Ketoconazole Therapy Research Articles

7203 A case of undifferentiated shock found to be due to voriconazole-related primary adrenal insufficiency

Abstract Disclosure: K.X. Zhang: None. C. Bergwitz: None. Primary adrenal insufficiency can be a rare effect observed with azole antifungal therapy, classically ketoconazole, via inhibition of cortisol and aldosterone synthesis. Whether primary AI can be observed with newer triazole drugs used for neutropenic prophylaxis and treating invasive fungal infections is far less understood. We describe a case of a 65-year-old man with medical history notable for COPD and gout, who was on voriconazole for Aspergillus pneumonia, and admitted to the medical ICU with confusion and undifferentiated shock. His potassium was 6.5 mmol/L, sodium 133 mmol/L, bicarbonate 18 mmol/L, and blood pressure 72/63 requiring pressor support. Voriconazole was withdrawn. He also had a fever to 101.7F that was attributed to a gout flare, and he received a course of high dose prednisone. His shock and electrolyte abnormalities quickly resolved, and he was discharged on isavuconazole. At the 1 week mark, he was found to have a morning cortisol 2.3 ug/dL, potassium 5.4 mmol/L, and sodium 134 mmol/L, along with fatigue, nausea, and hypotension, which prompted resumption of steroid and mineralocorticoid replacement. One month after completing his course of isavuconazole, morning cortisol normalized to 11.0 ug/dL and ACTH 22.3 pg/mL. We present a convincing clinical story supporting the etiology of this patient’s initial shock as primary adrenal insufficiency related to a voriconazole effect. This case illustrates how iatrogenic AI can be a missed diagnosis in the emergency room setting. Primary AI has classically been reported following ketoconazole therapy, but there are only 4 reports of primary AI involving the newer triazole posaconazole, and none for voriconazole or isavuconazole. Due to the rarity of this effect, AI due to voriconazole was not on the initial shock differential and timely endocrine labs to seal the diagnosis (morning cortisol, ACTH, and renin/aldosterone levels) were not obtained. If our patient had not received steroids serendipitously for gout, he may have been at risk for adrenal crisis. Whereas central AI is more common and induced by chronic use of systemic steroids, it is important to also think about AI caused by antifungal therapy with newer azoles. Presentation: 6/3/2024

Use of local thermal therapy as an adjunct to topical ketoconazole therapy for cutaneous protothecosis

Use of local thermal therapy as an adjunct to topical ketoconazole therapy for cutaneous protothecosis

Ocular phenotype and therapeutic interventions in keratitis-ichthyosis-deafness (KID) syndrome

ABSTRACT Background To report ocular manifestations, clinical course, and therapeutic management of patients with molecular genetically confirmed keratitis-ichthyosis-deafness syndrome. Methods Four patients, aged 19 to 46, with keratitis-ichthyosis-deafness syndrome from across the UK were recruited for a general and ocular examination and GJB2 (Cx26) mutational analysis. The ocular examination included best-corrected visual acuity, slit-lamp bio-microscopy, and ocular surface assessment. Mutational analysis of the coding region of GJB2 (Cx26) was performed by bidirectional Sanger sequencing. Results All four individuals had the characteristic systemic features of keratitis-ichthyosis-deafness syndrome. Each patient was found to have a missense mutation, resulting in the substitution of aspartic acid with asparagine at codon 50 (p.D50N). Main ophthalmic features were vascularizing keratopathy, ocular surface disease, hyperkeratotic lid lesions, recurrent epithelial defects, and corneal stromal scarring. One patient had multiple surgical procedures, including superficial keratectomies and lamellar keratoplasty, which failed to prevent severe visual loss. In contrast, oral therapy with ketoconazole stabilized the corneal and skin disease in two other patients with keratitis-ichthyosis-deafness syndrome. The patient who underwent intracorneal bevacizumab injection showed a marked reduction in corneal vascularization following a single application. Conclusions Keratitis-ichthyosis-deafness syndrome is a rare ectodermal dysplasia caused by heterozygous mutations in GJB2 (Cx26) with a severe, progressive vascularizing keratopathy. Oral ketoconazole therapy may offer benefit in stabilizing the corneal and skin disease.

Oncological outcomes of metastatic castration resistant prostate cancer (mCRPC) treated with different therapies sequences after completion of docetaxel: a retrospective study in Songklanagarind Hospital

Objective: Many treatment options of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel chemotherapy have proved efficacious in clinical trials but, to date, knowledge regarding oncological outcomes is limited. Materials and Methods: We assessed the oncological outcome of 4 drugs (abi- raterone acetate, cabazetaxel, enzalutamide and ketoconazole) in a normal clinical setting in a university-based hospital. Our cohort consisted of 69 patients with post-docetaxel mCRPC. The primary endpoint was overall survival (OS). The secondary endpoint was predicted factor associated overall survival with all sec- ond-line mCRPC treatment outcomes according to the Cox proportional hazards regression model. Results: This cohort consisted of 69 patients with progressive mCRPC after docetaxel chemotherapy. Median overall survival following treatment with abiraterone acetate and ketoconazole was 25.92 and 9.59 months respectively (p < 0.05). Overall survival rates at 1-year following abiraterone acetate, cabazetaxel, enzalutamide and ketoconazole therapy were 76.3%, 83.3%, 100% and 41.9%, respectively. Multivariable analysis found that abiraterone acetate, cabazitaxel and enzalutamide significantly improved survival in comparison to ketoconazole (p < 0.001). Conclusion: Analysis of overall survival following second-line treatment of mCRPC post docetaxel in our study statistically significantly confirmed that abiraterone acetate, cabazitaxel and enzalutamide improve overall survival in comparison to ketoconazole. The study also found that enzalutamide treatment resulted in better outcomes in comparison to the other drugs.

Update Treatment of Male Androgenetic Alopecia

Background: Male androgenetic alopecia (MAGA), also known as androgenetic alopecia, is the most common hair loss in males who have a genetic predisposition. The pattern of baldness in MAGA starts from the frontal area in a triangular pattern, followed by progressive thinning of the vertex until baldness occurs. Generally, the diagnosis of MAGA is established by clinical examination. FDA has approved a combination of topical minoxidil and oral finasteride for MAGA treatment. Currently, there is another treatment option like dutasteride, a prostaglandin analog, ketoconazole, and co-adjuvant therapy like laser therapy, hair transplantation, and so on. Purpose: To provide an updated treatment for MAGA. Review: Etiopathogenesis of MAGA is influenced by genetic susceptibility and hormonal factors. The European Consensus Group set the evaluation diagnosis of MAGA to include a historyof hair fall, physical examination, hair examination, supporting examination, and clinical documentation. There are therapeutic options for MAGA, including antiandrogen therapies, androgen-independent therapies, and co-adjuvant therapies. The FDA has approved a combination of topical minoxidil and oral finasteride for MAGA treatment. MAGA may affect patients’ quality of life and self-esteem. In general, patients expect higher. Conclusion: MAGA is the most common progressive hair loss in males. The MAGA therapy is expected to achieve cosmetically significant regrowth and to slow additional hair loss.

Biofilm-forming fluconazole-resistant Candida auris causing vulvovaginal candidiasis in an immunocompetent patient: A case report

Rationale: Candida auris is a potential emerging pathogen among Candida and causes serious health threats globally. Patient concerns: We reported a case of vulvovaginal candidiasis caused by Candida auris. A 26-year-old female presented with complaints of vaginal discharge, itching and low back pain. Diagnosis: High vaginal swab culture yielded Candida. The strain was confirmed as Candida auris by amplification and sequencing the internal transcribed spacer region. Antifungal susceptibility testing revealed that the isolate was resistant to fluconazole, amphotericin B and clotrimazole and susceptible to ketoconazole and nystatin. The isolate also exhibited biofilm forming ability. Interventions: Her symptoms did not subside with initial management with fluconazole and clotrimazole. Later, she was started on ketoconazole therapy. The patient responded well to ketoconazole. Outcome and lessons: To the best of our knowledge, this is the first report about the presence of a drug resistant biofilm forming Candida auris strain isolated from a vaginal swab sample from Chennai area. Biofilm forming ability might contribute to its drug resistance. Nucleic acid analysis helps in rapid and accurate identification of such rare species.

Risk of Gynecomastia with Users of Proton Pump Inhibitors.

Proton pump inhibitors (PPIs) are commonly prescribed for many gastrointestinal diseases. A number of case reports have linked PPIs to gynecomastia in men, but large epidemiologic studies are lacking. To quantify the risk of gynecomastia with PPIs in male patients. Using the PharMetrics Plus™ health claims database from the United States, a retrospective cohort study of new PPI users and new amoxicillin users from 2006 to 2016 was conducted. Diagnosis of gynecomastia was identified by the International Classification for Diseases, 9th edition (ICD-9) and 10th edition (ICD-10) codes. Cases were defined as patients with two codes for gynecomastia within 90days, with the first code as the event code. Hazard ratios (HRs) were computed by adjusting for alcoholic cirrhosis, hyperthyroidism, testicular cancer, Klinefelter syndrome, and obesity, as well as the use of ketoconazole, risperidone, spironolactone, and androgen deprivation therapy. A sensitivity analysis defining exposure with two PPI prescriptions was also undertaken. There were 389 cases of gynecomastia diagnosed among 220,791 new PPI users, and 996 gynecomastia cases were diagnosed among 837,740 new amoxicillin users. The crude HR for PPI use compared to amoxicillin use was 1.70 (95% confidence interval [CI]: 1.461-1.976). The adjusted HR for the sensitivity analysis was 1.299 (95% CI: 1.146-1.473). The adjusted HR was 1.4795 (95% CI: 1.2431-1.7609) for patients over 50years old and 1.324 (95% CI: 1.1133-1.5745) for patients 50years old or younger. This large retrospective cohort study suggests that patients who used PPIs are at higher risk of developing gynecomastia. Clinicians may want to convey this information to male patients who require long-term PPI therapy.

Efficacy of azole therapy for tegumentary leishmaniasis: A systematic review and meta-analysis

BackgroundSeveral 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.MethodologyPRISMA 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.ResultsA 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.ConclusionsAvailable 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.

A potential in situ gel formulation loaded with novel fabricated poly(lactide-co-glycolide) nanoparticles for enhancing and sustaining the ophthalmic delivery of ketoconazole.

Oral ketoconazole therapy is commonly associated with serious hepatotoxicity. Improving ocular drug delivery could be sufficient to treat eye fungal infections. The purpose of this study was to develop optimized ketoconazole poly(lactide-co-glycolide) nanoparticles (NPs) with subsequent loading into in situ gel (ISG) formulation for ophthalmic drug delivery. Three formulation factors were optimized for their effect on particle size (Y1) and entrapment efficiency (Y2) utilizing central composite experimental design. Interaction among components was studied using differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. Ketoconazole crystalline state was studied using X-ray powder diffraction. Six different polymeric ISG formulations were prepared and loaded with either optimized NPs or a pure drug. The prepared ISG formulations were characterized for in vitro gelation, drug release and antifungal activity. The permeation through human epithelial cell line was also investigated. The results revealed that all the studied formulation parameters significantly affected Y1 and Y2 of the developed NPs. DSC and FTIR studies illustrated compatibility among NP components, while there was a change from the crystalline state to the amorphous state of the NPs. The in vitro release from the ISG formulations loaded with drug NPs showed sustained and enhanced drug release compared to pure drug formulations. In addition, ISG loaded with NPs showed enhanced anti-fungal activity compared to pure drug formulations. Alginate–chitosan ISG formulation loaded with optimized ketoconazole NPs illustrated higher drug permeation through epithelial cell lines and is considered as an effective ophthalmic drug delivery in the treatment of fungal eye infections.

A Comparative Study of Efficacy, Safety and Relapse Rate of Three Drugs; Systemic Ketoconazole, Systemic Itraconazole and Topical Oxiconazole in the Treatment of Pityriasis Versicolor

Aim : The aim of our study was to evaluate the efficacy, safety and relapse rate of systemic Ketoconazole, systemic Itraconazole and topical Oxiconazole in the treatment of pityriasis versicolor. Study design : 94 patients who had pityriasis versicolor were included in the study. The patients were given Ketoconazole, Itraconazole and Oxiconazole randomly and were followed up at the interval of 15 days, 1 month and 3 months for assessement of clinical and mycological cure. Results : In assessment of clinical parameters maximum improvement in scaling, pigmentation and pruritus was seen in Oxiconazole group compared to itraconazole and ketoconazole group. During the study it was observed that rate of clinical cure was maximum in Oxiconazole group (76.67%) as compared to Itraconazole (58.82%) and Ketoconazole group (46.66%). Mycological cure during visit 2 in Oxiconazole group was (83.33%), as compared to (88.2%) Itraconazole group and (88.7%) Ketoconazole group. During visit 3, mycological cure was present in 93.3% cases in Oxiconazole group, 94.1% in Itraconazole group and 93.3% in Ketoconazole group. During visit 4 mycological cure was assessed which showed 88.7% cure rate in Oxiconazole group compared to 88.2% in Itraconazole group and 88.7% in Ketoconazole group. These results suggested presence of relapse in 6.6% cases in both Oxiconazole and Ketoconazole group and 5.9% cases in Itraconazole group. There were no side effects with oxiconazole group while cases treated with ketoconazole and itraconazole had side effects like nausea and urticaria. Conclusion : According to the present study we conclude that topical Oxiconazole therapy was more effective as compared to systemic Itraconazole and Ketoconazole therapy in early improvement of scaling, pigmentation and pruritus secondary to Pityriasis versicolor with no significant side effects.

A Comparative Study of Efficacy, Safety and Relapse Rate of Three Drugs; Systemic Ketoconazole, Systemic Itraconazole and Topical Oxiconazole in the Treatment of Pityriasis Versicolor

<strong>Aim</strong>: The aim of our study was to evaluate the efficacy, safety and relapse rate of systemic Ketoconazole, systemic Itraconazole and topical Oxiconazole in the treatment of pityriasis versicolor. <strong>Study design</strong>: 94 patients who had pityriasis versicolor were included in the study. The patients were given Ketoconazole, Itraconazole and Oxiconazole randomly and were followed up at the interval of 15 days, 1 month and 3 months for assessement of clinical and mycological cure. <strong>Results</strong>: In assessment of clinical parameters maximum improvement in scaling, pigmentation and pruritus was seen in Oxiconazole group compared to itraconazole and ketoconazole group. During the study it was observed that rate of clinical cure was maximum in Oxiconazole group (76.67%) as compared to Itraconazole (58.82%) and Ketoconazole group (46.66%). Mycological cure during visit 2 in Oxiconazole group was (83.33%), as compared to (88.2%) Itraconazole group and (88.7%) Ketoconazole group. During visit 3, mycological cure was present in 93.3% cases in Oxiconazole group, 94.1% in Itraconazole group and 93.3% in Ketoconazole group. During visit 4 mycological cure was assessed which showed 88.7% cure rate in Oxiconazole group compared to 88.2% in Itraconazole group and 88.7% in Ketoconazole group. These results suggested presence of relapse in 6.6% cases in both Oxiconazole and Ketoconazole group and 5.9% cases in Itraconazole group. There were no side effects with oxiconazole group while cases treated with ketoconazole and itraconazole had side effects like nausea and urticaria. <strong>Conclusion</strong>: According to the present study we conclude that topical Oxiconazole therapy was more effective as compared to systemic Itraconazole and Ketoconazole therapy in early improvement of scaling, pigmentation and pruritus secondary to Pityriasis versicolor with no significant side effects.

Efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer

To assess the efficacy of low dose ketoconazole therapy for Chinese patients with castration resistant prostate cancer (CRPC) and explore possible prognosis factors. From August 2006 to August 2011, 71 patients with CRPC were analyzed retrospectively, who received oral ketoconazole 200 mg, three times a day with prednisone 5 mg, twice a day. Prostate specific antigen (PSA) response rate was defined as the percentage of patients with PSA decline ≥ 50% compared to baseline PSA level during low dose ketoconazole therapy. Multivariate Logistic regression analysis and receiver operating characteristic curve were used to assess the prognostic factors and their accuracy. The mean initial serum PSA level was (205 ± 38) ng/ml for these patients with mean age (69 ± 1) years old. After first androgen deprivation therapy failure, the prostate cancer progressed into castration resistant stage. The baseline PSA was (93 ± 24) ng/ml and the baseline serum testosterone was (0.13 ± 0.02) ng/ml. During the low dose ketoconazole therapy, 31 patients (43.7%) had PSA decrease and 22 cases (31.0%) were effective with PSA decline more than 50%. PSA doubling time and baseline serum testosterone were positive correlation with PSA response rate by multivariate Logistic regression analysis. Patients with PSA doubling time of ≥ 3.0 months had a PSA response rate of 64.3% and the PSA response rate in those with < 3.0 months decreased to 22.8%, hazard rate (HR) = 0.149 (95% confidence interval [CI] 0.029 - 0.766), P = 0.023, area under the curve (AUC) = 0.707. The PSA response rate for patients with baseline serum testosterone ≥ 0.1 and < 0.1 µg/L were 55.6% and 5.7%, respectively, HR = 0.068 (95%CI 0.012 - 0.380), P = 0.002, AUC = 0.749. The common adverse reactions included liver dysfunction (17.9%), renal dysfunction (16.4%), fatigue (11.9%), nausea (6.0%) and anorexia (4.5%) and so on. Low dose ketoconazole therapy was a moderate, low toxicity hormonal therapy option for patients with CRPC. PSA doubling time ≥ 3 months and baseline serum testosterone ≥ 0.1 µg/L were predictors of desired effect for low dose ketoconazole therapy.

CASE REPORT: LOW DOSE CYCLOSPORINE COMBINED KETOCONAZOLE CURES A DOG OF STERILE NODULAR PANNICULITIS

An eight-year-old neutered male Cocker Spaniel with multiple subcutaneous masses on the right flank was presented to National Taiwan University Veterinary Hospital. The masses were excised and submitted for histopathologic evaluation and bacterial culture. A diagnosis of severe panniculitis was made and no microorganism was identified with bacterial culture. The patient did not respond well and showed significant side effects from prednisolone therapy. Later, low-dose cyclosporine was used instead and the lesions resolved. Complete remission was observed when ketoconazole was added in order to increase the blood concentration of cyclosporine in the patient. There were no adverse side effects noted during this combination therapy. The patient has remained free of the disease at the time this report was written. In conclusion, low-dose cyclosporine combined with ketoconazole therapy is safe and effective for treating sterile nodular panniculitis, when glucocorticoid does not provide an adequate clinical result.

Medical therapy for Cushing's disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers.

Morbidity and mortality in Cushing's disease (CD) patients are increased if patients are not appropriately treated. Surgery remains the first line therapy, however the role of medical therapy has become more prominent in patients when biochemical remission is not achieved/or recurs after surgery, while waiting effects of radiation therapy or when surgery is contraindicated. Furthermore, use of preoperative medical therapy has been also recognized. In addition to centrally acting therapies (reviewed elsewhere in this special issue), adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are frequently used. A PubMed search of all original articles or abstracts detailing medical therapy in CD, published within 12 months (2013-2014), were identified and pertinent data extracted. Although not prospectively studied, ketoconazole and metyrapone have been the most frequently used medical therapies. A large retrospective ketoconazole study showed that almost half of patients who continued on ketoconazole therapy achieved biochemical control and clinical improvement; however almost 20% discontinued ketoconazole due to poor tolerability. Notably, hepatotoxicity was usually mild and resolved after drug withdrawal. Etomidate remains the only drug available for intravenous use. A new potent inhibitor of both aldosterone synthase and 11β-hydroxylase, following the completion of a phase II study LCI699 is being studied in a large phase III with promising results. Mifepristone, a glucocorticoid receptor antagonist, has been approved for hyperglycemia associated with Cushing's syndrome based on the results of a prospective study where it produced in the majority of patients' significant clinical and metabolic improvement. Absence of both a biochemical marker for remission and/or diagnosis of adrenal insufficiency remain, however, a limiting factor. Patient characteristics and preference should guide the choice between different medications in the absence of clinical trials comparing any of these therapies. Despite significant progress, there is still a need for a medical therapy that is more effective and with less adverse effects for patients with CD.

Clinical activity of abiraterone acetate in patients with castration-resistant prostate cancer who received prior ketoconazole therapy.

99 Background: Studies have shown activity of Abiraterone acetate (AA) in patients (pts) with castration-resistant prostate cancer (CRPC) who have received prior ketoconazole. Prostate-specific antigen (PSA) response to AA in relation to previous PSA response to ketoconazole was investigated. Methods: A retrospective analysis was conducted to determine the clinical activity of AA in men with CRPC who have received prior ketoconazole therapy at our institution. Time to PSA progression (PSA TTP) was defined by PCWG2 criteria, a PSA reduction of 50% or more was considered as PSA response. Results: Thirty four pts were identified. Nineteen pts (56%) had previous PSA responses on ketoconazole, with a median PSA TTP of 11 months (95% confidence interval [CI] 6.8-19.9). Subsequently, 11 of 34 (33%) of pts achieved a PSA response on AA, with a median PSA TTP of 6 months (95% CI 4.9-9.5). Among the 19 pts having a PSA response on ketoconazole, only four (21%) pts subsequently had PSA response to AA. Two of these pts had transient PSA response with PSA TTP less than 3 months on kKetoconazole, one patient discontinued Ketoconazole due to side effects, one patient had intermittent non-castrate testosterone levels. In contrast, 7 of 15 (46.7%) pts without prior PSA response to ketoconazole subsequently achieved PSA response on AA (p=0.11). Of note, PSA reduction of less than 50% on AA was observed in 9 of 34 pts (26%), which was associated with a longer median PSA TTP compared to pts who had PSA-progressive disease (5.9 months [95% CI 3.5-7.3] vs.1.5 months [95% CI 1.0-3.5], p=0.028). Five of these nine patients had a prior PSA response to ketoconazole but required drug discontinuation for reasons other than disease progression. Conclusions: PSA response to prior ketoconazole therapy is associated with lower PSA response rate to subsequent AA. The observation suggests that there is a biologically distinct subset of patients who are ketoconazole-resistant but abiraterone-sensitive, the underlying mechanism needs to be further investigated.

Biochemical response to ketoconazole therapy in post-chemotherapy mCRPC patients.

174 Background: Ketoconazole for the treatment of metastatic castration resistant prostate cancer (mCRPC) has never been investigated in randomized trials. In fact, although ketoconazole is a less potent inhibitor of the CYP-17 enzyme systems compared to abiraterone, there is no head-to-head evidence demonstrating that this translates into improved survival. We analyzed biochemical response rates in post-chemotherapy mCRPC patients who were treated with ketoconazole 200 mg TID plus prednisone 5 mg BID at a single center in Denmark. Methods: Between 2008 and 2012, where neither abiraterone nor enzalutamide was available in Denmark, a total of 30 post-chemotherapy mCRPC patients were managed with ketoconazole. Percent change in prostate-specific antigen (PSA) and alkaline phosphatase (ALP) from baseline were registered. Overall survival was calculated from the initiation of ketoconazole. Results: At initiation of ketoconazole, median age was 66 (range: 58 to 76). Median PSA was 547 ng/ml (65 to 4,241). Median ALP was 159 U/L (51 to 750). The median number of prior cancer therapies was five (three to nine). The median time on ketoconazole treatment was 150 days (14 to 648). A total of 44% patients had any decline in PSA, whereof 31% experienced a decline of &gt;=50%. At three months, a total of 19 patients still received ketoconazole, whereof 26% sustained a PSA decline of &gt;=50% from baseline. A total of 71% experienced any decline in ALP, whereof 36% experienced a maximum decline of &gt;=50%. At three months, 7 of 19 patients (36%) sustained an ALP decline of &gt;=50% from baseline. At follow-up, 28 of 30 patients had died. The median overall survival was 10.5 months (95%CI: 8.3-12.6). Conclusions: Compared to the post-chemotherapy phase II study of abiraterone (58 patients) our cohort most likely had a larger tumor burden (e.g. higher PSA, more therapies prior to start of ketoconazole). Nonetheless, we demonstrated a reasonably comparable maximum &gt;=50% PSA response-rate (43% in phase II) and three-months response-rate &gt;=50% (36% in phase II). Also a significant decline in ALP was demonstrated here which has not been reported in abiraterone trials. Given the large difference in expenditure, a head-to-head comparison of abiraterone and ketoconazole in mCRPC patients still seem justified.

Factitious Cushing's syndrome masquerading as Cushing's disease

Factitious Cushing's syndrome is extremely rare. The diagnosis is challenging as cross-reactivity of synthetic corticosteroids or their metabolites in immunoassay measurements of plasma or urinary cortisol can make distinguishing between true and factitious Cushing's syndrome difficult. Adrenocorticotropin (ACTH) is usually suppressed in factitious Cushing's syndrome. A 54-year-old woman presented with clinical and biochemical features of Cushing's syndrome and an unsuppressed ACTH concentration. She denied recent exogenous corticosteroid use. Initial investigations revealed a markedly elevated urinary free cortisol, mildly elevated midnight salivary cortisol and normal morning cortisol concentration. Plasma ACTH was not suppressed at 13 ng/l (RR 10-60 ng/l). A pituitary MRI was normal, but inferior petrosal sinus sampling (IPSS) revealed a post corticotrophin releasing hormone ACTH ratio >20:1 in the left petrosal sinus. Ketoconazole therapy amplified discordance between the urinary free and morning plasma cortisol concentrations. Further investigation of this discordance using high-pressure liquid chromatography tandem mass spectrometry (HPLC-MS/MS) revealed a urinary free cortisol excretion of only 20 nmol/24 h, but prednisolone excretion of 16,200 nmol/24 h. Factitious Cushing's syndrome can mimic endogenous ACTH-dependent hypercortisolism during initial investigations and IPSS. This case highlights the importance of (i) recognizing the significance of discordant results; (ii) using an ACTH assay capable of reliably differentiating ACTH-dependent from ACTH-independent Cushing's syndrome; and (iii) appreciating that IPSS is only useful to localize the source of ACTH in confirmed ACTH-dependent Cushing's syndrome. In this case, measurement of corticosteroids by HPLC-MS/MS was essential in reaching the correct diagnosis.

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate‐resistant prostate cancer

Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366). As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC.

Systematic Review of Oral Treatments for Seborrheic Dermatitis

Seborrheic dermatitis (SD) is normally treated with topical corticosteroids and antifungals. Oral therapies can be prescribed in severe or unresponsive cases. This review aims to assess the quantity and quality of published reports on oral therapies for SD. MEDLINE and Embase databases and the reference listings of publications were searched for any publication using oral treatment for SD. The quality of the included publications was assessed using a modified 27 item checklist by Downs and Black. Twenty-one publications (randomized controlled trials, open trials and case reports) covering eight oral therapies (itraconazole, terbinafine, fluconazole, ketoconazole, pramiconazole, prednisone, isotretinoin and homeopathic mineral therapy) were identified. Most of the publications investigated oral antifungals and the quality of the evidence was generally low. The clinical efficacy outcome reported varied considerably between the studies, preventing statistical analysis and direct comparison between treatments. However, ketoconazole therapy was associated with more relapses compared with other treatments. Itraconazole dosing regimen for SD was generally 200 mg/day for the first week of the month followed by 200 mg/day for the first 2 days for 2-11 months. Terbinafine was prescribed at 250 mg/day either as a continuous (4-6 weeks) or as an intermittent regimen (12 days per month) for 3 months. Fluconazole has administered daily (50 mg/day for 2 weeks) or weekly (200-300 mg) for 2-4 weeks. Ketoconazole dosing regimen was 200 mg daily for 4 weeks. Finally, a single 200 mg dose of pramiconazole was administered to patients. This review also highlights key areas for consideration when designing future studies.

Peripheral Blood Mononuclear Cells of Mycetoma Patients React Differently to Madurella mycetomatis Antigens than Healthy Endemic Controls

Peripheral Blood Mononuclear Cells of Mycetoma Patients React Differently to Madurella mycetomatis Antigens than Healthy Endemic Controls