Drug treatment of Cushing's syndrome

El tratamiento farmacológico, aunque no constituye la primera línea de tratamiento en el hipercortisolimo endógeno, desempeña un importante rol en determinados pacientes con síndrome de Cushing. Diversos fármacos pueden ser utilizados, de forma aislada o combinada. El ketoconazol es una opción útil, económica, con determinada seguridad y eficacia a largo plazo. Se realiza una revisión de los medicamentos con mejores resultados, dosis, eficacia, efectos adversos y perspectivas, teniendo en cuenta ensayos clínicos en los que han sido empleados(AU)

Although the drug treatment is not a first line therapy for endogenous hypercortisolism, it plays a key role in certain patients suffering Cushing's syndrome. Several drugs may be used in isolation or in combination. Ketoconazol is a useful, economic, safe and efficacious option at long term. A review was made of drugs with best results, doses, efficacy, adverse effects and perspectives, taking into account clinical assays in which they have been used(AU)

Pseudotumor cerebri during Cushing's disease treatment with ketoconazole / Pseudotumor cerebral durante o tratamento de doença de Cushing com cetoconazol

Benign intracranial hypertension (Pseudotumor cerebri) has been described as related to the reduction in steroid levels in Cushing's disease (CD), especially after surgical remission. Ketoconazole is a common and effective adjuvant therapy for hypercortisolism, but the major concern is liver enzyme dysfunction. We describe here the case of a 12-year old girl with CD who developed benign intracranial hypertension during treatment with ketoconazole. She presented headache, vomiting, a black spot on her right temporal visual field, and signs of elevated intracranial pressure. Pituitary image was normal on magnetic resonance image (MRI), and all symptoms improved after treatment with acetazolamide. We call attention to the diagnosis of this disorder in CD patients, especially children on ketoconazole treatment, because it could be confounded with adrenal insufficiency and lead to definitive severe visual impairment.

Hipertensão intracraniana benigna (Pseudotumor cerebral) tem sido descrita relacionada à redução dos níveis de esteroides séricos na doença de Cushing (DC), especialmente após a remissão cirúrgica. O cetoconazol é uma opção efetiva e de uso rotineiro como adjuvante na terapêutica do hipercortisolismo, tendo como paraefeito mais temido a toxicidade hepática. Relatamos o caso de uma menina com 12 anos de idade portadora de DC que desenvolveu hipertensão intracraniana benigna durante tratamento com cetoconazol. Apresentou-se com cefaleia, vômitos, comprometimento do campo visual temporal direito e sinais de hipertensão intracraniana. A ressonância magnética (RM) de hipófise era normal e todos os sinais e sintomas resolveram-se com uso de acetazolamida. Chamamos a atenção para esse diagnóstico nos pacientes com DC, especialmente crianças, em tratamento com cetoconazol, porque ele pode ser confundido com insuficiência adrenal e causar comprometimento visual severo e definitivo.

Ketoconazole therapy: an efficacious alternative to achieve eucortisolism in patients with Cushing's syndrome

El síndrome de Cushing (SC) es un trastorno grave que requiere frecuentemente tratamiento medicamentoso. Cincuenta y cuatro pacientes (44 mujeres, 10 varones) de 14-63 años de edad con SC, recibieron ketoconazol (KTZ) previo a cirugía (n=27), como complemento luego de cirugía y/o radioterapia (n=16), o como tratamiento primario (n=11). La dosis de mantenimiento fue de 600 (500 - 600) mg/día (mediana-IC95) durante 15 días a 13 años. Los signos clínicos, hepatograma y cortisol libre urinario (CLU) fueron evaluados antes y durante tratamiento con KNZ. El CLU cayó a valores normales o subnormales en 85% de los pacientes, 5 a 150 días luego de iniciar el tratamiento; aún sin normalizar, el CLU disminuyó a 12-48% de los valores pre-tratamiento en el resto de los pacientes acompañándose de mejoría de los signos clínicos. Los efectos colaterales fueron: insuficiencia adrenal (18.5%), toxicidad hepática reversible (11%), "rash" cutáneo (5.5%) e intolerancia gástrica (3.7%); en 11% de los pacientes se observó un fenómeno de "escape". Veinticuatro pacientes (44.4%) fueron tratados por períodos prolongados, de uno a trece años. Este estudio confirma que el KTZ constituye un tratamiento eficaz y generalmente bien tolerado del SC, en particular: a) como preparación para cirugía b) en casos de hipercortisolismo residual luego de cirugía o en espera de resultados de radioterapia, c) como una alternativa razonable en pacientes con SC de origen desconocido y, d) como tratamiento crónico en casos de hipercortisolismo no resuelto luego de fracaso de las terapéuticas habituales.

Cushing's syndrome (CS) is a serious condition requiring drug management in diverse clinical settings. Fifty four patients (44 females, 10 males) with CS, aged 14-63, received ketoconazole (KTZ) prior to surgery (n= 27), as complementary therapy after surgery and/or radiotherapy (n= 16), or as primary treatment (n= 11). It was given at a 600 (500 - 600) mg/day (median - CI95) maintenance dose for periods ranging from 15 days to 13 years. Clinical signs, hepatic enzymes and urinary free cortisol (UFC) were evaluated before and during KTZ treatment. UFC normalised or decreased to subnormal values in 85% of the patients, in 5 to 150 days after starting treatment; although failing to normalise, UFC decreased to 12-48% of pre-treatment values in the remaining patients. Clinical signs improved throughout. Side effects were adrenal insufficiency (18.5%), reversible hepatic toxicity (11%), allergic skin rash (5.5%) and gastric intolerance (3.7%); in 11% of patients, an "escape phenomenon" was observed. Twenty-four out of the total (44.4%) were treated for prolonged periods, from one up to 13 years. In conclusion, this study confirms that KTZ is an effective and generally well tolerated treatment for CS particularly: a) shortly before surgery, b) because of persistent hypercortisolism after surgery or awaiting the results of radiotherapy, c) as a reasonable option in patients with CS of unknown aetiology and, d) as long-term therapy in any case of unsolved hypercortisolism after failure of current treatments.

[ comparison between systemic fluconazol and ketoconazol effectivity in the treatment of tinea versicolor]

Tinea Versicolor is a common superficial fungal skin infection. Topical drugs are often effective in limited lesions; but in extensive cases, systemic drugs are more suitable. Previous studies have shown that Ketoconazole and Fluconazole are effective in 42-97% and 74-100% of lesions respectively. Theaim of this study is to compare the effectiveness of a single dose of 400mg Ketoconazole with two doses of 300mg of Fluconazole with 2 weeks interval. Sixty patients with extensive tinea versicolor [body involved area >/= 25%] were randomly assigned to treatment with either a single dose of 400mg of Ketoconazole or with two doses of 300mg of Fluconazole with 2 weeks interval. One month after the treatment, the improvement rate and side effects were evaluated by clinical examination and questionnaire. Sixty patients were participated initially in the study. Sixty cases [66.7%] completed the study. They were 51 males and 9 females, with a mean age of 30 years. At the follow up visit [one month after the end of treatment], the improvement rate for Ketoconazole [87.9%] was not significantly different from Fluconazole [81.5%]. [Fisher test: P=0.37]. Fluconazole has shown to be as effective as Ketoconazole in the treatment of extensive tinea versicolor. Due to the hepatotoxicity of Ketoconazole, Fluconazole appears to be more suitable in the treatment of extensive tinea versicolor

Tratamiento de las micosis profundas. Estado actual / Treatment of deep mycosis. Present state

Se hace una revisión de los antifúngicos disponibles en el mercado internacional en la actualidad, se profundiza más en el anfotericín B, con sus virtudes y reacciones adversas, así como de otros antifúngicos, sobre todo los derivados azoles, imidazólicos y los triazoles, como compuestos con buenos resultados y menos reacciones secundarias, en particular el fluconazol y el itraconazol y sus características

Ketoconazole-induced liver damage

Five cases (four females, one male) of ketoconazole-related liver damage are presented, two of whom died. All patients received ketoconazole (400 mg/day) for various mycoses. In the four women the first signs of hepatotoxicity appeared after four weeks of therapy. One fatal case developed massive necrosis with fulminant liver failure and the other, submassive necrosis. In four cases cholestasis was a prominent finding. Biochemical evidence of biliary stasis may persist for several months, as occurred in the three surviving patients of our series. The two fatal cases continued receiving the drug in spite of its adverse effects. Consequently, repeated evaluation is recommended to detect early signs of liver involvement.

Hiperpigmentación cutáneo-mucosa en pacientes HIV positivos / Muco-cutaneous hyperpigmentation in HIV patients

Las alteraciones en la pigmentación cutáneo-mucosa en los pacientes infectados por el virus HIV pueden ser frecuentes, pero su etiología está aún en discusión. Se analizó el seguimiento dermatológico desde 1988 hasta 1995 de 320 casos infectados por el virus del HIV, donde 61 eran mujeres y 259 varones, cuyas edades promedio fueron de 26,6 años en los primeros y 22,2 en los segundos. Del total de casos (320), se observó hiperpigmentación cutáneo-mucosa difusa en el 16,32 por ciento de los casos e hiperpigmentación de mucosa y semimucosa oral exclusivamente en 2 mujeres (0,77 por ciento) y 12 varones (4,18 por ciento). En nuestra experiencia, la hiperpigmentación se comportó como un marcador de mal pronóstico, dado que en menos de 6 meses de su aparición, los pacientes presentaron complicaciones más severas que los llevaron a la muerte

Combination therapy in Kala-azar.

128 untreated cases of Kala-azar were divided in 4 equal groups of 32, Group A was treated with Sodium Stibogluconate (SSG) in the dose of 20 mg/kg/body wt. for 30 days. Group B was treated SSG plus allopurinol in the dose of 20 mg/kg/body wt. orally in divided dosage for 30 days. Group C received SSG plus Ketoconazole 600 mg orally in divided dosage for 30 days. Group D in addition to SSG also received levamisole in single oral daily dose of 13 mg/kg/body wt. for 30 days. Response of Group B, C and D was compared to Group A. Results from this study revealed combination of allopurinol with SSG to be statistically not superior to SSG alone.

An efficacy study of itraconazole in the treatment of Penicillium marneffei infection.

OBJECTIVES: to evaluate the efficacy and safety of itraconazole in treating P. marneffei infection. METHODS: Ten patients with previously untreated P. marneffei infection were given oral itraconazole at a dose of 200 mg twice a day for 2 months, followed by a dose of 100 mg once a day for 1 month. Efficacy was determined by the clinical and microbiological cure. RESULTS: All but one patient were seropositive for human immunodeficiency virus (HIV). Two patients died during therapy. Clinical improvement was evident in 8 patients. In 7 of these, the mean duration for becoming culture negative was 57 days. Five patients presented with relapse of P. marneffei infection within four months after completion of treatment. CONCLUSIONS: Itraconazole was shown to be effective in the initial treatment of P. marneffei infection. Relapse after treatment is common and long-term suppressive therapy is recommended.

Itraconazol: estudo multicêntrico em dermatofitoses / Itraconazole: multicentric study in dermatophytosis

Setenta e quatro doentes com dermatofitoses foram tratados com itraconazol. Todos receberam 100 mg ao dia, durante 14 dias. Ao final de duas semanas de tratamento os índices de cura foram de 77%, percentual que subiu a 83%, duas semanas após o final do tratamento. Nove dos 74 (12%) relataram efeitos colaterais, sendo o tratamento interrompido em três deles. Esses resultados sugerem ser o itraconazol um medicamento útil no tratamento das dermatofitoses

Hiperplasia nodular focal do fígado observada num paciente submetido à terapêutica prolongada com ketoconazol / Focal nodular hyperplasia of the liver observed in a patient subjected to a prolonged therapy with ketoconazole

Os autores apresentam o caso de um paciente do sexo masculino com hiperplasia nodular focal do fígado e história de uso prolongado de ketoconazol, sem nenhum tratamento prévio com estrógenos ou andrógenos de qualquer espécie, e sem nenhuma causa aparente de hiperestrogenismo. Sugerimos, neste trabalho, uma associaçäo etiopatogênica entre o uso prolongado de ketoconazol e a hiperplasia nodular focal do fígado, visto que esta droga pode levar a auma inibiçäo da esteroidogênese e aumento da relaçäo estrógeno/testosterona (E/T), que apresenta importante papel na patogênese de vários tumores hepáticos

El caso de infecciosas: Leishmaniasis cutanea / The case of infectious: Leishmaniasis cutaneous

Se presenta el caso de un agricultor quien padecio lesion cutanea ulcerosa cronica producida por Leishmaniasis sp. la cual curo con tratamiento con Metilglucamina mas Cimetidina

Hepatite tóxica causada por ketoconazol: relato de quatro casos / Ketoconazole causing toxic hepatitis: report of 4 cases

Säo descritos quatro casos de hepatite tóxica por ketoconazol. Todas eram mulheres e tomavam a droga de oito a 16 semanas (200mg/dia). O quadro clínico, em todas, foi superponível ao de uma hepatite viral. A normalizaçäo clínico-laboratorial ocorreu entre 60 e 90 dias após a suspensäo da droga, näo tendo havido óbito. Em uma das pacientes, o ketoconazol foi reintroduzido após normalizaçäo clínico-laboratorial, tendo ocorrido nova hepatite tóxica após 15 dias; a segunda suspensäo da droga foi seguida de cura da hepatite

Hepatitis tóxica por ketoconasole / Toxic hepatitis due to ketoconasole

Se presenta un caso de hepatitis aparecido al cabo de 25 días de tratamiento oral con 200 mg diarios de ketoconazol y que regresó rápida y totalmente con la supresión del tratamiento. Se revisa la literatura pertinente, la que señala que la hepatotoxicidad del ketoconazol no es dosis-dependiente sino que atribuible a hipersensibilidad y que puede manifestarse por ascenso de transaminasas y fosfatasas; por hepatitis benigna o incluso por necrosis masiva e insuficiencia hepática aguda