Ketoconazole Tablets Research Articles

Role of intracameral Caspofungin in the management of Aspergillus keratitis: A case report

Abstract A 48-year-old male patient with a history of fall of dust in his right eye while driving came for a second opinion. On examination, he had a dry-looking ulcer with feathery margins and a hypopyon, suggestive of fungal keratitis. Scraping showed septate fungal filaments. Aspergillus niger grew in culture, and the patient was asked to use frequent natamycin eye drops. However, the hypopyon continued to increase, so ketoconazole tablets were added. Intracameral injection of Amphotericin B was advised, but in view of a severe shortage of the drug in the region, injection of Caspofungin (CAS) was given intracamerally with patient consent. With a combination of oral, topical, and intracameral antifungal medication, the ulcer slowly resolved over a period of 1 month, leaving behind a nebulomacular corneal scar in a quiet eye. Intracameral CAS may provide a safe and effective alternative to voriconazole and amphotericin B in the setting of Aspergillus keratitis.

Similarity of dissolution profiles from biorelevant media: Assessment of interday repeatability, interanalyst repeatability, and interlaboratory reproducibility using ibuprofen and ketoconazole tablets

Biorelevant media are increasingly being employed as dissolution media in drug development, including in smaller volumes than 900ml and under non-sink conditions. The objectives were to assess interday repeatability, interanalyst repeatability, and interlaboratory reproducibility of dissolution profiles from biorelevant media, as well as to assess the impacts of biorelevant media production method and biorelevant medium volume on dissolution profiles. Ibuprofen and ketoconazole tablets were subjected to dissolution testing in 500ml, 300ml, and 40ml of fasted state simulated gastric fluid (FaSSGF), fed state simulated gastric fluid (FeSSGF), fasted state simulated intestinal fluid version 2 (FaSSIF-V2), and fed state simulated intestinal fluid version 2 (FeSSIF-V2). f2 was used to assess repeatability and reproducibility of dissolution profiles. Results indicate favorable interday repeatability (83 of 88 comparisons were similar), favorable interanalyst repeatability (19 of 21 comparisons were similar), and favorable interlaboratory reproducibility (10 of 14 comparisons were similar) of dissolution profiles from biorelevant media, with commercial media showing greater interlaboratory reproducibility than ‘from scratch’ media. However, biorelevant medium production had low impact on profiles when one analyst conducted all medium preparations and study procedures at one location. Additionally, biorelevant media detected differences when products were not similar. Overall, biorelevant media showed favorable repeatability and reproducibility performance.

The Safety of Oral Ketoconazole in the Treatment of Skin Diseases (Single Blinded, Therapeutic, Comparative Study)

Background: Ketoconazole was introduced in 1981 as the first in a series of antifungal agents that are characterized by nitrogen-containing ring. Ketoconazole acts against many different kinds of fungi such as candida, dermatophytes and as pergillus. Also oral ketoconazole had proved its effectiveness in the treatment of cutaneous Leishmaniasis. Objective: To evaluate the safety of oral ketoconazole in the treatment of different skin diseases like cutaneous Leishmaniasis (CL), tineacapitis, tineacorporis and tineaversicolor. Patients and Methods: This is a single, blinded, therapeutic, controlled study that was carried out in the Department of Dermatology, Baghdad Teaching Hospital, Baghdad, Iraq, during the time, January 2015 to July 2016. In total, 951 patients with acute cutaneous leishmaniasis, tineacapitis, tineacorporis and tineaversicolor were enrolled in this study. The diagnosis was confirmed by smear and histopathology. Patients were divided into two groups: 51 patients in Group 1; 24 of them were treated with oral ketoconazole tablets 200 mg twice daily for 6 weeks and 27 of them were treated orally with a combination of zinc sulfate 10 mg/kg/day and ketoconazole for 6 weeks. All patients were seen regularly every 2 weeks for 6 weeks of treatment period, then monthly for the next three months as follow up period. Liver enzymes monitoring was done for every patient in this study every two weeks. Elevated liver enzymes were considered as features of hepatotoxicity in the examined patients. While group 2 included 900 patients and was divided into 3 subgroups: A: 600 patients with tineacapitis and tineacorporis, B: 100 patients with tineaversicolor, and C: 200 patients with CL. All patients in group 2 were treated with oral KC tablets 200 mg twice daily for 6 weeks. The dose of oral KC in children is 3.3 - 6.6 mg/Kg/day. All patients in group 2 were not investigated for ketoconazole biochemical side effects but watched for any clinical symptoms and signs of any side effects. Results: After six weeks, 951 patients had completed the treatment. In the first group (51 patients), only two out 27 patients (7.4%) from the combined group showed elevated liver enzymes while the ketoconazole treated group showed no increase in liver enzymes, hence only 3.9% showed elevated liver enzymes that went to normal during follow up. In the second group (900 patients) there were no clinical symptoms and signs in favor of hepatic toxicity or other related organs. Conclusion: Ketoconazole has been used tremendously in treating of different skin diseases including fungal and Leishmania infection but without side effects, accordingly this drug seems safe to be used in treatment of different skin diseases whether adults or children.

No Increased Risk of Ketoconazole Toxicity in Drug-Drug Interaction Studies.

In July 2013 the U.S. Food and Drug Administration (FDA) released a safety announcement regarding the use of ketoconazole and its adverse drug reactions. The FDA report advised against the use ketoconazole tablets as a first-line treatment for any fungal infections because of the risk of potentially serious drug-drug interactions and liver and adrenal gland complications. The European Medicines Agency (EMA) also proposed to limit the use of oral ketoconazole in fungal infections because of the same risk of harmful effects and interactions. In addition, the FDA also advised against the use of oral ketoconazole in drug interaction studies, in which it has been extensively used as an index inhibitor of drug metabolism. The aim of this investigation was to evaluate the risks of ketoconazole-induced hepatotoxicity described by the FDA and EMA in published drug interaction studies with ketoconazole and compare these data with the toxicity reported for ketoconazole when used as antifungal treatment. In the drug interaction studies (2355 participants; healthy volunteers and patients; median treatment duration, 6 days), only 40 participants were reported to have increased liver transaminase activity (1.7%), and no deaths were reported or associated with ketoconazole. In studies investigating ketoconazole treatment, patients were treated for 276 days (median), and 5.6% of patients had elevated liver enzyme activity. Because of the short treatment period in drug interaction studies the risk of drug-induced hepatic injury is considered very low. As such, we recommend that ketoconazole remain a safe CYP3A index inhibitor for use in drug interaction studies with healthy volunteers.

Treatment of Acute Cutaneous Leishmaniasis by Oral Zinc Sulfate and Oral Ketocanazole Singly and in Combination

Background: Cutaneous Leishmaniasis (CL) is an endemic disease in many countries and caused by different species of Leishmania parasite. It results in a deformed scar after a relatively long period. Many therapies have been tried in treatment of this disease. Objective: To compare the effect of oral zinc sulfate and oral ketoconazole singly and in combination in the treatment of acute cutaneous leishmaniasis. Patients and Methods: This single, blinded, therapeutic, controlled study was conducted in the Department of Dermatology, Baghdad Teaching Hospital, Baghdad, Iraq, during the period, January 2015 to July 2015. Seventy-five patients with acute CL were enrolled in this study. The total numbers of lesions were 327, and the duration of lesions ranged from 4 to 12 (6.9 ± 0.7) weeks. The diagnosis was confirmed by smear and histopathology. Patients were divided into three groups: 24 patients in Group A were treated with oral zinc sulfate capsules 10 mg/kg/day for 6 weeks; 24 patients in Group B were treated with ketoconazole tablets 200 mg twice daily for 6 weeks and 27 patients in Group C were treated orally with a combination of zinc sulfate and ketoconazole for 6 weeks. All patients were seen regularly every 2 weeks for 6 weeks of treatment period, then monthly for the next three months as follow up period. Healing of the lesions was assessed by using Sharquie’s modified Leishmania score to assess the objective response to the topical or systemic therapy. Results：After six weeks, 75 patients have completed the treatment, 24patients received zinc sulfate capsule, 24 patients received oral ketoconazole and 27 patients received a combination of both treatments. The cure rate was (60%) in the group receiving oral zinc sulfate capsuleand (50%) in the one receiving oral ketoconazole tablet (P = 0.146) and (96%) in the combination group (P ? 0.04). Conclusion: The combination therapy using oral zinc sulfate and oral ketoconazole gave a high cure rate. The combination therapy is a new mode of therapy as both drugs act in a synergistic way.

Comparative Evaluation of Ketoconazole Tablet and Topical Ketoconazole 2% in Orabase in Treatment of Candida-Infected Denture Stomatitis

Denture stomatitis is a common and recurring problem of denture wearers. Ketoconazole tablet is one of the antimycotic drugs that often has been used to treat this condition, but systemic use of this drug has some adverse effects that frequently lead to unfavorable compliance and treatment failure. This study was designed to compare the efficacy of topical ketoconazole 2% in orabase and ketoconazole tablet. Thirty patients with denture stomatitis (positive culture) were divided into two groups. The first group received ketoconazole tablet (orally used 200 mg per day) for 14 days and the second group received 2% topical ketoconazole in orabase applied twice daily on the mucosal denture surface. Candida cultures were taken from the palatal mucosa before and on days 7 and 14 after commencement of the therapy. The mean of colonies before and 7 and 14 days after medication were calculated. One-way ANOVA and paired t-test were used for data analysis (alpha=0.05). The mean of colonies number before receiving medication in the tablet and topical application groups were 454 and 441 respectively. The mean of colonies number after receiving medication in tablet and topical application group were 137 and 176 (on the seventh day) and 122 and 96 (on the 14th day), respectively; there was no significant difference between the two groups after medication (p=0.18). Topical ketoconazole 2% in orabase can be useful in managing denture stomatitis. This topical medication has fewer side effects, whereas systemic administration of ketoconazole tablet is associated with some complications. The application of topical ketoconazole 2% in orabase ointment can be considered in the treatment of denture stomatitis and has comparable efficacy with the ketoconazole tablet.

Bioequivalence studies and sugar-based excipients effects on the properties of new generic ketoconazole tablets formulations and stability evaluation by using direct compression method

In this work we described the development of a new solid oral formulation of ketoconazole, a broad-spectrum antifungal agent that belongs to the class II of Biopharmaceutics Classification System (BCS). The ketoconazole raw material supplier was selected to present a best flow and compactation. In addition we used direct compression and superdisintegrants associated to polyols to enhance the dissolution of the ketoconazole tablets. The dissolution was evaluated based in level C in vivo/in vitro correlation established. The best formulation was obtained with croscarmellose/maltose association that in the accelerated stability assays presented no differences on quality specifications and no drug-excipients interaction by DSC analyses. In this work it was possible to confirm the use of sugar-based excipients as suitable dissolution enhancers in pharmaceutical technology and real processes conditions.

In Vitro Release—In Vivo Microbiological and Toxicological Studies on Ketoconazole Lipid Granules

In some multidrug therapy programs, ketoconazole (KTZ) may be administered with some antacids that could modify its dissolution rate and reduce its absorption, thus leading to therapeutic failures. The primary aim of this study was to evaluate the influence of Compritol HD5 ATO and Compritol 888 ATO on this interaction in comparison with commercial KTZ tablets. The second aim was to prepare lipid granules of KTZ that could be an alternative to the commercial formulation. Therefore, six KTZ sustained-release granules were prepared with different lipid concentrations, because they were found to be more suitable than tablets that are dissolved only in gastric medium. The results confirmed that the dissolution rate of KTZ granules was significantly reduced in the presence of antacids. The ideal formulation was selected as granules including 5% of Compritol lipids in relation to the suitability of the target profile. Therapeutic effects of orally administered, ideal KTZ granule formulations, and commercial tablets were evaluated in vivo by the experimental model of murine vulvo-vaginal candidiasis (VVC) with and without antacids. It was found that formulations were very effective on VVC, and the therapeutic effect decreased significantly in the presence of antacids. Histopathological studies were carried out for vagina, stomach, and liver tissues and hepatoxicity was also examined. The levels of reduced glutathione (GSH) were measured to assess the oxidative stress induced by KTZ and function of the liver. It was observed that orally administered formulations of KTZ were successful in treating candidiasis in mice without irritancy in stomach. However, liver tissues were damaged. The decreased GSH levels indicated toxicity in our study. This study suggested that in vitro release and in vivo microbiological-toxicological properties of KTZ were affected by antacids and drug-excipient interactions. Lipid granules of KTZ prepared with Compritol 888 ATO could be proposed as a new KTZ solid dosage form with optimum dissolution and therapeutic characteristics.

Treatment of cutaneous leishmaniasis with ketoconazole cream

BACKGROUND: Cutaneous leishmaniasis (CL) is endemic in many countries. It has been recognized as a major public health problem in Iran. Many drugs have been suggested for the treatment of CL but most of them used intramuscularly or intravenously. Recently, a ketoconazole tablet has been used for the treatment of CL. OBJECTIVE: To compare the efficacy of ketoconazole cream with placebo in the treatment of CL. METHODS: The study was a double-blind, placebo-controlled trial. Patients with proven CL were treated with ketoconazole cream or placebo cream. The duration of treatment was 21 days and the patients were visited on days 7, 14 and 21. Follow-up was for 1 month after the end of treatment. RESULTS: The study was completed in 73 patients (45 male, 28 female). The mean age of the patients was 19.9 years. A total of 38 patients received ketoconazole and 35 patients were treated with the placebo cream. At the end of treatment (day 21), complete healing had occurred in 15.7% of the ketoconazole group in comparison with 14.3% of the patients who were treated with the placebo cream ( p =0.86). One month after the end of treatment the lesions in 28.9% of the ketoconazole group and 22.8% of the placebo group were healed ( p =0.55). CONCLUSION: Although the ketoconazole tablet has been reported to be effective in the treatment of some cases of CL, the low response rate in patients receiving ketoconazole cream indicates that it cannot be used as the single agent in the treatment of CL patients.

Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs.

To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CL(tot)) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CL(tot) appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K(i) values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 microM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CL(tot) values estimated from in vitro K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CL(tot) of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.

Effect of pharmacotechnical design on the in vitro interaction of ketoconazole tablets with non-systemic antacids

In certain polytherapy programs, ketoconazole can be administered with some antacids that could modify its dissolution rate and reduce its absorption leading to therapeutic failures. The aim of this work was to evaluate the influence of some excipients on this interaction in vitro. In this way, six formulations of directly compressible ketoconazole tablets were developed. The results confirmed that the dissolution rate of ketoconazole tablets was significantly reduced in the presence of antacids. Nevertheless this interaction was remarkably avoided in some of the formulations checked and in some conditions. In this way, the inclusion of a disintegrant (sodium starch glycolate) not only increased the dissolution rate of ketoconazole in the tablets, as expected, but it also modified the degree in which the dissolution rate was decreased in the presence of antacids. It was proved that a suitable selection of the excipients and therefore the modification in the rate in which the drug was released, could play an important role to modify a pharmacokinetic interaction based on a reduction of the solubility of the drug as a function of the pH value of the medium.

A Novel Multivariate Approach for Estimating the Degree of Similarity in Bioavailability between Two Pharmaceutical Products

Statistical assessment of bioavailability and bioequivalence of drug products is generally carried out with a univariate analysis by independently comparing each relevant parameter [such as, area under the drug concentration curve (AUC) and peak drug concentration (Cmax)] of the test and reference products. The assumption is made that AUC andCmaxare independent of each other. In reality, AUC,Cmax, and other pharmacokinetic parameters are dependent on each other. Therefore, a multivariate approach is theoretically superior. In this report, a novel multivariate approach to determine the bioavailability and bioequivalence of pharmaceutical products is described. The method determines the bivariate confidence ellipse (CE) betweenCmaxand AUC and the trivariate confidence ellipsoid (CED) amongCmax, AUC, and eitherTmaxor MRT for test and reference products. The similarity between the test and reference products can be assessed by the fraction of overlapping areas of CE and volumes of CED. The method and its comparison with conventional univariate analysis are demonstrated with data obtained from a bioequivalence study of ketoconazole tablets.

Oral Ketoconazole and Miconazole Vaginal Pessary Treatment for Vaginal Candidosis

This prospective study was carried out on 250 patients having clinical and mycological evidence of vaginal candidosis. One hundred patients received ketoconazole orally (400 mg/day for 5 days), another 100 patients received miconazole vaginal pessary treatment (one 100 mg tablet locally for 14 days), while the other 50 patients received combination therapy of oral ketoconazole and miconazole vaginal tablets. Although all 3 regimens were significantly effective in relieving patients symptoms and physical signs, the combination therapy gave the best results. There was 98% symptomatic relief with the combination therapy in contrast to 82% and 78% in the oral ketocanozole and vaginal micronazole groups respectively (p less than 0.001). Mycological cure rates were also significantly higher in the combination therapy group (94% versus 80% and 76%). The relapse rate was least in the combination group 2% versus 8% and 12%. The combination therapy is recommended for the best results in vaginal candidosis.

The effect of ketoconazole and transdermal estradiol on serum sex steroid hormones levels

In this randomized, open-label trial, 24 subjects were studied. There were 12 subjects with essential hypertension and 12 normotensive controls who received, after an initial control period, 48 h of treatment with a transdermal estradiol patch or ketoconazole tablets every 8 h for six doses, or in combination. LHRH (100 micrograms) and ACTH (250 micrograms) were given at 48 h of each treatment. Each treatment was one week apart. In both normotensive and hypertensive men ketoconazole reduced adrenal and gonadal androgens, raised 11-deoxycortisol and 17 alpha-hydroxyprogesterone levels; blunted the rise of cortisol to ACTH and had no effect on the response of LH to LHRH. Transdermal estradiol raised serum estradiol levels, blunted the time to peak plasma concentration of LH to LHRH and produced a normal response to ACTH. Although baseline level of total and free testosterone and DHEA-S were lower in hypertensive men, the response of the pituitary (LH) to LHRH and adrenal axis with ACTH were similar in both normotensive and hypertensive men. Blood pressure was unaffected by any of the treatment interventions in either normotensive or hypertensive men. Although ketoconazole or transdermal estradiol reduce androgens, there was no evidence that this reduction in androgens was involved with the short term regulation of blood pressure in hypertensive men.

Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS).

To correlate oral ketoconazole absorption with gastric acid secretion in patients with the acquired immunodeficiency syndrome (AIDS). Prospective measurement of maximal acid output and oral ketoconazole absorption with and without 0.1-N hydrochloric acid. Hospital in-patients in university medical center. Ten consecutive male patients with AIDS. Maximal acid output was determined after pentagastrin stimulation in all patients. Serum ketoconazole levels were measured the day after ingestion of a 200-mg ketoconazole tablet in the fasted state. On the final day, ketoconazole was ingested with 200 mL of 0.1-N hydrochloric acid. Maximal acid output was below 15 mEq/h in 7 of 10 patients. In all 7, the area under the serum ketoconazole concentration-time curve was below normal (1.4 +/- 0.9 mg/h.L; mean +/- SE), and absorption was normalized by hydrochloric acid (9.9 +/- mg/h.L). Two of three patients with maximal acid outputs above 15 mEq/h had normal ketoconazole absorption (15.1 +/- 6.7 mg/h.L). The bioavailability of oral ketoconazole is reduced in patients with AIDS, largely as a result of gastric hypochlorhydria. Ketoconazole tablets should therefore be given with acid in these patients.

Effect of pH on Disintegration and Dissolution of Ketoconazole Tablets

The effect of pH on the in vitro disintegration, dissolution, and solubility of ketoconazole tablets was studied. One 200-mg ketoconazole tablet was added to each of five different buffer solutions having pH values of 2 to 6;900 ml of each solution containing the ketoconazole was placed in a stationary basket dissolution device and stirred at 500 rpm at 37 degrees C for 60 minutes. Single 1-ml samples of each solution were obtained at 1,3, and 5 minutes after addition of the drug, and then every 5 minutes for the duration of the sampling period. This same procedure was repeated using two 200-mg tablets in the buffer solution at pH 3. The effect of pH on ketoconazole solubility was studied by gradually increasing the pH of a ketoconazole solution at pH 3 to pH 10. Samples of this solution were analyzed periodically after allowing a short period for equilibration of pH. All samples were assayed spectrophotometrically against blanks, and concentrations were determined by comparison with a standard curve. Disintegration of ketoconazole tablets occurred within 5 minutes in each buffer solution and was unaffected by pH. At pH 2 and 3, dissolution of ketoconazole was greater than 85% complete after five minutes, and all ketoconazole had dissolved after 30 minutes. As pH increased, the rate and extent of dissolution slowed; only 10% of ketoconazole was dissolved after 60 minutes at pH 6. Ketoconazole precipitated rapidly from solution as the pH of the dissolution medium exceeded 5.5. There was no difference in the rate or extent of dissolution of ketoconazole for the two doses studied at pH 3. In the buffer solutions tested, dissolution but not disintegration of ketoconazole tablets is pH-dependent. Dissolution characteristics of 200- and 400-mg doses of ketoconazole are similar at pH 3.