Combination Of Ketoconazole Research Articles

Efficacy of Combination of Topical Ketoconazole 2% Cream and Adapalene 0.1% Gel versus Topical Ketoconazole 2% Cream Alone in Treatment of Pityriasis Versicolor

Pityriasis Versicolor (PV) is a superficial skin infection caused by Malassezia yeasts, resulting in hypo and hyperpigmented macules. It affects up to 40% of individuals, often leading to itching, decreased quality of life, and social stigma. Objective: To compare the efficacy of combination of topical ketoconazole 2% cream and adapalene 0.1% gel versus topical ketoconazole 2% cream alone in treatment of pityriasis versicolor. Methods: A comparative cross-sectional study was conducted at the Department of Dermatology, Nishtar Hospital, Multan, spanning from November 2020 to April 2021. Total 90 patients were divided equally into two groups: Group A received a combination of Ketoconazole 2% cream and adapalene 1% gel, while Group B received Ketoconazole 2% cream alone. The efficacy of both treatments was evaluated and compared. The study utilized SPSS version 26.0 for data analysis. Results: In terms of gender, 52.22% were male, and 47.78% were female across both groups. The mean duration of the disease was 5.84 ± 3.26 years in Group A and 6.04 ± 3.11 years in Group B, with an overall mean of 5.95 ± 3.17 years. The efficacy of Group A was 91.11%, with 41 participants showing positive results, while Group B had an efficacy of 75.56%, with 34 participants showing positive results. Conclusions: The study findings indicate that using a combination of adapalene 0.1% gel and ketoconazole 2% cream is more efficacious than using ketoconazole 2% cream alone in treating PV

COMPARATIVE STUDY OF EFFICACY OF COMBINED TREATMENT WITH KETOCONAZOLE 2% CREAM AND ADAPALENE 0.1% GEL VS. KETOCONAZOLE 2% CREAM MONOTHERAPY IN PITYRIASIS VERSICOLOR

Background: Pityriasis Versicolor (PV) is an infection of the superficial layers of skin caused by Malassezia yeasts. It is a non-contagious disease characterized by hypo and hyperpigmented macules on the body. Up to 40% of people face itching, decreased quality of life, social stigmatization, and embarrassment due to the lesions. Adapalene with Ketoconazole provides an efficient option for PV patients due to better toxicity profile and rapid action on the lesions.
 Objective: Comparison of efficacy of combined therapy with Ketoconazole 2% cream and adapalene 1% gel against Ketoconazole 2% cream monotherapy in Pityriasis Versicolor.
 Methods: Total 90 patients (45 in each group) were included in the study. Group-A was treated with combination of Ketoconazole 2% cream & adapalene 1% gel while group-B was given Ketoconazole 2% cream monotherapy. Study design was randomized controlled trial and SPSS version 26 was used for data analysis.
 Results: Mean age of the patients was 24.3±4.3 and 23.3±3.9 years in group-A and B, respectively. There were 30 males (66.7%) & 15 females (33.3%) in group-A while 35 males (77.8%) and 10 females (22.2%) in group-B. Mean duration of disease was 2.0±0.9 months in group-A & 2.3±1.2 months in group-B.The efficacy of combined therapy with Ketoconazole 2% cream & adapalene 1% gel was found to be better when compared with Ketoconazole 2% cream monotherapy in Pityriasis Versicolor. Difference between two groups (p=0.011) was statistically significant.
 Conclusion: It was concluded that adapalene 0.1% gel & ketoconazole 2% cream in combination is more effective than ketoconazole 2% cream monotherapy in the treatment of PV.
 Recommendation: It is recommended to use a combination of adapalene 0.1% gel & ketoconazole 2% cream than ketoconazole 2% cream monotherapy in the treatment of PV.
 

Development of stable self-nanoemulsifying composition and its nanoemulsions for improved oral delivery of non-oncology drugs against hepatic cancer

Cancer remains a major health concern and second leading cause of mortality worldwide. The highest cancer-related mortalities are observed in low and middle-income countries (LMIC) due to unaffordable cost of medicines and lack of safe and effective chemotherapy. Therefore, the key goal of the present research was to develop affordable, safe, efficacious and stable nanoemulsion (NE) system co-loaded with Tadalafil (TDF) and Ketoconazole (KTZ) for repurposing against hepatic cancer. The batch number 1 of SNEDDS was selected as optimized batch based on dispersion time, viscosity and stability. The NE displayed particle size of 41±5 nm (PDI: 0.189±0.064) and Zeta potential of -27.1 mV. The NE exhibited controlled in-vitro release of both TDF (52.37 ± 3.41%) and (KTZ 52.31 ± 3.88%) in PBS pH 6.8 after 24 h. Moreover, the in-vitro hemolysis study showed moderate hemolytic activity of NE towards blood cells. In addition, the in-vitro cytotoxicity study revealed more cytotoxicity of NE than plain TDF and KTZ against HepG2 cell line after 48 h of incubation. Moreover, the HepG2 cellular uptake of TDF and KTZ was found to be substantially higher from NE when compared to the plain TDF and KTZ. Furthermore, NE was found to be stable for more than 6 months with no phase separation and creaming. Stable, safe, effective and affordable NE was developed which might be used as an alternative strategy in the treatment of hepatic cancer and its similar anticancer effect against other cancers need to be validated. Further, TDF and KTZ combination would a potentials approach over approved chemotherapy against hepatic cancer.

Characterization of Therapeutic Targets from Aspergillus fumigates in response to Adjunctive Combination Therapy (Ketoconazole with EDTA)

Background: The Kingdom (Fungi) comprises numerous species that are associated with numerous fungal diseases. Moreover, the fungal resistance, stagnation in the development of antifungal agents and unacceptably high mortality rate associated with some resistant fungus indicate that alternative therapeutic options should be considered. Objective: The objective of this study was to find out new therapeutic targets of A.fumigatus in response to adjunctive combination, i.e., Ketoconazole (KTZ) plus EDTA. Methods: A.fumigatus was cultured in the absence and presence of a sublethal dose (MIC 50) of EDTA, KTZ and a combination of KTZ plus EDTA. The cytosolic proteins were extracted by mechanical grinding of fungal cells. The protein profile was studied by using a proteomic approach and the identification of protein was done by MALDI-TOF/MS. The morphological effect of the combination on A. fumigatus was studied by Scanning Electron Microscopy (SEM) and toxic effect on erythrocytes by haemolytic assay. Result: The combination of KTZ with EDTA was non-toxic up to 500 μg/ml by MTT assay. It inhibits the expression of the following proteins: Glutamatedehydrogenase, Phenyl alanyl t-RNA synthetase POD G, CaO19-5601, AN6454.2 (Conserved domain; MFS (Major Facilitator Superfamily), serine/threonine-protein kinase and dipeptidyl peptidase (identified by peptide mass fingerprinting). Some of these proteins are involved in hyphal development. Morphological defects on the development of fungus (like disrupted hyphal tips, phialide) were observed. Conclusion: These targets can be used for novel drug development as some of them are involved in fungal virulence, and adjunctive combination therapy can be an optimistic approach.

Ketoconazole 2% cream versus a combination of ketoconazole 2% cream and adapalene 0.1% gel in the treatment of pityriasis versicolor

Background and aim Pityriasis versicolor is a common chronic superficial fungal infection that manifests during or after puberty in hot humid temperatures. Topical treatments, which are the first line of treatment, are divided into nonspecific and specific antifungal agents; however, the therapeutic approaches for pityriasis versicolor depend mainly on synthetic antifungal drugs, in particular ketoconazole. However, due to the frequent recurrence of this disease, and the widespread application of azole drugs, resistant strains have emerged leading to increasingly failed treatment rates. Retinoic acid creams are also effective against pityriasis versicolor. Especially adapalene gel that has less irritation compared with other topical retinoid products and also has rapid onset of action. Therefore, we aimed to evaluate the efficacy and safety of a combination treatment of ketoconazole cream 2% and adapalene gel 0.01% in the treatment of pityriasis versicolor. Patients and methods In all, 100 patients were divided equally into two groups: group 1 patients were treated with topical application ketoconazole 2% cream and adapalene 0.1% gel once daily for a total duration of 2 weeks. Group 2 patients were treated with a topical application ketoconazole 2% cream for a total duration of 2 weeks. Results There was significant improvement rates in the combined group than ketoconazole-only group with P value=0.023. Adepalene+ketoconacole group had more irritation as a side effect than the ketoconazole group with significant P value=0.001. Conclusion The combination of adapalene 0.1% gel and ketoconazole 2% cream is safe, rapid, and effective in the treatment of pityriasis versicolor.

Synergistic cortisol suppression by ketoconazole-osilodrostat combination therapy.

SummaryHere, we describe a case of a patient presenting with adrenocorticotrophic hormone-independent Cushing’s syndrome in a context of primary bilateral macronodular adrenocortical hyperplasia. While initial levels of cortisol were not very high, we could not manage to control hypercortisolism with ketoconazole monotherapy, and could not increase the dose due to side effects. The same result was observed with another steroidogenesis inhibitor, osilodrostat. The patient was finally successfully treated with a well-tolerated synergitic combination of ketoconazole and osilodrostat. We believe this case provides timely and original insights to physicians, who should be aware that this strategy could be considered for any patients with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic.Learning pointsKetoconazole–osilodrostat combination therapy appears to be a safe, efficient and well-tolerated strategy to supress cortisol levels in Cushing syndrome.Ketoconazole and osilodrostat appear to act in a synergistic manner.This strategy could be considered for any patient with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic.Considering the current cost of newly-released drugs, such a strategy could lower the financial costs for patients and/or society.

ROLE OF COMBINED KETOCONAZOLE AND TAMSULOSIN IN SUCCESSFUL TRIAL OF VOIDING WITHOUT CATHETER (TWOC) IN PATIENTS WITH ACUTE URINARY RETENTION DUE TO BENIGN PROSTATIC OBSTRUCTION

Objective: To compare the frequency of patients with successful Trial of voiding without catheter (TWOC) after acute urinary retention secondary to benign prostatic hyperplasia in patients taking ketoconazole and tamsulosin vs tamsulosin alone.
 Study Design: A randomized controlled trial. 
 Place and Duration: The current study was conducted at Urology Ward, Liaquat National Hospital, Pakistan for a period of six months.
 Methodology: A total of 162 patients presenting with acute urinary retention were divided into two groups. Group A received tamsulosin 0.4mg OD and ketoconazole 200mg while Group B received tamsulosin and placebo. Trial of voiding without a catheter was induced after one week of medication. SPSS version 20 was used for data compilation and analysis.
 Results: In Group-A, 85.2% of patients were able to void as compared to group B, where only 74.1% of patients were able to void (p<0.05). Successful trial of voiding without catheter was observed in 79.0% and 60.5% in patients of Group-A and Group-B respectively. The association of successful TWOC with the two study groups was found significant (p=0.010).
 Conclusion: TWOC in men catheterized for AUR due to BPH was significantly more successful if treated in a combination of ketoconazole and tamsulosin as compared to tamsulosin only.

Simultaneous determination the concentration change of ketoconazole and dexamethasone acetate: application to drug-drug interaction in human keratinocyte

BackgroundThe combination of ketoconazole and dexamethasone acetate is one of the commonly used treatments in dermatology regiment for skin inflammation accompanied by fungal infections. This interaction of ketoconazole and dexamethasone may make the drug much effective, decrease the adverse reaction or toxic effects. At present, there was no information about the interaction of these two external drugs. Therefore, it was necessary to build a model to measure the levels and evaluate the interaction of ketoconazole and dexamethasone acetate in skin cells. MethodsIn our study, the determination methodology of ketoconazole and dexamethasone acetate in human keratinocyte (HaCaT cells) was established and the interaction of these two drugs in cells was explored. HaCaT cells were cultured in medium containing ketoconazole, then they were sequentially cultured with or without dexamethasone acetate treatment for another 1, 2, 4, 8 and 12 h. The samples were then harvested and the concentrations were quantified by enhanced BCA (the bicinchoninic acid) protein assay. Furthermore, the analytes in the cell suspension were also prepared and analyzed by LC-MS method. ResultsAs a result, ketoconazole and dexamethasone acetate were detected at the concentration range of 0.02 to 5 μg/mL and 0.2 to 100 μg/mL, respectively. The RSD (relative standard deviation) and RE (relative error) of precision and accuracy of the two analytes in the cell suspension were all less than 15 %. The matrix effect values variations were all less than 15%. The results showed that there was no significant difference in the concentration of ketoconazole with or without dexamethasone acetate treatment within 12 h. ConclusionsA simple, sensitive and rapid LC-MS method which could quantify these two analytes in cells simultaneously was developed for the first time. The results of the concentration changes meant that no interaction occurred when dexamethasone sequentially administrated for 12 h after ketoconazole treatment. This method was successfully applied to establish the cell pharmacokinetics methodology and preliminary studied the metabolism of drug-drug interaction of ketoconazole and dexamethasone acetate.

Conduite à tenir en cas d’association d’un alpha-bloquant et d’un inhibiteur puissant du cytochrome 3A4

Combination of alpha-blockers with potent CYP3A4 inhibitors is either contra-indicated or not recommended. We searched data supporting this classification and guiding prescribers when such an interaction occurs. We analyzed reports published by the French agency for drug safety, reference books and performed search in databases of pharmacokinetics studies and case or case series related with these interactions. The classification of the potential severity of these interactions defined by the French agency for drug safety evolved over time. Our literature search did not identify any cases or case series reporting serious clinical consequences of such interactions and no pharmacoepidemiological studies on the association between alpha-blockers and inhibitors of CYP3A4. The content of the summaries of product characteristics indicate that the combination of ketoconazole with alfuzosin, silodosin and tamsulosin increases the area under the curve of the alpha-blocker 3 fold. Data demonstrating the clinical consequences of an association between alpha-blocker and a potent CYP3A4 inhibitor are lacking. The 3 fold increase of the area under the curve for alfuzosin, silodosin and tamsulosin associated with ketoconazole while the association with the two first is contra-indicated and is not recommended with the third raises questions. This lack of data leaves doctors and pharmacists in a situation of uncertainty on how to proceed when such an interaction occurs.

Enhanced effect in combination of curcumin- and ketoconazole-loaded methoxy poly (ethylene glycol)-poly (ε-caprolactone) micelles.

In order to enhance water-solubility and realize controlled release while keeping synergistic effects of ketoconazole and curcumin, drug-loaded methoxy poly (ethylene glycol)-b-poly (ε-caprolactone) micelles were prepared through thin membrane hydration method. Transmission electric microscopy and dynamitic light scattering characterization revealed the formation of ketoconazole- and curcumin-loaded micelles with an average size of 44.70nm and 39.56nm, respectively. The drug-loaded micelles endowed the two drugs' slow controlled release with water-solubility enhanced to 85 and 82000 folds higher than the corresponding raw drugs, respectively. In vitro antifungal activity test, chequerboard test and inhibition zone test indicated that efficacy of ketoconazole-loaded micelles was improved by introduction of curcumin-loaded micelles with a low fractional inhibitory concentration index (0.073). Biofilm formation inhibition assay also demonstrated that participation of curcumin-loaded micelles obviously strengthened the inhibition of fungal biofilms formation induced by ketoconazole-loaded micelles. The high synergistic activity of combinations is encouraging and the MPEG-PCL micelle is a potential drug delivery system for the combination of ketoconazole and curcumin.

An Endocrine Picture In Disguise: A Progressive Olfactory Neuroblastoma Complicated With Ectopic Cushing Syndrome

ABSTRACT Objective: To describe a unique case of a 61-year-old patient presenting with ectopic Cushing syndrome as a paraneoplastic phenomenon due to adrenocorticotropic hormone (ACTH)-secreting bone metastasis of an olfactory neuroblastoma (ON). Methods: We report a detailed case, with clinical, biochemical, and imaging findings and compare it with existing literature. Results: A patient with an ON, with subsequent 10-year stable disease after initial craniofacial surgery, presented with paraparesis due to progressively metastasized ON disease located in the thoracic spine. During palliative chemotherapy, severe hypokalemia and muscle weakness developed, being part of paraneoplastic Cushing syndrome. Examination showed that metastatic bone lesions were mostly responsible for the ectopic secretion of ACTH, with just a few ACTH-secreting tumor cells located in the primary tumor. She was treated with a combination of ketoconazole and metyrapone that controlled cortisol levels. However, low potassium levels ...

Etomidate as an emergency treatment for uncontrolled hypercortisolism in metastatic adrenocortical carcinoma

Adrenocortical carcinoma is a rare malignancy of poor prognosis with frequent excessive secretion of cortisol or androgens or both. The treatment could be challenging, especially in advanced or metastatic cases. We present the case of a 26-year-old woman with a multiple metastatic adrenocortical carcinoma. A few months prior to diagnosis, she developed clinical signs of virilization and a Cushing's syndrome. Mitotane and ketoconazole combination therapy was initiated after histopathological confirmation. A surgical resection of the left adrenal gland was performed. The tumor was classified pT2Nx (score Weiss 9, Ki67 10%). Cisplatin-Etoposide chemotherapy was started 20 days postoperatively. In the presence of persistent severe and life-threatening hypercortisolism (Urinary free cortisol [UFC] > 20-fold the upper limit of the normal range [ULN]), adding metyrapone was indicated but this drug is not available in Belgium. An alternative urgent treatment with etomidate (0.3 mg/kg/hour) by continuous intravenous infusion was administrated for 24 hours. The inhibition of the adrenal cortisol production was rapid prompting a need for a substitution by hydrocortisone (8 hours after treatment initiation). UFC decreased to less than 5-fold the ULN. One month later, the medical evaluation shows normalized UFC and regression of metastasis after 2 cycles of chemotherapy. Etomidate, mostly known as anesthetic, is a strong enzymatic inhibitor of the 11β-hydroxylase implicated in the last step of the adrenal cortisol steroidogenesis. There are only limited data on its use in severe hypercortisolism. This case illustrates its utility and efficacy in acute phase of hypercortisolism while waiting for action of other adrenal-directed therapies.

Synthesis and Antimicrobial Studies of Pyrimidine Pyrazole Heterocycles

Prompted from the diversity of the wider use and being an integral part of genetic material, an effort was made to synthesize pyrimidine pyrazole derivatives of pharmaceutical interest by oxidative cyclization of chalcones with satisfactory yield and purity. A novel series of 1,3-dimethyl-6-hydroxy-2,4-dioxo-5-(1′-phenyl-3′-aryl-1H-pyrazol-5′-yl)-1,2,3,4-tetrahydropyrimidines (5a–d) and 1,3-diaryl-6-hydroxy-4-oxo-2-thioxo-5-(1′-phenyl-3′-aryl-1H-pyrazol-5′-yl)-1,2,3,4-tetrahydropyrimidines (5e–l) has been synthesized. The structures of these compounds were established on the basis of FT-IR, 1H NMR, 13C NMR, and mass spectral analysis. All the synthesized compounds were screened for their antimicrobial activity against bacteria and fungi. Among all the compounds, 5g was found to be the most active as its MIC was 31.25 µg/mL against S. aureus and B. cereus. The compounds 5h, 5c, and 5e also possess antibacterial activity with MIC values as 62.50, 125.00, and 500.00 µg/mL, respectively. The compounds 5c and 5j were found to have antifungal activity against Aspergillus spp. As antifungal drugs lag behind the antibacterial drugs, therefore we tried in vitro combination of these two compounds with standard antifungal drugs (polyene and azole) against Aspergillus spp. The combination of ketoconazole with 5c and 5j showed synergy at 1 : 8 (6.25 : 50.00 µg/mL) and 1 : 4 (25 : 100 µg/mL) against A. fumigatus (ITCC 4517) and A. fumigatus (VPCI 190/96), respectively.

Effects of Ketoconazole on the Pharmacokinetic Properties of CG100649, A Novel NSAID: A Randomized, Open-Label Crossover Study in Healthy Korean Male Volunteers

BackgroundCG100649, a novel selective cyclooxygenase-2 inhibitor that also inhibits carbonic anhydrase I/II, is expected to reduce the cardiovascular risk typical of other NSAIDs. Concurrent medications may influence the activities of the cytochrome P450 (CYP) 3A enzyme through which CG100649 is metabolized. ObjectivesThis study was designed to evaluate the influence of ketoconazole, a known strong inhibitor of CYP3A, on the pharmacokinetic properties of CG100649. MethodsThis randomized, open-label, 2 × 2 crossover study was conducted in healthy Korean male volunteers. Each subject received the following 2 treatments in a randomly allocated sequence, separated by a washout period of 42 days: single oral dose of CG100649 6 mg, and concurrent dosing of CG100649 6 mg and ketoconazole 400 mg followed by ketoconazole 400 mg/d over 4 days. Blood samples for pharmacokinetic analysis were collected at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 240, 384, and 480 hours after dosing of CG100649 in each sequence. Tolerability assessments were performed throughout the study. ResultsThirty subjects participated, and 26 subjects completed the study. Seventeen adverse events (AEs) were reported in 10 subjects, and all AEs were recovered without any sequelae. No serious AEs were reported. Six subjects receiving the single dose of CG100649 had 9 AEs, and 7 subjects receiving the combination of ketoconazole and CG100649 had 8 AEs. The Cmax of CG100649 with CG100649 only and with concurrent administration of CG100649 + ketoconazole were similar (10.7 and 11.0 ng/mL, respectively). The CG100649 AUClast with concurrent ketoconazole was 1.29-fold greater than that with CG100649 only (2074.0 and 2685.8 ng · h/mL) and demonstrated a statistically significant difference (P < 0.05). However, there were no statistically significant differences in vital signs, clinical laboratory test results, ECGs, or AEs between treatments. ConclusionAlthough the AUC of CG100649 increased by 29% with the concurrent medication of ketoconazole, it is considered that concurrent administration of CG100649 with ketoconazole would not change the safety profile of CG100649. ClinicalTrials.gov identifier: NCT01154764.

Role of combined use of ketoconazole and tamsulosin in management of acute urinary retention due to benign prostatic obstruction (a randomized controlled trial)

Ketoconazole has the ability to lower serum testosterone to castrate level within 48 h. As the prostate is an androgen-dependent organ, we investigated the effect of the use of tamsulosin in combination with ketoconazole in cases of acute urinary retention (AUR) due to benign prostatic obstruction (BPO). We recruited patients with AUR secondary to BPO but those with hepatic or renal impairment were excluded. Following urethral catheterization, the participants were randomized into two equal groups. The first group received tamsulosin (0.4 mg o.d.) and ketoconazole (200 mg t.d.s.) while the second one had tamsulosin and placebo. The drugs were maintained for 7 days and then the patients were put on trial without catheter (TWOC). The successful cases were assessed with peak flow rate (PFR) and the post-void residual urine volume (PVRV) was also estimated. We included 106 men with a mean age of 64.1±5.2 years and a mean prostate size of 61.6±14.6 g in the two groups. The received medications were well tolerated by all patients and none of them had discontinued the prescribed drugs. The incidence of the successful TWOC was significantly higher in the combined treatment group (77.35%) compared to the tamsulosin group (58.84%; P=0.01). Among those who had a successful TWOC, the PFR and the PVRV were also significantly better in the combined treatment group compared to the other one (P=0.001). Patients with AUR due to BPO can be treated safely with a combination of ketoconazole and tamsulosin to get a better success rate of TWOC.

Tu1407 Extracorporeal Magnetic Stimulation for Sacral Nerve is as Effective as Biofeedback Therapy in Patients With Rectal Hyposensitivity

Background: Asimadoline, a peripherally-restricted highly selective kappa-opioid receptor (KOR) agonist, has been shown to be efficacious in relieving pain or discomfort, urgency, stool frequency and other symptoms in diarrhea-predominant-IBS (D-IBS) patients with at least moderate pain (Mangel et al 2008). The mechanism of action for this therapeutic effect is thought to involve activation of up-regulated KORs on visceral afferent terminals in the gut wall. KOR activation in the central nervous system (CNS) can lead to aquaresis, dysphoria, and sedation. Penetration of asimadoline into the CNS is poor due to its amphiphilic structure and because it is a substrate for P-glycoprotein (P-gp), thus, there is no evidence for CNS effects of asimadoline in the IBS dose range (1-2 mg/day). Aim: The potential for drug interaction-induced CNS effects with ketoconazole, an inhibitor of P-gp and cytochrome P450 3A4 (CYP3A4), which plays a role in the metabolism of asimadoline, was assessed in this study. Methods: This was a single center, double-blind, placebo-controlled, randomized, two-period, crossover drug interaction study. Twelve healthy male subjects (Caucasian, 1840 years) received ketoconazole 200 mg bid for 3 days followed by a combination of ketoconazole 200 mg and asimadoline 1.5 mg bid (3 fold higher than the 0.5 mg bid clinical dose for IBS) from Days 4 to 9 and a single morning dose on Day 10 in one period and the same treatments but with ketoconazole placebo in a second period, with a 14 day washout between treatments. Pharmacodynamic tests aimed at detecting activity of asimadoline in the CNS included plasma antidiuretic hormone concentrations, the Critical Flicker Fusion test, the Profile of Mood State and the Bond & Lader visual analogue scale of mood and alertness, performed on Days 1, 4, 7 and 10. Primary pharmacokinetic variables were plasma asimadoline Cmax and AUC0-τ after a single dose on Day 4 and after multiple doses on Day 10. Results: The Cmax of asimadoline was approximately doubled with ketoconazole compared to placebo co-administration (from 46.2 to 98.9 ng/mL on Day 4 and from 50.7 to 112.1 ng/mL on Day 10). Mean AUCτ values were 3-fold higher during ketoconazole compared to placebo treatment. Although co-administration of ketoconazole led to a 2to 3-fold increase in asimadoline Cmax and AUC, no effects were observed on any of the CNS pharmacodynamic endpoints. Conclusions: There were no CNS pharmacodynamic effects even at plasma asimadoline levels 8-fold higher than those achieved at the IBS dose. These data provide further evidence for the peripheral restriction of asimadoline and suggest that dose adjustment when co-administered with ketoconazole or other CYP3A4 / P-gp inhibitors is not required.

Tu1406 Impact of Concurrent use of PPIs or Anti-Depressants on Efficacy of Rifaximin for IBS Without Constipation

Background: Asimadoline, a peripherally-restricted highly selective kappa-opioid receptor (KOR) agonist, has been shown to be efficacious in relieving pain or discomfort, urgency, stool frequency and other symptoms in diarrhea-predominant-IBS (D-IBS) patients with at least moderate pain (Mangel et al 2008). The mechanism of action for this therapeutic effect is thought to involve activation of up-regulated KORs on visceral afferent terminals in the gut wall. KOR activation in the central nervous system (CNS) can lead to aquaresis, dysphoria, and sedation. Penetration of asimadoline into the CNS is poor due to its amphiphilic structure and because it is a substrate for P-glycoprotein (P-gp), thus, there is no evidence for CNS effects of asimadoline in the IBS dose range (1-2 mg/day). Aim: The potential for drug interaction-induced CNS effects with ketoconazole, an inhibitor of P-gp and cytochrome P450 3A4 (CYP3A4), which plays a role in the metabolism of asimadoline, was assessed in this study. Methods: This was a single center, double-blind, placebo-controlled, randomized, two-period, crossover drug interaction study. Twelve healthy male subjects (Caucasian, 1840 years) received ketoconazole 200 mg bid for 3 days followed by a combination of ketoconazole 200 mg and asimadoline 1.5 mg bid (3 fold higher than the 0.5 mg bid clinical dose for IBS) from Days 4 to 9 and a single morning dose on Day 10 in one period and the same treatments but with ketoconazole placebo in a second period, with a 14 day washout between treatments. Pharmacodynamic tests aimed at detecting activity of asimadoline in the CNS included plasma antidiuretic hormone concentrations, the Critical Flicker Fusion test, the Profile of Mood State and the Bond & Lader visual analogue scale of mood and alertness, performed on Days 1, 4, 7 and 10. Primary pharmacokinetic variables were plasma asimadoline Cmax and AUC0-τ after a single dose on Day 4 and after multiple doses on Day 10. Results: The Cmax of asimadoline was approximately doubled with ketoconazole compared to placebo co-administration (from 46.2 to 98.9 ng/mL on Day 4 and from 50.7 to 112.1 ng/mL on Day 10). Mean AUCτ values were 3-fold higher during ketoconazole compared to placebo treatment. Although co-administration of ketoconazole led to a 2to 3-fold increase in asimadoline Cmax and AUC, no effects were observed on any of the CNS pharmacodynamic endpoints. Conclusions: There were no CNS pharmacodynamic effects even at plasma asimadoline levels 8-fold higher than those achieved at the IBS dose. These data provide further evidence for the peripheral restriction of asimadoline and suggest that dose adjustment when co-administered with ketoconazole or other CYP3A4 / P-gp inhibitors is not required.

A Phase II Clinical Trial of Neoadjuvant Ketoconazole and Docetaxel Chemotherapy Before Radical Prostatectomy in High Risk Patients

Patients with high risk prostate cancer (prostate specific antigen greater than 20 ng/ml, Gleason score greater than 7, or clinical stage T2b or greater) have been shown to have a 30% to 40% biochemical recurrence rate after definitive local therapy. Looking for improvement on these outcomes, we conducted a phase II clinical trial examining the combination of ketoconazole and docetaxel in the neoadjuvant setting before radical prostatectomy. A total of 22 patients with clinically localized, high risk prostate cancer were enrolled in the study. For 12 weeks they were treated with neoadjuvant docetaxel and ketoconazole, with dosing based on phase I data. Patients were monitored for tolerance of therapy and dosing adjustments were made for significant toxicities. Radical prostatectomy with extended lymph node dissection was subsequently performed and patients were followed postoperatively for biochemical recurrence. At a median followup of 18 months 8 patients remained biochemically free of recurrence after surgery alone. An additional 6 patients received salvage therapy and had an undetectable prostate specific antigen. Of the 22 patients 16 experienced National Cancer Institute grade 3 or 4 toxicity at some point during the therapy. However, 16 patients completed all 4 cycles of chemotherapy. Neoadjuvant ketoconazole combined with docetaxel has appreciable but acceptable toxicity with 73% of the patients completing all 4 courses of therapy. Of those who underwent radical prostatectomy 36% remained continuously biochemically free of recurrence at a median followup of 18 months.

Mitotane, Metyrapone, and Ketoconazole Combination Therapy as an Alternative to Rescue Adrenalectomy for Severe ACTH-Dependent Cushing's Syndrome

Mitotane is highly effective in the long-term management of Cushing's syndrome but has a slow onset of action. Mitotane combined with fast-acting steroidogenesis inhibitors might avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism. Our objective was to assess the efficacy and safety of combination therapy with mitotane, metyrapone, and ketoconazole in severe ACTH-dependent Cushing's syndrome. Eleven patients with severe Cushing's syndrome participated in this follow-up study in a tertiary referral hospital. High-dose therapy combining mitotane (3.0-5.0 g/24 h), metyrapone (3.0-4.5 g/24 h), and ketoconazole (400-1200 mg/24 h) was initiated concomitantly. Twenty-four-hour urinary free cortisol (UFC) excretion (normal values 10-65 μg/24 h) was monitored. Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737 μg/24 h (range 853-22,605) at baseline to 50 μg/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. In seven patients, metyrapone and ketoconazole were discontinued after 3.5 months (range 3.0-6.0) of combination therapy, and UFC excretion remained controlled by mitotane monotherapy (UFC 17 μg/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgery and are presently in remission. Four of them recovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and γ-glutamyl transferase levels (P = 0.012 and P = 0.002, respectively). When surgical treatment for severe ACTH-dependent Cushing's syndrome is not feasible, combination therapy with mitotane, metyrapone, and ketoconazole is an effective alternative to bilateral adrenalectomy, a procedure associated with significant morbidity and permanent hypoadrenalism.

Improved treatment of visceral leishmaniasis (kala-azar) by using combination of ketoconazole, miltefosine with an immunomodulator—Picroliv

Visceral leishmaniasis (VL) caused by the parasite Leishmania donovani, is a potentially fatal disease. It is characterized by prolonged fever, enlarged spleen and liver, substantial weight loss and progressive anemia. Available drugs are toxic, costly and require prolonged treatment duration viz; 28 days of oral treatment with miltefosine, 30 days infusion with Amphotericin B and 21 days intramascular with paromomycin sulfate. Drug combination for VL clinically proved to shorten the duration of treatment. The efficacy of drugs is also compromised due to suppression of immune function during the course of infection. To combat this situation leishmanicidal efficacy of already marketed standard antifungal drug, ketoconazole under the approach of ‘therapeutic switching’ in combination with standard antileishmanial drug, miltefosine and a potent immunomodulator agent, picroliv were evaluated in L. donovani/hamsters model. Animals treated with combination of ketoconazole (50mg/kg, 5 days, po)+miltefosine (5mg/kg, 5 days, po) showed augmentation in efficacy against leishmania parasite (72%) in comparison to those treated with ketoconazole (54.67%) and miltefosine (54.77%) separately. Co-administration of picroliv (10mg/kg, 12 days, po) has further enhanced antileishmanial efficacy from 72% to 82%. Significant generation of ROS, RNS and H2O2 and increased phagocytosis was observed in animals treated with ketoconazole+miltefosine; however, addition of picroliv to this combination did not alter the level of metabolites and phagocytosis due to its antioxidative and nonleishmanicidal characteristics, respectively. Significant rise in cell mediated immunity witnessed in this group reveals the role played by the immunomodulator, picroliv and justifies the significance of enhanced cell mediated immunity in the therapy. These findings suggest a new strategy for leishmanial chemotherapy at reduced cost and toxicity.