Ketoconazole treatment of nail infection in chronic mucocutaneous candidiasis

ABSTRACT. Chronic mucocutaneous candidiasis is an immunodeficiency disorder which has significant morbidity due to mucous membrane, skin and nail infection. Attempts at reconstitution of immunological abnormalities have had only limited success. Ketoconazole is a newly available oral antifungal agent with activity against candida species. Prolonged administration of ketoconazole to four children with chronic mucocutaneous candidiasis caused marked improvement at infected sites. Resolution of nail infections took up to 12 months.     

Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer

PURPOSE: High-dose (400 mg.) oral ketoconazole 3 times daily with replacement doses of hydrocortisone has become a standard treatment option for patients with advanced prostate cancer which progresses after androgen deprivation. However, toxicity can hinder the ability to deliver treatment and the cost of the regimen can be substantial. Therefore, a prospective phase II study was conducted to assess the efficacy and safety of a regimen of low dose (200 mg.) oral ketoconazole 3 times daily with replacement doses of hydrocortisone in men with androgen independent prostate cancer. MATERIALS AND METHODS: The study included 28 patients with progressive prostate cancer despite anorchid levels of testosterone and ongoing testicular androgen suppression. Treatment consisted of low dose ketoconazole and replacement doses of oral hydrocortisone (20 mg. every morning and 10 mg. at bedtime). At the time of disease progression patients were treated with high dose ketoconazole and continued on the same dose of hydrocortisone. Adrenal androgen levels were measured, and baseline and followup levels correlated with clinical outcome. RESULTS: Overall, 13 (46%) of 28 patients had a prostate specific antigen decrease of more than 50% (95% confidence interval 27.5% to 66.1%). Median duration of prostate specific antigen decrease for all responders was 30+ weeks and 5 patients continue to exhibit a response, ranging from 36+ to 53+ weeks. In general, therapy was well tolerated. There were no grade 4 toxicities. Grade 3 toxicities included hepatotoxicity in 1 patient and depression in 2. The most common toxicities were nausea (29% grades 1 and 2), dry skin (18% grade 1) and fatigue (14% grade 1). Four (14%) patients discontinued low dose ketoconazole due to toxicities. Of the 16 patients who received high dose ketoconazole after disease progression with low dose ketoconazole, 3 were removed from treatment due to toxicity and no patient responded to high dose ketoconazole. There was no difference in the distribution of pretreatment endocrine values between responders and nonresponders, and the magnitude of change in adrenal androgen levels was not associated with response to therapy, although a potential association could easily have been missed due to small sample size. CONCLUSIONS: The regimen of low dose ketoconazole with replacement doses of hydrocortisone is well tolerated and has moderate activity in patients with progressive androgen independent prostate cancer.     

Clinical comparison of the efficacy and tolerability of once daily Canesten with twice daily Nizoral (clotrimazole 1% cream vs. ketoconazole 2% cream) during a 28-day topical treatment of interdigital tinea pedis

The effects of two topical cream formulations containing clotrimazole 1% and ketoconazole 2%, respectively, were clinically compared in a double-blind, randomized manner for a 28-day therapy of interdigital tinea pedis in 106 treated patients. Ketoconazole was to be used twice daily whereas clotrimazole was administered only once daily. The primary response criterion defined as the number of patients with cure or improvement after 28 treatment days was comparable with 62.0% vs. 64.0% (clotrimazole vs. ketoconazole) for the full analysis set of 100 (50 vs. 50) patients. The mycological response revealed a negative culture and microscopy in 53.1% vs. 52.1% of the patients after 14, in 76.0% vs. 79.2% after 28, and in 83.7% vs. 76.9% after 56 days of observation, indicating a possibly better long-term efficacy of clotrimazole. The development of the overall score of tinea-related signs and symptoms did not show relevant differences between the two drugs and continuously decreased from 11+/-5 in both groups at baseline to 2+/-2 vs. 2+/-1 at day 56. As to the remission and improvement rates of single symptoms, better results were obtained under clotrimazole than under ketoconazole particularly for pruritus (97.8 vs. 89.6%) and burning/stinging (97.5 vs. 89.4%) which both are perceived as most bothersome by the patients. Furthermore, both substances appeared as comparably safe and well tolerable (8 vs. 7 adverse events with only 1 vs. 3 drug related). In conclusion, a successful therapy of tinea pedis can be achieved with both clotrimazole and ketoconazole within 28 days of treatment and once-daily clotrimazole is equally effective as twice-daily ketoconazole with favourable influences on the most irritating symptoms of the disease. Mycological and reliable clinical cure cannot be observed during two weeks after start of treatment.     

洗发水中违禁抗真菌药物的检测

建立了HPLC法同时检测洗发水中违禁氟康唑、酮康唑、特康唑和硝酸咪康唑的含量。采用C18柱，流动相为0.34％硫酸氢四丁铵-乙腈（95：5），检测波长210mn。4个组分均在1～100μg/ml浓度范围内线性关系良好。平均回收率分别为101.2％、101．8％、102．4%和101．7％，RSD分别为0．44%、0．59%、0．50％和0．61％。检测限分别为10．4、1．4、5．6和1．3ng。     

A double-blind, randomized, placebo-controlled study to assess the efficacy of ketoconazole for reducing the risk of ovarian hyperstimulation syndrome

OBJECTIVE: To evaluate the role of ketoconazole in prevention of ovarian hyperstimulation syndrome (OHSS) in women with the polycystic ovary syndrome (PCOS) undergoing ovarian stimulation with gonadotropins. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: University hospitals.One hundred nine women with PCOS who were referred for treatment with gonadotropins. INTERVENTION(S): Fifty patients were randomly assigned to receive two ampoules of hMG beginning on day 2 or 3 of the cycle and ketoconazole (50 mg every 48 hours) starting on the first day of hMG treatment. Fifty-one patients received the same amount of hMG plus one tablet of placebo every 48 hours. MAIN OUTCOME MEASURE(S): Follicular development, E(2) level, and pregnancy rate. RESULT(S): The total number of hMG ampoules and duration of treatment to attain ovarian stimulation were higher among ketoconazole recipients. The serum E(2) level and number of patients with dominant follicles on day 9 of the cycle were greater in placebo recipients. Serum E(2) level and total number of follicles at the time of hCG administration did not differ between the two groups. The cancellation rate and OHSS rate were similar in the two groups. CONCLUSION(S): Ketoconazole does not prevent OHSS in patients with PCOS who are undergoing ovarian stimulation. It may reduce the rate of folliculogenesis and steroidogenesis.     

A successful case of pregnancy in a woman with ACTH-independent Cushing’s syndrome treated with ketoconazole and metyrapone

Cushing’s syndrome (CS) is a rare disease caused by a chronic excess of cortisol. Hypercortisolaemia may affect reproductive system leading to infertility in women. However, some of the patients remain fertile, although pregnancy is uncommon. In our report, we describe the case of a 31-years old woman suffering from hypertension, oligomenorrhea, easy bruising, muscle weakness and elevated levels of cortisol. During hospitalization, high level of serum cortisol with stiff diurnal rhythm and undetectable plasma ACTH concentration were found. The overnight 1?mg dexamethasone (DEX) suppression test and the test with 8?mg of DEX were performed – plasma cortisol levels after both doses of DEX were over expected values. Thus, the diagnosis of ACTH independent hypercortisolaemia was established. After three weeks of ketoconazole treatment, high level of β-HCG was found corresponding to the third week of pregnancy. The ketoconazole was shift to metyrapone but afterwards ketoconazole was added again. The treatment was well tolerated and pregnancy proceeded without complications. US scan revealed a 2?cm adenoma of the left adrenal gland, confirmed by CT. An adrenalectomy was performed. Concluding, we think that medical treatment of CS in pregnant women is well tolerated and safe both for the mother and fetus.     

Exploring the feasibility of the use of biopolymers as a carrier in the formulation of amorphous solid dispersions – Part I: Gelatin

Biopolymers have rarely been used so far as carriers in the formulation of amorphous solid dispersions (ASD) to overcome poor solubility of active pharmaceutical ingredients (APIs). In an attempt to enlarge our knowledge on this topic, gelatin, type 50PS was selected. A screening study was initiated in which twelve structurally different poorly soluble biopharmaceutical classification system (BCS) Class II drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen) were selected for evaluation. Solid dispersions of five different drug loadings of these twelve compounds were prepared by lyophilization and evaluated for their solid state properties by mDSC and XR(P)D, and in vitro dissolution performance. Even without any process optimization it was possible to form either fully amorphous or partially amorphous systems, depending on the API and API to carrier ratio. Hence in this respect, gelatin 50PS behaves as any other carrier. Dissolution of the API from the solid dispersions significantly exceeded that of their crystalline counterparts. This study shows the potential of gelatin as a carrier to formulate amorphous solid dispersions.     

白藜芦醇通过拮抗hPXR对P-gp的影响

目的研究白藜芦醇通过拮抗hPXR对P-gp基因(MDR1)、蛋白表达及活性的影响。方法在LS174T细胞中,采用瞬时共转染报告基因实验研究白藜芦醇对PXR介导的MDR1的转录调节作用,并进一步应用Real-Time定量PCR和Western blot方法检测白藜芦醇作用24 h后对利福平诱导的P-gp基因和蛋白变化的影响,罗丹明转运实验考察P-gp活性的变化。结果双荧光素酶报告基因检测结果显示,25和50μmol.L-1白藜芦醇可通过拮抗PXR将利福平对MDR1的诱导作用由4.70倍分别降至1.76倍和0.69倍(P<0.01),在过表达hPXR的LS174T细胞中,50μmol.L-1白藜芦醇可以将利福平诱导的MDR1 mRNA水平由1.8倍降至1.3倍(P<0.05),Western blot结果表明白藜芦醇也可降低利福平诱导的P-gp表达。此外,罗丹明转运实验显示,25和50μmol.L-1白藜芦醇可以将利福平抑制的累积量由77.7%升至91.7%和95.1%(P<0.05),表明白藜芦醇可降低利福平诱导的P-gp活性。结论白藜芦醇可以通过拮抗PXR而影响P-gp的基因、蛋白表达及活性。