Qualitative and quantitative assessment of related substances in the Compound Ketoconazole and Clobetasol Propionate Cream by HPLC-TOF-MS and HPLC

Related substances in pharmaceutical formulations are associated with their safety, efficacy and stability. However, there is no overall study already published on the assessment of related substances in the Compound Ketoconazole and Clobetasol Propionate Cream. In this work, a reliable HPLC-TOF-MS qualitative method was developed for the analysis of related substances in this preparation with a quick and easy extraction procedure. Besides the active pharmaceutical ingredients, two compounds named ketoconazole impurity B′ optical isomer and ketoconazole impurity E were identified. Furthermore, a new HPLC method for qualitative and quantitative assessment on related substances and degradation products, which were found in the stability test, was established and validated. The single standard to determine multi-components method was applied in the quantitative analysis, which was an effective way for reducing cost and improving accuracy. This study can provide a creative idea for routine analysis of quality control of the Compound Ketoconazole and Clobetasol Propionate Cream.

Ketoconazole Associated Hepatotoxicity: A Systematic Review and Metaanalysis

Objective To evaluate the incidence of Ketoconazole associated hepatotoxicity and related factors Methods Literature retrieval was conducted by using multi-databases for meta-analysis on Ketoconazole associated hepatotoxicity. The data were collected with a standardized form. Overall estimation of incidence of hepatotoxicity for specific study type was calculated by using a DerSimonian-Laird random-effects model owing to the substantial differences among the studies. Results Totally 204 eligible studies were included in the analysis. The incidence of Ketoconazole associated hepatotoxicity was 3.6%-4.2%. The dosage and duration specific subgroup analyses did not show any significant difference among groups, while the age specific subgroup analysis showed the incidence in children and people aged 〉60 years was 1.4% （95% CI 0.5%-4.2%） and 3.2% （95% Cl： 1.1%-8.7%） respectively. Additionally, the incidence of the hepatotoxicity was higher in people who had oral administration of ketoconazole beyond the provisions of the usage instructions, and the incidence was 5.7% （95% CI： 4.5%-7.2%）. Conclusion Ketoconazole associated hepatotoxicity was common. Off-label use might increase the risk of liver damage. Well-designed large sample studies are needed to identify the risk factors in future.

Spectrophotometric method for the determination of ketoconazole based on amplification reactions

This paper describes a sensitive spectrophotometric method developed for determination of Ketoconazole (KC) in tablets based on amplification reactions. Ketoconazole was oxidized with periodate, resulting in formation of KC2t and iodate ions. After masking the excess periodate with molybdate, the iodate was treated with iodide to release iodine. The liberated iodine was transformed to ICl2 species and extracted as ion-pair with rhodamine 6G into toluene for spectrophotometric measurement at 535 nm. A linear calibration graph was obtained between 0.2136 mg/mL and 1.7088 mg/mL of Ketoconazole with a molar absorptivity of 5 105 mol L 1 cm 1. The procedure was successfully applied for the determination of ketoconazole in tablet formulation.

The prognostic factors of effective ketoconazole treatment for metastatic castration-resistant prostate cancer： who can benefit from ketoconazole therapy？

We investigated the prognostic value of some variables of effective ketoconazole treatment for metastatic castration-resistant prostate cancer （mCRPC）. In total, 163 patients with mCRPC were eligible, receiving ketoconazole 200-400 mg three times daily with replacement doses of prednisone. Progression-free survival （PFS） was calculated from the beginning of the ketoconazole therapy to the onset of disease progression. The prognostic value of different variables for PFS was assessed by Cox regression analysis. The median PFS was 2.6 months （0.5-8.6 months） for these patients. The serum testosterone level changed during therapy, which decreased when the prostate-specific antigen （PSA） declined; the serum testosterone level increased as the levels of PSA relapsed. The median PFS values for patients associated with different factors were the following： 1.4 and 3.5 months for a nadir PSA of ≥ 0.2 and 〈0.2 ng ml- 1, respectively （hazard rate （HR）=4.767, P〈0.001）; 3.1 and 1.6 months for a baseline testosterone of ≥0.1 and 〈0.1 ng m1-1, respectively （HR=2.865, P=0.012）; 2.8 and 1.9 months for a baseline haemoglobin of ≥ 120 and 〈120 g 1-1, respectively （HR= 1.605, P〈0.001）; and 3.0 and 1.9 months for a PSA doubling time （PSADT） of ≥ 2.0 and 〈2.0 months, respectively （HR= 1.454, P=-0.017）. A risk model was constructed according to the four factors that divided patients into three subgroups of low risk （0-1 factors）, moderate risk （2 factors） and high risk （3-4 factors） with PFS values of 3.6, 3.0 and 1.4 months, respectively （HR=1.619, P〈0.001）. A nadir PSA of ≥0.2 ng m1-1, a baseline testosterone of 〈0.1 ng m1-1, a baseline haemoglobin of 〈 120 g I- 1 and a PSADT of 〈2 months were associated with a poor PFS. This risk model could provide evidence to predict the survival benefit of ketoconazole therapy.

Exploring the safety and efficacy of adding ketoconazole to tacrolimus in pediatric renal transplant immunosuppression

BACKGROUND Guatemala is a developing country in Central America with limited health resources.In order to expand successful renal transplant care to children and adolescents at the lowest possible cost,our pediatric renal transplant clinic uses a post-transplant tacrolimus-sparing strategy via inhibition of CYP3A4.AIM To study the safety,efficacy and the associated cost reduction of ketoconazole in combination with tacrolimus in this pediatric population.METHODS A retrospective chart review was carried out among the cohort of pediatric renal transplant recipients treated at the Foundation for pediatric renal patients(Fundación para el Niño Enfermo Renal-FUNDANIER),a pediatric tertiary care renal transplant center in Guatemala City,Guatemala.Patient charts were reviewed to ascertain the number of transplant recipients who were transitioned from tacrolimus based immunosuppression to combination therapy with ketoconazole and tacrolimus.Twenty-five post-transplant patients that used ketoconazole combined with tacrolimus were identified.Anthropometric,clinical and laboratory data was collected from patient charts before and after the transition.RESULTS Of the 25 patient charts reviewed 12(48%)patients were male and the average patient age was 13 years.Twenty-four(96%)transplants were from living donors.There was a non-significant difference between the mean tacrolimus doses six months and two months prior to ketoconazole:-0.10±0.04(95%CI:0.007,-0.029),P=0.23.However,the difference between the mean tacrolimus doses six months prior to ketoconazole initiation and six months after ketoconazole addition was significant:0.06±0.05(95%CI:-0.034,-0.086)P<0.001.All tacrolimus doses were reduced by 45%after the addition of ketoconazole.Therapeutic levels of tacrolimus ranged between 6.8-8.8 ng/mL during the study period and patients demonstrated an increase in estimated glomerular filtration rate.The combination of tacrolimus and ketoconazole resulted in a 21%reduction in cost.CONCLUSION Patients experienced an effective dose-reduction of tacrolimus with the administration of ketoconazole.There was no relevant variations in tacrolimus serum levels,number of rejections,or significant liver toxicity.The strategy allowed a cost reduction in pediatric immunosuppressive therapy.

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.

Synergistic Effects of Tetrandrine on the Antifungal Activity of Topical Ketoconazole Cream in the Treatment of Dermatophytoses:A Clinical Trial

Objective：To evaluate the synergistic effects of tetrandrine（TET）on the antifungal activity of topical ketoconazole（KCZ）in the treatment of dermatophytoses.Methods：The minimum inhibitory concentrations（MICs）for KCZ and combined KCZ and TET were compared in vitro.A randomized,double-blind trial was conducted among 97 patients with dermatophytoses who were assigned to 3 groups and received： treatment with combination of 2%KZC and 2%TET cream（KCZ＋TET group）,or only 2%KZC cream（KCZ group）,or 2%TET cream（TET group）.Patients with tinea corporis and/or tinea cruris were treated for 2 weeks, separately.The patients with tinea pedis and/or tinea manuum were treated for 4 weeks.Results：Compared with KZC alone,combined use of KZC and TET showed lower MICs against clinical isolates of dermatophytes （P0.05 for all）.In the patients with tinea corporis and/or tinea cruris,the rates of overall cure（clinical cure plus mycologic clearance）were 81.25%vs.33.33%for combined treatment and KZC monotherapy,respectively, after 4 weeks.All clinical indices were significantly different between the combination therapy and only KCZ therapy groups（P0.05）.Among the patients with tinea pedis and/or tinea manuum after 4 weeks treatment,the overall cure rates in the KCZ ＋ TET group and KCZ group were 75.00%vs.40.00%,respectively.In the KCZ ＋ TET group,all the clinical indices were significantly better than those in the KCZ group and TET group（P0.05）. The rates of overall efficacy in the TET group were all zero.No local skin redness or itching was observed during TET treatment.No clinically significant changes were found in post-treatment routine blood,urine,or stool tests, ECG,or tests for liver and kidney function;no serious adverse events occurred.Conclusion：TET synergistically enhanced the clinical efficacy of topical KZC cream in the treatment of dermatophytoses.

Combining cytochrome P-450 3A4 modulators and cyclosporine or everolimus in transplantation is successful

AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors(CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one(n = 59) received everolimus(target blood level, 3-8 ng/m L) and the other(n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl(MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4(CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/m L in 2 mo, and 50-65 ng/m L thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/m L until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators.RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up(66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group(20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate thanthe other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. CONCLUSION: Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.

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.

Tinea capitis caused by Microsporum Canis in a child:a case report

We report a tinea capitis caused by Microsporun Canis.A 6-year-old girl who had a history contact with dogs and cats in rural area.The girl suffered from scalp mass,pustules and itching for 2 months.There were two round patches in right scalp which the several pustules scattered on it.The morphology of the colony on the culture medium,the morphological characteristics under the microscope and the results of molecular sequencing confirmed that the girl’s tinea capitis was caused by Microsporun Canis.The girl was cured with the treatment of oral administration of itraconazole and ketoconazole ointment for external use for ten days.