High-dose Ketoconazole Research Articles

Light and electron microscopic study on the effect of ketoconazole on the liver of adult male albino rats

Objective The aim of this study was to evaluate the structural, ultrastructural, and biochemical changes in albino rats' liver treated with different doses and durations of ketoconazole and the possible recovery after cessation of treatment. Background Ketoconazole is an imidazole drug commonly used in treatment of fungal infection. It induces variable degree of hepatotoxicity. Materials and methods Fifty adult male albino rats were used in this study. The rats were divided into five groups. Group 1 was the control group. Group II (low dose treated) included 10 rats treated with ketoconazole at a dose of 40 mg/kg body weight orally for 7 days. Group III (high dose treated) included 10 rats treated with ketoconazole at a dose of 100 mg/kg body weight orally for 14 days. Group IV (arrested low dose) included 10 rats treated with low dose ketoconazole for 7 days followed by cessation of treatment for 7 days. Group V (arrested high dose) included 10 rats treated with high dose ketoconazole for 14 days followed by cessation of treatment for 14 days. At the end of each experimental period, animals were killed, blood samples were collected for biochemical study, and liver tissue samples were obtained for histological study. Results Ketoconazole-treated rats showed destructive changes of liver tissue in the form of marked congested dilated blood vessels, hepatocyte necrosis and complete tissue loss, periportal fibrosis, and elevated serum transaminase. However, nearly complete recovery of liver tissue and improvement in serum enzymes occurred among those treated with low dose, whereas those treated with high dose still showed persistence of some changes. Conclusion Ketoconazole induced marked histological changes in the liver tissue especially with high dose.

Upon failure of first-line ADT, should second-line hormonal manipulation without survival benefit data still be used?

The androgen receptor (AR) is an important target in castrationresistant prostate cancer (CRPC) as the progression of the disease is still largely dependent on androgen signalling. The recommendation to continue with androgen deprivation therapy is reasonable, as cessation and restoration of testosterone levels may have an adverse impact on survival. Antiandrogen withdrawal may also be attempted in all patients, as some patients are long-term responders. In one study, 19% of patients showed no signs of progression 1 year after antiandrogen withdrawal.1 Bissada et al. reported on a case in which the duration of response was for more than 3 years after antiandrogen withdrawal.2 First-generation antiandrogens such as flutamide, bicalutamide, and nilutamide have shown to be effective against prostate cancer relapse after failure of first-line androgen deprivation therapy (ADT). Studies have indicated PSA responses of 14e48% with bicalutamide and up to 50% with nilutamide.3e9 Among patients with minimal or no bone scan involvement and low baseline prostate-specific antigen (PSA) who were started on high-dose ketoconazole, PSA levels decreased by at least 75%.10 But high doses of ketoconazole have been linked to clinically significant toxicity. Therefore, as shown in a small, retrospective study, lowdose ketoconazole may be an option for patients with biochemical failure who have failed ADT.11 With second-line hormonal manipulation using ketoconazole, response rates of between 11% and 13% were reported. There was also a marked palliation of pain in a subset of patients. Low-dose ketoconazole appears to be well

Itraconazole and clarithromycin as ketoconazole alternatives for clinical CYP3A inhibition studies.

High-dose ketoconazole (400 mg q.d. for ≥5 days) has been the gold-standard strong cytochrome P450 3A (CYP3A) inhibitor in drug development drug-drug interaction (DDI) studies. In 2013, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) advised against using this ketoconazole regimen following review of clinical safety reports. We systematically evaluated 19 strong CYP3A inhibitors from regulatory guidances and a literature database to identify itraconazole (200 mg b.i.d. on day 1, q.d. on days 2-6) and clarithromycin (500 mg b.i.d. for 7 days) as acceptable ketoconazole alternatives.

Abiraterone acetate for prostate cancer: a new era of hormonal therapies

Abiraterone acetate for prostate cancer: a new era of hormonal therapies

Malformation spectrum induced by ketoconazole after single administration to pregnant rats during the critical period – comparison with vitamin A‐induced malformation spectrum

Azole derivatives have teratogenic effects in rodents. In the present study, malformations and their sensitive windows induced by high-dose ketoconazole (KCZ), an azole derivative, without maternal toxicity were investigated. In addition, the malformation spectrum determined was compared with that induced by vitamin A palmitate (VAP). Pregnant rats were administered a single dose of KCZ by oral gavage on specific individual days from gestational days 8 to 15 (GDs 8-15). Maternal animals were subjected to necropsy on GD 20, and the obtained fetuses were examined for external, visceral and skeletal malformations. The malformation spectrum of VAP was identified from available published data (Noda, Sato, and Udaka, 1982) and a complementary study (single administration of VAP at 1 200 000 IU kg(-1) ). Embryonic lethality was observed in dams given KCZ on GDs 9-12 with peak incidence on GDs 10 and 11 with complete resorption. KCZ induced major malformations included cleft palate, digital anomalies, misshapen limbs and unique discontinuous ribs, and the sensitive window for each was identified. Compared with the malformations induced by VAP, unique malformations (e.g. discontinuous ribs by KCZ, neural tube defects by VAP), similar malformations with similar sensitive windows (e.g. digital and limb malformations) and similar malformations with different sensitive windows (e.g. embryonic lethality and cleft palate) were distinguished, suggesting that the mechanisms of several of the types of KCZ-induced malformation are related to excessive vitamin A.

High-dose ketoconazole in castration-resistant, metastatic prostate cancer patients previously treated with docetaxel chemotherapy: Single institution retrospective review.

e15151 Background: Chemotherapy remains the standard of care for castration-resistant prostate cancer (CRPC) patients who have progressed through androgen deprivation therapy (ADT). However, there is no standard of care in patients who have progressed on or after treatment with docetaxel chemotherapy. Ketoconazole inhibits adrenal steroid synthesis and has shown activity in prostate cancer. This retrospective study describes our single institution experience with ketoconazole and hydrocortisone in metastatic CRPC patients. Methods: A retrospective study of metastatic CRPC patients who have progressed on or after docetaxel based chemotherapy and received treatment with ketoconazole and hydrocortisone was done. All patients had proven adenocarcinoma of the prostate and a rising PSA levels despite androgen deprivation therapy with luteinizing hormone-releasing agonist therapy and docetaxel chemotherapy. All patients received 400 mg of ketoconazole three times a day and hydrocortisone 30 mg in the morning and 10 mg in the evening. Response was defined as a decline in PSA of at least 50% from the pretreatment level and confirmed by a second PSA value 2 or more weeks later. Partial response was defined as either a stabilization of PSA or decline in PSA less than 50% from pre-treatment levels. Results: A total of 15 patients with CRPC were treated with ketoconazole and hydrocortisone. Six (40%) of the 15 patients had a greater than 50% decrease in their PSA values. One patient has been on Ketoconazole for 21 months with continued PSA response. Eight (57%) of the 14 patients experienced toxicity but there were no grade 3 or 4 toxicities. Conclusions: High-dose ketoconazole with hydrocortisone remains a possible choice in metastatic CRPC patients who have progressed on or after treatment with docetaxel chemotherapy. It has a fair toxicity profile, low cost, and ease of administration. Although uncommon, a durable response was observed in two of the fifteen patients in this retrospective single institution review. No significant financial relationships to disclose.

A Phase I Clinical Study of High Dose Ketoconazole Plus Weekly Docetaxel for Metastatic Castration Resistant Prostate Cancer

This phase I study of high dose ketoconazole and docetaxel was designed against castration resistant prostate cancer to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of co-administered docetaxel and ketoconazole. Patients with metastatic castration resistant prostate cancer received weekly docetaxel for 3 of every 4 weeks plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole). The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly, increasing from 5 to 43 mg/m(2), with starting doses of 600, 800 or 1,200 mg ketoconazole daily. Decreases in prostate specific antigen of 50% or greater were seen in 62% of patients. Of 25 patients with soft tissue disease 7 (28%) had a partial response. Median overall survival was 22.8 months and was significantly greater in docetaxel naïve patients than in patients pretreated with docetaxel (36.8 vs 10.3 months, p = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (p <0.01). Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1,200 mg daily, 1.6-fold with 800 mg daily and approximately 1.3 to 1.5-fold with 600 mg daily. Combination regimens using 600 mg ketoconazole daily were fairly well tolerated and the maximum tolerated dose of docetaxel was 32 mg/m(2). Results suggest that the combination has significant antitumor activity in castration resistant prostate cancer. The long survival in the docetaxel naïve cohort warrants additional, larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.

Ketoconazole and Prednisone to Prevent Recurrent Ischemic Priapism

To our knowledge no standard therapy exists for the prevention of recurrent ischemic priapism. We used ketoconazole and prednisone with dosing titrated according to serum testosterone levels to suppress sleep related erections in an attempt to prevent recurrent episodes. Eight patients with recurrent ischemic priapism were treated with ketoconazole and prednisone. Two patients had sickle cell anemia and 6 had idiopathic recurrent ischemic priapism. Testosterone was measured on initial presentation, and ketoconazole and prednisone dosing was titrated to approximately 200 ng/dl testosterone and based on the presence or absence of recurrent ischemic priapism episodes. The International Index of Erectile Function-5 questionnaire was administered to evaluate for erectile dysfunction. Patients were seen monthly and therapy was withdrawn after 6 months. Mean testosterone before and after treatment was 468 and 275 ng/dl, respectively. Mean followup was approximately 1.5 years. One patient had 2 recurrent ischemic priapism episodes while on ketoconazole and prednisone treatment. Another patient experienced an increase in testosterone from 361 to 432 ng/dl after initiation of therapy, and 3 recurrent ischemic priapism episodes requiring emergency corporal irrigation. After dose titration testosterone was 184 ng/dl and the patient has had no subsequent episodes. Mean International Index of Erectile Function-5 score was 24.8 points. There were no recurrent ischemic priapism episodes after withdrawal of ketoconazole and prednisone, and no reported symptoms of hypogonadism. Ketoconazole and prednisone therapy was well tolerated in these 8 patients with recurrent ischemic priapism, and with testosterone monitoring and dose titration it was successful in preventing recurrent episodes while preserving sexual function.

Enhanced Interaction between Warfarin and High-Dose Ketoconazole: A Case Report

This case describes the increased anticoagulation effect associated with the use of high-dose ketoconazole. A 59-year-old man treated with warfarin for aortic valve replacement was prescribed high-dose ketoconazole and hydrocortisone for the treatment of prostate cancer. Despite lowering the warfarin dosage by 35% during the start of high dose ketoconazole, an additional dose reduction was required subsequently when the INR rose from 2.62 to 3.82 within nine days. After a total dose reduction of 43%, the INR returned to therapeutic range within two weeks. The Naranjo probability scale revealed a probable adverse reaction of increased anticoagulant effect associated with high dose ketoconazole. Due to the inhibition of warfarin metabolism by ketoconazole, patients taking high dose ketoconazole concomitantly with warfarin may need their warfarin dosage reduced by more than is currently recommended, as well as receive more frequent INR monitoring to avoid over anticoagulation.

Inhibition of Luteinizing Hormone Secretion by Testosterone in Men Requires Aromatization for Its Pituitary But Not Its Hypothalamic Effects: Evidence from the Tandem Study of Normal and Gonadotropin-Releasing Hormone-Deficient Men

Studies on the regulation of LH secretion by sex steroids in men are conflicting. Our aims were to determine the relative contributions of testosterone (T) and estradiol (E2) to LH regulation and localize their sites of negative feedback. This was a prospective study with three arms. The study was conducted at a General Clinical Research Center. Twenty-two normal (NL) men and 11 men with GnRH deficiency due to idiopathic hypogonadotropic hypogonadism (IHH) participated. Medical castration and inhibition of aromatase were achieved using high-dose ketoconazole (KC) for 7 d with 1) no sex steroid add-back; 2) T enanthate 125 mg im starting on d 4; or 3) E2 patch 37.5 microg/d starting on d 4. Blood sampling was performed every 10 min for 12 h at baseline, overnight on d 3-4 and d 6-7. Mean LH levels, LH pulse amplitude, and GnRH pulse frequency were assessed at baseline, d 3-4, and d 6-7. In NL men, KC caused a 3-fold increase in mean LH on d 3-4, which was stable on d 6-7 with no add-back. Addition of T reduced LH levels (34.6+/-3.9 to 17.4+/-3.6 IU/liter, P<0.05) by slowing GnRH pulse frequency (13.3+/-0.4 to 6.7+/-1.0 pulses/12 h, P<0.005). LH amplitude increased (6.9+/-1.0 to 12.1+/-1.4 IU/liter, P<0.005). E2 add-back suppressed LH levels (36.4+/-5.6 to 19.0+/-2.4 IU/liter, P<0.005), by slowing GnRH pulse frequency (11.4+/-0.2 to 8.6+/-0.4 pulses/12 h, P<0.05) and had no impact on LH pulse amplitude. In IHH men, restoring normal T levels caused no suppression of mean LH levels or LH amplitude. E2 add-back normalized mean LH levels and decreased LH amplitude from 14.7+/-1.7 to 12+/-1.5 IU/liter (P<0.05). 1) T and E2 have independent effects on LH. 2) Inhibition of LH by T requires aromatization for its pituitary, but not hypothalamic effects. 3) E2 negative feedback on LH occurs at the hypothalamus.

Response to low‐dose ketoconazole and subsequent dose escalation to high‐dose ketoconazole in patients with androgen‐independent prostate cancer

High-dose ketoconazole (HDK) in combination with steroids has been recognized as an effective secondary hormonal therapy in androgen-independent prostate cancer (AIPC). However, HDK causes more severe adverse events than low-dose ketoconazole (LDK). To the authors' knowledge, relatively little is known regarding the efficacy of LDK in AIPC. The efficacy of LDK and of subsequent dose escalation from LDK to HDK was evaluated as secondary hormonal therapy in patients with AIPC. In a single institution, patients with AIPC treated with LDK (at a dose of 200 mg orally 3 times daily) as secondary hormonal therapy with or without concomitant steroids were retrospectively identified. In addition, patients were identified who received dose escalation to HDK (400 mg orally 3 times daily) after experiencing a rising prostate-specific antigen (PSA) level. Thirty-nine of 138 eligible patients (28.3%, 95% confidence interval [95% CI], 20.9-36.6%) treated with LDK experienced PSA declines > or =50%. The median time to disease progression or dose escalation on LDK was 3.2 months (range, 0.1(+)-61 months). Dose escalation to HDK was subsequently performed in 55 patients (39.9%), 7 of whom (12.7%) demonstrated a subsequent PSA decline > or =50%. A longer duration of primary androgen deprivation therapy and total duration of all previous hormonal therapies was associated with a longer time to progression with LDK (P < .05). The most common reversible adverse effect of LDK was NCI Common Toxicity Criteria Grade 1 or 2 fatigue (12.3%). LDK is associated with a PSA response rate comparable to HDK as secondary hormonal therapy in patients with AIPC, but with less toxicity. Although uncommon, additional durable responses occurred in some patients after dose escalation.

Influence of high-dose ketoconazole on the pharmacokinetics of docetaxel

Objective: The pharmacokinetics (PK) of docetaxel are characterized by large inter-individual variability in systemic drug exposure (AUC) and drug clearance. The PK variability is thought to be largely related to differences in the catalytic function of CYP3A, involved in docetaxel metabolism and elimination. As variability in efficacy and toxicity is associated with variability in docetaxel AUC and clearance, reducing inter-individual PK variability may help improve the risk-benefit ratio of docetaxel therapy. We investigated if high-dose ketoconazole, a potent CYP3A inhibitor, could result in a uniform reduction of docetaxel clearance and reduce the inter-individual variability in docetaxel AUC and clearance.Methods: Seven patients were treated in a randomized-cross over design with intravenous docetaxel (100 mg/m2) followed 3 weeks later by docetaxel (15 mg/m2) given in combination with orally administered ketoconazole (400 mg 3 times daily, up to 47 hours after docetaxel infusion) or vice versa. Docetaxel plasma concentration-time data were described by a three-compartment PK model. Ketoconazole plasma concentration-time data were described by a one-compartment PK model. Results: Docetaxel clearance was reduced by 50% (P = .018) from 32.8 ± 13.7 L/hr to 16.5 ± 8.15 L/hr upon ketoconazole co-administration, albeit with large inter-individual variability (fractional change in clearance, range 0.31 – 0.66). In the presence of ketoconazole, inter-individual variability in clearance and AUC, expressed as coefficient of variation, was increased from 41.6 to 49.5% and from 28.0 to 35.1%, respectively, and not, as we had hypothesized, reduced.Conclusion: Inhibition of CYP3A by concomitant high-dose ketoconazole administration does not result in a uniform reduction of docetaxel clearance and does not reduce the inter-individual variability in docetaxel AUC or clearance. This approach is unsuitable as method to achieve a uniform docetaxel PK profile.

Response to low-dose ketoconazole and subsequent dose escalation to high-dose ketoconazole in patients with androgen-independent prostate cancer

4646 Background: High dose ketoconazole (HDK) in combination with steroids has been recognized as an effective secondary hormonal therapy in androgen independent prostate cancer (AIPC). However, HDK causes more severe adverse events than low dose ketoconazole (LDK). Relatively little is known about the efficacy of LDK in AIPC. We evaluated the efficacy of LDK and of subsequent dose escalation from LDK to HDK as secondary hormonal therapy in patients with AIPC. Methods: We retrospectively identified patients with AIPC in a single institution treated with LDK (200 mg PO TID) as secondary hormonal therapy with or without concomitant steroids. Additionally, patients were identified who received dose escalation to HDK (400 mg PO TID) after experiencing a rising prostate-specific antigen (PSA). Results: 138 patients were eligible for the study. Median age was 64 years (range: 41–84); median PSA at initiation of ketoconazole was 37.4 ng/ml (range: 0.8–2279). Patients received LDK as either second (25.4%), third (50.0%) or fourth (21.7%) line hormonal therapy. Thirty-nine of 138 patients (28.3%, 95% CI 20.9%–36.6%) treated with LDK treatment experienced PSA declines ≥50%. Median duration of LDK was 6.4 months in responders and 2.9 months in non-responders. Dose escalation to HDK subsequently was performed in 55 (40%) patients, seven of whom (12.7%) demonstrated a subsequent PSA decline ≥50% (5 LDK responders and 2 LDK non-responders, respectively). Overall time to progression with LDK with or without dose escalation was 3.5 months (range 0.1+–61 months). The most common reversible adverse effect on LDK was grade 1 or 2 fatigue (12.3%). 41.8% of dose escalation group experienced either aggravation or development of toxicities. The most common toxicities on HDK were nausea (16.4%) and fatigue (14.5%). Conclusions: LDK is associated with a PSA response rate comparable to HDK as secondary hormonal therapy in patients with AIPC, and appears to be less toxic. Few patients responded to the dose escalation from LDK to HDK but durable additional responses occurred in some. No significant financial relationships to disclose.

LONG-TERM OUTCOME FOR MEN WITH ANDROGEN INDEPENDENT PROSTATE CANCER TREATED WITH KETOCONAZOLE AND HYDROCORTISONE

The combination of high dose ketoconazole and hydrocortisone (HDK) is active against androgen independent prostate cancer (AIPC). Median response times with HDK tend to be brief but a significant minority of AIPC patients benefit with extended responses. Well characterized response and survival information, especially in the cohort of patients who experience these longer, more durable, responses has not been previously reported. Characterization of this subgroup is of particular interest since men with long-term responses derive the greatest benefit from HDK therapy. The medical records of 78 patients with AIPC treated with HDK between March 1991 and February 1999 were retrospectively reviewed. Baseline clinical and laboratory factors predictive of prolonged response and survival were identified. The median baseline prostate specific antigen (PSA) before the initiation of HDK was 25.1. The number of patients with zero, 1 to 3, and more than 3 lesions on bone scan were 25, 35 and 18, respectively. Median and mean time to PSA progression was 6.7 and 14.5 months. Median and mean survival time was 38.0 and 42.4 months, respectively. Response time and survival were highly correlated (r = 0.799). A total of 34 (44%) men had a greater than 75% decrease in PSA. The median survival times in men with more vs less than a 75% decrease were 60 vs 24 months, respectively. In a Cox proportional hazard regression, prolonged survival was predicted by percent PSA decrease, extent of disease on bone scan and baseline PSA. Ketoconazole can induce prolonged responses, occasionally lasting for years. Long responses are more likely to occur in men initiating HDK earlier in the course of disease before the cancer burden becomes excessive.

An evaluation of high-doses ketoconazole with hydrocortisone substitution in hormone-refractory prostate cancer

We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal biosynthesis, for treating patients with progression of hormone-refractory prostate cancer. The study comprised 35 patients with progressive disease despite salvage treatment with estramustine with or without vinblastine. Treatment consisted high-doses ketoconazole (400 mg three times daily) and hydrocortisone substitution. Patients were monitored clinically and with serial PSA measurements every 3 months. The principal endpoint of the study was PSA response to applied therapy. Of the 35 patients, 18 (51.4%) showed a decrease in PSA 50% with a median duration of 30 weeks (range 6-60 weeks). A PSA reduction 50% was seen in 15 of 31 patients (48.4%) with established metastasis. Twelve patients (34.2%), all of whom had metastasis, exhibited a PSA decrease 80% with median duration of 9 months (range 3-48 months). The median time to progression was 6.3 months (range 0-27 months) and the median survival time was 12.5 months (range 3-48 months). Twelve (34.3%) reported toxicity related to ketoconazole, whereas no patients required discontinuation of therapy. It is apparent from this study that a reasonable percentage of patients failing salvage chemotherapy (estramustine with or without vinblastine) respond favorably to high-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trail of ketoconazole should be considered when progression of PSA occurs, following initial hormonal androgen deprivation.

Low Dose Ketoconazole With Replacement Doses of Hydrocortisone in Patients With Progressive Androgen Independent Prostate Cancer

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. 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. 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. 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.

Importance of Inhibin B in the Regulation of FSH Secretion in the Human Male

Regulation of FSH secretion in the male involves a complex balance between stimulation by GnRH from the hypothalamus, inhibitory feedback by sex steroids (T and E2) and inhibin B (Inh B) from the gonads, and autocrine/paracrine modulation by activin and follistatin within the pituitary. The aim of the present study was to delineate the feedback control of FSH in the human male with specific reference to the relative roles of sex steroids vs. Inh B. Two experimental human models were used: 1) normal (NL) men subjected to acute sex steroid withdrawal (-T, -E2, + Inh B), and 2) functional castrate males (-T, -E2, -Inh B). Nine NL men (age range, 25-45 yr) and three castrate males (age range, 23-47 yr) were studied. The NL men underwent acute sex steroid suppression using high dose ketoconazole (1-g loading dose, followed by 400 mg, orally, four times daily for 150 h). Gonadotropin secretion was characterized by frequent blood sampling every 10 min for 12 h at baseline and on d 3 and 6 of sex steroid ablation. In the three castrate subjects, blood sampling was performed every 5 min for 24 h 8 wk after discontinuing androgen replacement therapy. In the NL men, treatment with ketoconazole resulted in a decline to castrate levels in T (451 +/- 20 to 38 +/- 7 ng/dl; P < 0.0005) and E2 (39 +/- 4 to 15 +/- 2 pg/ml; P < 0.005) and a modest, but significant, decline in Inh B levels, which remained within the normal range (183 +/- 19 to 136 +/- 13 pg/ml; P < 0.005). This suppression of sex steroids was associated with a more marked increase in mean LH (9.5 +/- 0.9 to 24.9 +/- 2.0 IU/liter; P < 0.0001) than FSH levels (5.1 +/- 0.7 to 10.0 +/- 1.5 IU/liter; P < 0.005), with the latter not exceeding the normal adult male range. The castrate subjects had a mean T level of 66 +/- 8 ng/dl, an E2 level of 20 +/- 1 pg/ml, and undetectable Inh B levels. Despite a similar sex steroid milieu, the mean FSH levels observed in NL men after acute sex steroid ablation were approximately 6-fold lower than those seen in the castrate subjects (10.0 +/- 1.5 vs. 59.5 +/- 17.7 IU/liter; P < 0.0005). In contrast, mean LH levels in the NL men were less than 3-fold lower than those in castrate subjects (24.9 +/- 2.0 vs. 66.8 +/- 20.1 IU/liter; P < 0.005). From this human model of acute sex steroid withdrawal, we conclude that Inh B is likely to be the major feedback regulator of FSH secretion in the human male.

Administration of high-dose ketoconazole, an inhibitor of steroid synthesis, prevents posttraumatic anxiety in an animal model

Acute psychological stress is the presumed immediate cause of post-traumatic stress disorder (PTSD), and may also contribute to other anxiety disorders. Abnormal activity of the hypothalamic-pituitary-adrenal (HPA) axis has been tentatively implicated in some of the features of these disorders. Ketoconazole (KTCZ), an imidazole derivative, is a potent inhibitor of gonadal and adrenal steroidogenesis. The aim of this study was to explore the effects of KTCZ blockade of adrenal steroidogenesis, and consequent elevation of adreno-corticotropic hormone (ACTH), on a model of chronic post-traumatic anxiety in rats. Amelioration of anxious behaviors after reduction of corticosterone would suggest that corticosterone (and by implication cortisol in humans) is an important mediator of anxious symptoms: exacerbation of such behaviors would suggest that corticosterone elevations are only secondary, and possibly implicate corticotropin releasing hormone (CRH) and/or ACTH in the pathogenesis of anxious symptoms. We exposed rats for 10 min to cat scent, a prima facie valid model for acute psychological stress, with and without high dose KTCZ for 14 days. Treatment with KTCZ abolished the chronic behavioral effects of acute exposure to a cat scent. Lower levels of anxious behavior in KTCZ-treated and exposed rats were accompanied by lower plasma corticosterone, ACTH and prolactin (PRL) levels compared to untreated exposed rats. Results in this model implicate corticosterone, but not ACTH, in the pathogenesis of chronic anxiety following acute psychological stress.

EFFICACY OF MICROTUBULE-ACTIVE DRUGS FOLLOWED BY KETOCONAZOLE IN HUMAN METASTATIC PROSTATE CANCER CELL LINES

Once a relapse occurs following primary endocrine treatment, metastatic prostate cancer is one of the most therapy-resistant human neoplasms. Ketoconazole is used for complete androgen deprivation, and recent data suggest it has direct activity against prostate cancer cells. LNCaP, DU145, and PC3 cells, human prostate cancer cell lines, and HL60, a human leukemia cell line, were lysed and soluble proteins were harvested. Cells were plated in 96-well flat bottom plates and then exposed to the pharmacological agents, ketoconazole, vinblastine and paclitaxel. DNA synthesis was monitored by 3H-thymidine incorporation. We demonstrate that ketoconazole exerts a cytostatic effect on a panel of human prostate cancer cell lines, with IC50 of 4 to 5 microg./ml., 12 microg./ml., and 25 microg./ml. for LNCaP, PC3/PC3M, and DU145 cells, respectively. On the other hand, using microtubule-active drugs, vinblastine and paclitaxel, we found that PC3M and PC3 cells were more resistant than either DU145 or LNCaP cells. This resistance was associated with a lesser degree of Raf-1 and Bcl-2 phosphorylation following exposure to microtubule-active drugs. Combinations of microtubule-active drugs with ketoconazole were a beneficial treatment in DU145 cancer cells. Furthermore, ketoconazole blocked recovery of all the prostate cancer cell lines following 24 hours-pulse treatment with vinblastine. Pulse-administration of vinblastine followed by continuous administration of ketoconazole warrants investigation in the treatment of hormone-independent metastatic prostate cancer.

Administration of high dose ketoconazole prevents anxiety-related behavior in an animal model of post-traumatic stress disorder

Administration of high dose ketoconazole prevents anxiety-related behavior in an animal model of post-traumatic stress disorder