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The role of ketoconazole in current prostate cancer care.
Patel, V, Liaw, B, Oh, W
Nature reviews. Urology. 2018;(10):643-651
Abstract
Ketoconazole is a nonselective steroid 17α-hydroxylase/17,20 lyase (CYP17A1) inhibitor that has been used, off-label, as a second-line therapy for castration-resistant prostate cancer (CRPC). The drug has shown clinical efficacy without survival benefit. Despite not improving survival, ketoconazole has beneficial characteristics, such as its low cost, a relatively favourable toxicity profile compared with chemotherapy, and its efficacy both before and after chemotherapy. The approval of several new, highly effective treatments, including abiraterone acetate, enzalutamide, and apalutamide, warrants re-evaluation of the role of ketoconazole and other classic agents in achieving the optimal timing and sequencing of available agents to prolong survival and maintain patients' quality of life. In the current CRPC treatment landscape, we believe that ketoconazole can be considered in patients with nonmetastatic CRPC and in those with metastatic CRPC who do not respond to, tolerate, or have access to chemotherapy and other standard therapeutic options.
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Ketoconazole-Associated Liver Injury in Drug-Drug Interaction Studies in Healthy Volunteers.
Banankhah, PS, Garnick, KA, Greenblatt, DJ
Journal of clinical pharmacology. 2016;(10):1196-202
Abstract
Ketoconazole is a potent CYP3A inhibitor in vivo, and frequently serves as an index CYP3A inhibitor in drug-drug interaction (DDI) studies with healthy volunteers. Limitations restricting the use of systemic ketoconazole in such studies have been recently imposed by regulatory agencies in the United States, the European Union, and elsewhere. A risk of ketoconazole-associated liver injury in the context of DDI studies was cited as the primary justification for these measures. To evaluate the basis for these restrictions, we analyzed a series of published DDI studies identified from a review of existing literature. The study set consisted of 53 DDI studies, and included 971 healthy volunteers with systemic ketoconazole exposure in addition to the victim drug under study. Ketoconazole-associated abnormalities in serum chemistry values indicative of liver injury were observed in 4 subjects, representing a prevalence of 0.41% within the study population. There were no major adverse reactions or instances of hepatic failure. All abnormalities indicative of liver injury resolved upon discontinuation of ketoconazole treatment. The findings from this review do not support restriction of ketoconazole as an index CYP3A inhibitor in DDI studies involving healthy volunteers.
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Female pattern hair loss.
Ioannides, D, Lazaridou, E
Current problems in dermatology. 2015;:45-54
Abstract
Female pattern hair loss, or female pattern androgenetic alopecia, is a nonscarring alopecia with a multi-factorial etiology that mostly affects postmenopausal women and is characterized by a reduction in hair density over the crown and frontal scalp. The clinical picture is characterized by a diffuse rarefaction of scalp hair over the mid-frontal scalp and a more-or-less intact frontal hairline without any signs of inflammation or scarring. Although the disease poses only a cosmetic concern, it is chronic and may have a significant negative psychological impact on the affected person. The aim of treating female pattern hair loss is to reduce hair loss and, to a certain extent, succeed in promoting hair regrowth. Various treatment methods are available, but it remains unclear which are the most effective. Early initiation of treatment and the combination of various modalities seem to be more efficacious than monotherapy.
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An unusual inflammatory rash.
Gathings, RM, Abide, JM, Brodell, RT
JAMA pediatrics. 2014;(2):185-6
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Management of diabetes mellitus in Cushing's syndrome.
Munir, A, Newell-Price, J
Neuroendocrinology. 2010;:82-5
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Abstract
Active Cushing's syndrome is associated with insulin resistance induced by the high and prolonged circulating level of glucocorticoids. In endogenous Cushing's syndrome the overall incidence of diabetes mellitus and insulin resistance is very likely to be under-reported as not all patients are actively investigated with glucose tolerance tests. Whilst it is common clinical experience that management of diabetes mellitus is necessary in patients with Cushing's syndrome there is a dearth of literature-based evidence to support which regimes are the most effective. Therefore, a pragmatic approach is necessary on an individualized patient basis, whereby patients are stratified according to the severity of their impaired glucose homeostasis. The most effective means of control of diabetes mellitus in a patient with active Cushing's syndrome is to lower the levels of circulating cortisol. This may initially be achieved by using adrenal steroidogenesis blockade with drugs including metyrapone, ketaconazole, or, on occasion, mitotane. The rapid action of metyrapone is particularly suitable in this circumstance. Despite this, diabetes-specific therapy is often necessary and metformin and PPAR-γ agonists may be of use, but in the acute setting insulin therapy is frequently needed. Definitive management directed against source driving Cushing's syndrome is often highly effective at either reducing the severity of diabetes, or allowing its complete resolution. Patients experiencing diabetes mellitus in the context of exogenously administered glucocorticoids may well require insulin therapy for the period that the high levels of steroids are being administered. Despite resolution of Cushing's syndrome after definitive treatment patients may continue to exhibit insulin resistance. This and other cardiovascular risk factors require ongoing and long-term attention.
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Sources of variability in ketoconazole inhibition of human cytochrome P450 3A in vitro.
Greenblatt, DJ, Venkatakrishnan, K, Harmatz, JS, Parent, SJ, von Moltke, LL
Xenobiotica; the fate of foreign compounds in biological systems. 2010;(10):713-20
Abstract
Despite the extensive use of ketoconazole as an index inhibitor of human cytochrome P450 3A (CYP3A) isoforms in vitro, literature reports of the quantitative inhibitory potency of ketoconazole are highly variable. In 51 published studies reporting 76 values of ketoconazole inhibition constants (K(i)) versus in vitro clearance of 31 different CYP3A substrates, the K(i) values ranged from 0.001 µM to 25 µM. The geometric mean was 0.1 µM (90% confidence interval: 0.07 to 0.15 µM), and the median was 0.08 µM. Even for one specific substrate metabolized to one specific metabolite (midazolam α-hydroxylation), variability was still extensive (K(i) range: 0.004-0.18 µM). Only about 20% of overall variability in K(i) was explained by a combination of incubation, duration, and microsomal protein concentration. The remaining variation is unexplained, but could be attributable to factors such as: in vitro clearance by non-CYP3A pathways; incorrect assignment of inhibition mechanism; and variable relative content of CYP3A4 and CYP3A5 in different microsomal preparations. However, the role of these factors still is not established. Until sources of variation are more clearly defined, variability can be minimized by use of low microsomal protein concentrations, short incubation periods, and data analysis procedures that use untransformed reaction velocities and inhibition models that allow for mixed competitive-noncompetitive mechanisms.
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Management of dyslipidemia in Cushing's syndrome.
Greenman, Y
Neuroendocrinology. 2010;:91-5
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Abstract
Cardiovascular risk factors such as hypertension, hyperlipidemia and glucose intolerance are highly prevalent in Cushing's syndrome. Lipid abnormalities have been reported in 40-70% of patients, including those with 'subclinical' disease. Surgical cure is associated with significant amelioration of lipid profile in the majority of patients. Treatment of persistent hyperlipidemia should be conducted according to the accepted general principles in use for other medical conditions. Nevertheless, patients requiring medical treatment for persistent hypercortisolism present specific challenges, according to the selected therapeutic agent. For example, treatment with the adrenolytic drug o,p'DDD is associated with a prominent increase in cholesterol levels that necessitates intensive use of lipid lowering agents. The use of ketoconazole, a potent inhibitor of cytochrome P450 3A4 (CYP3A4), may significantly increase plasma concentrations of certain statins (such as simvastatin and atorvastatin) that undergo metabolism by the same pathway, thus increasing the risk of complications and side effects. Therefore, preference should be given to HMG-CoA inhibitors that are metabolized by different pathways, such as pravastatin. In summary, hyperlipidemia should be aggressively treated in patients with Cushing's syndrome in view of the increased cardiovascular morbidity and mortality associated with this disorder.
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Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: systematic review and meta-analysis of randomized clinical trials.
Playford, EG, Webster, AC, Sorrell, TC, Craig, JC
The Journal of antimicrobial chemotherapy. 2006;(4):628-38
Abstract
OBJECTIVES This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections. METHODS Systematic review and meta-analysis of randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal or another antifungal agent or regimen in non-neutropenic critically ill adult patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005) and EMBASE (1980 to week 36, 2005). We also hand-searched reference lists, abstracts of conference proceedings and scientific meetings (1998-2004) and contacted authors of included studies and pharmaceutical manufacturers. The primary outcomes assessed were all-cause mortality and proven invasive fungal infections. Two reviewers independently applied selection criteria, performed quality assessment and extracted data using an intention-to-treat approach. Data were synthesized using the random effects model and expressed as relative risk with 95% confidence intervals. RESULTS Twelve unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a non-absorbable agent) involving 1606 randomized patients were included. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by one-quarter (relative risk 0.76, 95% confidence interval 0.59-0.97) and invasive fungal infections by about one-half (relative risk 0.46, 95% confidence interval 0.31-0.68). No significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or Candida krusei was demonstrated, although the confidence intervals of the summary effect measures were wide. Adverse effects requiring treatment discontinuation were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics. CONCLUSIONS Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one-half and total mortality by one-quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.
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Ketoconazole and Flutamide in the treatment of disseminated intravascular clotting from prostate cancer: a case report and review.
Chakrapee-Sirisuk, S, Amornpichetkul, K, Visudhiphan, S, Sangruchi, T, Srimuninnimit, V, Sinlarat, P
Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2001;(10):1495-501
Abstract
Disseminated intravascular clotting (DIC) is a well-recognized complication of malignancy. Prostatic cancer can produce chronic DIC as well as acute severe DIC. Treatment of DIC are general supportive measures including heparin, transfusion of blood, platelets and clotting factors, but the most important aspect is correction of underlying malignant diseases i.e. cancer of the prostate gland. For metastatic prostatic cancer presenting with an emergency oncologic condition, the treatment of choice is surgical orchiectomy, but surgery may not be possible in the presence of severe DIC. Ketoconazole and Flutamide are drugs with different mechanisms for hormonal manipulation of this cancer. Due to severe DIC, we combined both drugs trying to put maximum therapeutic effect on this life threatening profound DIC patient.