Oral Ketoconazole Research Articles

Skin kinetics of azole antifungal drugs.

Skin kinetics of orally administered drugs in general have not been a subject of intensive investigation. Most work in this field has been performed with topically administered agents, including the antifungal agents. Skin kinetics of antifungals have received little interest in the past, and the work that has been performed was restricted mainly to topical application since very few systemically active antifungals were available. This chapter is a review of the available data on skin kinetics of topical antifungals and griseofulvin, which has been for a long time the only oral antifungal. In addition, skin kinetics of oral and topical ketoconazole and itraconazole will be discussed in detail.KeywordsStratum CorneumSebaceous GlandSkin SectionStratum GranulosumPityriasis VersicolorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Therapeutic Dilemmas in External Ocular Diseases

Three ocular conditions continue to pose therapeutic dilemmas for the practising clinician. Acanthamoeba keratitis, which presents with ocular pain, redness, tearing, photophobia and lid oedema, should be considered in any chronic, progressive corneal ulceration that is unresponsive to conventional treatment. Although the best treatment for this infection has yet to be defined, surgery should be reserved for those patients with progressive destructive disease or corneal penetration. Topical antibiotics and oral ketoconazole may be beneficial, as may surgical debridement in conjunction with topical antibiotic-antifungal combinations. However, since more than two-thirds of reported cases involve contact lens wearers, patients should be instructed as to the importance of regular lens care regimens. Giant papillary conjunctivitis occurs more frequently in soft contact lens wearers than in those wearing hard lenses, but may also occur in association with ocular prostheses, cataract surgery and corneal transplants. Symptoms of increased lens awareness, mucus accumulation, itching and blurred vision occur. Stopping use of contact lenses usually improves or eliminates these irritating effects, but is not always practical. Thus, resolution or improvement of symptoms while the patient continues to wear contact lenses is desirable, making lens hygiene essential in treatment. Pharmacological treatment includes the use of topical corticosteroids and agents that stabilise mast cells, such as cromolyn sodium. The dry eye syndrome can occur alone or as a part of Sjögren's syndrome. The irritation, redness, and other symptoms associated with ocular dryness are usually treated by preparations of either mucomimetics, polyvinyl alcohol or cellulose derivatives, which provide moisture and prevent evaporation from the surface of the eye.

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.

Tinea versicolor: Epidemiologic, clinical, and therapeutic aspects

Age of the patient, climate, season, and local environmental factors influence the onset and course of tinea versicolor (pityriasis versicolor). A number of effective topical therapies are available. In addition, a single dose of 400 mg of oral ketoconazole eliminates the disease and can be used prophylactically in some cases to prevent recurrence.

CYCLOSPORINE DOSE REDUCTION BY KETOCONAZOLE ADMINISTRATION IN RENAL TRANSPLANT RECIPIENTS

Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450 microsomal enzymes. Ketoconazole, an imidazole derivative, has been shown to inhibit the cytochrome P-450 enzyme system. Thirty-six renal transplant recipients receiving cyclosporine as part of a triple immunosuppressive drug regimen were started on 200 mg/day of oral ketoconazole. The dose of cyclosporine was reduced by 70% at the start of ketoconazole; this dose reduction was based on our previous experience with concomitant cyclosporine-ketoconazole therapy. Ketoconazole was started in patients who had been on cyclosporine for between 10 days and 74 months. The mean cyclosporine dose was 420 mg/day (5.9 mg/kg/day) before starting ketoconazole and 66 mg/day (0.9 mg/kg/day) one year after the addition of ketoconazole; this represents a cyclosporine dose reduction of 84.7% (P less than 0.0001). The mean trough whole-blood cyclosporine concentrations measured by HPLC, were 130 ng/mL preketoconazole and 149 ng/mL after 1 year of combination therapy. Mean serum creatinine and BUN levels were unchanged before and during ketoconazole administration, and no changes in liver function tests were noted. Cyclosporine pharmacokinetics were performed before and after at least three weeks of ketoconazole. Hourly whole-blood samples were measured by HPLC (parent cyclosporine only) and TDX (parent + metabolites). Combination therapy resulted in decreases in the maximum blood concentration and the steady-state volume of distribution divided by the fractional absorption, and increases in mean residence time and the parent-to-parent plus metabolite ratio (calculated by dividing the HPLC by the TDX value). The addition of ketoconazole to cyclosporine-treated patients resulted in a significant inhibition of cyclosporine metabolism and decrease in the dosage. There was minimal nephrotoxicity, and only four rejection episodes occurred on combined therapy. The concomitant administration of the two drugs was well tolerated, and there was no deleterious effect on the immunosuppressive activity of cyclosporine. This drug interaction provides a significant reduction in the costs associated with organ transplantation.

A prospective study to assess the efficacy of ketoconazole in the treatment of recurrent vaginal candidiasis

A prospective study of oral ketoconazole therapy was undertaken in 40 women who suffered from recurrent thrush. Symptoms were relieved within three days for half the women, and two-thirds of the women maintained an absence of symptoms for a period of at least a month. Over 80% of the patients assessed the treatment as being effective, with 90% preferring oral to topical therapy.

Efficacy of ketoconazole against Leishmania braziliensis panamensis cutaneous leishmaniasis

purpose, patients, and methods: The classic agent for cutaneous leishmaniasis is pentvalent antimony. However, there are no reports of the efficacy of antimony versus placebo or of the efficacy of any alternative therapy versus either antimony or placebo. In the present report, the oral antifungal agent ketoconazole (600 mg/day for 28 days) was compared to a recommended regimen of intramuscular Pentostam (20 mg antimony/kg, with a maximum of 850 mg antimony/day, for 20 days) in a randomized study of the treatment of Panamanian cutaneous leishmaniasis due to Leishmania braziliensis panamensis. A separate group of patients with this disease was administered placebo. results: Ketoconazole clinically cured 16 of 21 (76%) patients. The lesions on nine patients healed by 1 month after therapy, and the lesions healed by 3 months after therapy on the other seven patients. Side effects were limited to a 27% incidence of mild, reversible hepatocellular enzyme elevation and an asymptomatic, reversible, approximately 70% decrease in serum testosterone in all patients. Pentostam cured 13 of 19 (68%) patients; the lesions on seven patients healed by the end of therapy, and the lesions on four other patients healed by 1 month after the end of therapy. Side effects were a 47% incidence of mild, reversible hepatocellular enzyme elevation and the morbidity due to 20 intramuscular injections in almost all patients. The placebo group of 11 patients had a 0% cure rate. By 1 month after therapy, all placebo-treated patients demonstrated new lesions or one lesion that was 23% to 875% larger than before therapy. conclusion: Both ketoconazole and Pentostam were more effective than placebo against L. braziliensis panamensis cutaneous leishmaniasis. Oral ketoconazole is comparable in efficacy to this parenteral Pentostam regimen and can be recommended as initial treatment for this disease.

Skin surface electron microscopy in Pityrosporum folliculitis. The role of follicular occlusion in disease and the response to oral ketoconazole

The yeast Pityrosporum orbiculare is thought to cause the folliculitis associated with seborrheic eczema. However, a combination of mechanical and microbiological factors may be involved, with follicular occlusion leading to yeast overgrowth and folliculitis. Scanning electron microscopy was used to investigate this hypothesis. Skin biopsy specimens obtained from patients with Pityrosporum folliculitis were examined by scanning electron microscopy before and after oral ketoconazole therapy. Patients with active disease showed occlusion of noninflamed follicles, which resolved after ketoconazole treatment. Follicular occlusion was not present in biopsy specimens obtained from unaffected controls nor was it related to the presence of P orbiculare. These findings suggest that follicular occlusion may be a primary event in the development of this folliculitis, with yeast overgrowth a secondary occurrence. The beneficial effect of ketoconazole in this disease may be due to direct effects on the follicle.

Skin Surface Electron Microscopy in Pityrosporum Folliculitis

† The yeast<i>Pityrosporum orbiculare</i>is thought to cause the folliculitis associated with seborrheic eczema. However, a combination of mechanical and microbiological factors may be involved, with follicular occlusion leading to yeast overgrowth and folliculitis. Scanning electron microscopy was used to investigate this hypothesis. Skin biopsy specimens obtained from patients with<i>Pityrosporum</i>folliculitis were examined by scanning electron microscopy before and after oral ketoconazole therapy. Patients with active disease showed occlusion of noninflamed follicles, which resolved after ketoconazole treatment. Follicular occlusion was not present in biopsy specimens obtained from unaffected controls nor was it related to the presence of<i>P orbiculare</i>. These findings suggest that follicular occlusion may be a primary event in the development of this folliculitis, with yeast overgrowth a secondary occurrence. The beneficial effect of ketoconazole in this disease may be due to direct effects on the follicle. (<i>Arch Dermatol</i>. 1990;126:181-184)

Tinea versicolor

The characteristic pigmentary changes in tinea versicolor are easy to distinguish from dermatophyte infections of the skin. When specific identification is needed, the diagnosis can be confirmed microscopically with a potassium hydroxide preparation or Polysciences Multiple Stain. Tinea versicolor responds readily to topical therapy or oral ketoconazole, but recurrences are common.

Endogenous Candida Endophthalmitis: Management without Intravenous Amphotericin B

Eight consecutive cases of culture-proven endogenous Candida endophthalmitis (ECE) were managed between 1980 and 1988. All patients were treated with vitrectomy and injection of intravitreal amphotericin B. Blood cultures were negative in all patients, although Candida albicans was cultured from a foot ulcer in one patient. No systemic therapy was used in three patients, three patients received oral ketoconazole, and two patients received oral flucytosine postoperatively. Intravenous amphotericin B was not used because of lack of evidence of disseminated candidiasis and the systemic toxicity associated with its use. The ECE responded favorably to treatment in all cases. Final vision was better in patients with a shorter interval between onset of symptoms and initiation of antifungal therapy. Posttreatment visual acuities were: four eyes ≥ 20/50, two eyes at 20/80 to 20/200, and two eyes < 5/200. This series showed that ECE without evidence of disseminated disease can be treated successfully with vitrectomy and intravitreal amphotericin B.

Ketoconazole Decreases the Serum 1,25-Dihydroxyvitamin D and Calcium Concentration in Sarcoidosis-Associated Hypercalcemia*

Ketoconazole is an antifungal agent capable of inhibiting human steroid hormone synthesis, including renal 1,25-dihydroxyvitamin D [1,25-(OH)2D] synthesis. The ability of this drug to inhibit the extrarenal production of 1,25-(OH)2D, as occurs in human granuloma-forming disease states, including sarcoidosis, has not been evaluated. We examined the effect of ketoconazole on the 1,25-(OH)2D-calcium homeostatic mechanism in a hypercalcemic patient with sarcoidosis and on the synthesis of 1,25-(OH)2D3 in vitro by cultured pulmonary alveolar macrophages (PAM) from this and another host. Oral ketoconazole therapy (800 mg/day) decreased the serum 1,25-(OH)2D concentration 73% within 4 days; this was associated with a 15% decrease in the serum calcium concentration and a 57% decrease in the fractional urinary calcium excretion rate. In vitro, ketoconazole had a rapid onset, concentration-dependent inhibitory effect on sarcoid PAM 1,25-(OH)2D3 synthesis (ED50 = 0.1 mumol/L) that was not reversible by exposure to leukotriene C4, a potent stimulator of PAM 1,25-(OH)2D3 synthesis. Kinetic analysis of ketoconazole's action on the macrophage 1 alpha-hydroxylation reaction was examined at concentrations achieved in vivo when the drug is given orally. The velocity of the 1 alpha-hydroxylation reaction at ketoconazole concentrations of 0.01-1.0 mumol/L increased as the concentration of substrate 25-hydroxyvitamin D3 increased from 12-2000 nmol/L.

Skin surface electron microscopy in Pityrosporum folliculitis. The role of follicular occlusion in disease and the response to oral ketoconazole

The yeast Pityrosporum orbiculare is thought to cause the folliculitis associated with seborrheic eczema. However, a combination of mechanical and microbiological factors may be involved, with follicular occlusion leading to yeast overgrowth and folliculitis. Scanning electron microscopy was used to investigate this hypothesis. Skin biopsy specimens obtained from patients with Pityrosporum folliculitis were examined by scanning electron microscopy before and after oral ketoconazole therapy. Patients with active disease showed occlusion of noninflamed follicles, which resolved after ketoconazole treatment. Follicular occlusion was not present in biopsy specimens obtained from unaffected controls nor was it related to the presence of P orbiculare. These findings suggest that follicular occlusion may be a primary event in the development of this folliculitis, with yeast overgrowth a secondary occurrence. The beneficial effect of ketoconazole in this disease may be due to direct effects on the follicle.

Skin Surface Electron Microscopy in Pityrosporum Folliculitis

† The yeast<i>Pityrosporum orbiculare</i>is thought to cause the folliculitis associated with seborrheic eczema. However, a combination of mechanical and microbiological factors may be involved, with follicular occlusion leading to yeast overgrowth and folliculitis. Scanning electron microscopy was used to investigate this hypothesis. Skin biopsy specimens obtained from patients with<i>Pityrosporum</i>folliculitis were examined by scanning electron microscopy before and after oral ketoconazole therapy. Patients with active disease showed occlusion of noninflamed follicles, which resolved after ketoconazole treatment. Follicular occlusion was not present in biopsy specimens obtained from unaffected controls nor was it related to the presence of<i>P orbiculare</i>. These findings suggest that follicular occlusion may be a primary event in the development of this folliculitis, with yeast overgrowth a secondary occurrence. The beneficial effect of ketoconazole in this disease may be due to direct effects on the follicle. (<i>Arch Dermatol</i>. 1990;126:181-184)

Comparative morphological and biological studies on the itraconazole- and ketoconazole-resistant mutants ofCryptococcus neoformans

Studies were carried out on the resistance in vitro of Cryptococcus neoformans to the oral antifungal drugs itraconazole and ketoconazole. None of the six sensitive strains tested developed resistance to itraconazole or ketoconazole by serial transfer on Sabouraud's glucose agar plates containing increasing concentrations of either drug. One mutant resistant to itraconazole, and one mutant resistant to ketoconazole, were isolated from the progenies of yeast cells surviving after treatment with a mutagenic substance, N-methyl-N'-nitro-N-nitroso-guanidine. These mutants were capable of growing in the presence of high concentrations of the drugs to which they were resistant. The itraconazole- and ketoconazole-resistant mutants obtained by mutagenesis were compared morphologically and biologically. The itraconazole-resistant mutant was characterized by the formation of very rough colonies which varied in size and shape, production of a large number of cell clusters, complete loss of capsule formation, and major degenerative changes in the cells, while in the ketoconazole-resistant mutant these changes were less pronounced and no cell clusters were formed. The acquisition of resistance was more stable in the itraconazole-resistant mutant than in the ketoconazole-resistant mutant. Both mutants showed partial cross-resistance and complete loss of virulence for mice.

Oral and Gastrointestinal Candidosis: Prophylaxis During Immunosuppressive Therapy.

Patients with acute leukaemia and malignant lymphomas often are severely affected by fungal infections. There is in particular growing concern about disseminated candidosis. Oral, gastrointestinal and systemic candidosis seem to be closely linked. Predisposing factors are damaged mucosal barriers due to chemotherapy, protracted periods of neutropenia, and prolonged use of antibiotics and steroids. Oropharyngeal candidosis is very frequent. This can be prevented or controlled by the application of topical antifungals such as nystatin. The systemic application of antifungals is an alternative for patients who do not respond. Both oral ketoconazole and intravenous amphotericin B have been proven effective. Candida oesophagitis is also an important problem. Oral nystatin suspension can be helpful in mild cases. In others oral ketoconazole and intravenous amphotericin B have to be used. A whole range of measures has to be taken to prevent spread of the disease, i.e. H2-antagonists should be used only if definitely needed. Specific antifungal prophylaxis has also been discussed. Oral amphotericin B seems to be helpful. The azole itraconazole might be especially promising.

The role of Candida infections as an adverse effect upon head and neck cancer patients undergoing therapeutic radiation and the effect of antimycotic treatment.

Oral, pharyngeal and esophageal infections caused by Candida species occur very frequently when it comes to radiation therapy for head and neck cancer. In clinical terms oral candidosis is most often characterized by pseudomembranes or erythema. The erythematous form of oral candidosis has in particular to be distinguished from radiation mucositis. Candidosis of the oral and gastrointestinal tract often causes interruption of therapeutic radiation. Ketoconazole treatment is able to reduce the period of time during which the patient cannot be treated by radiation. Oral ketoconazole given at a daily dose of 200 mg is moreover superior to topical nystatin. To date, however, it is not yet clear if patients who have head and neck cancer in whom radiation therapy has to be started would profit from the prophylactic application of ketoconazole from start on.

Tinea Versicolor in the Eastern Province of Saudi Arabia

A total of 1150 clinically suspected cases of tinea versicolor were examined in Dammam Central Hospital in a geographic region where many predisposing factors exist. Saudi patients comprised 66.8% ...

Fungal Peritonitis Complicating Peritoneal Dialysis: Report of 27 Cases and Review of Treatment

The clinical features, treatment and outcome of 27 cases of fungal peritonitis were studied. Twenty-one cases occurred in patients receiving CAPD and six in patients on intermittent peritoneal dialysis. Twenty-five cases were due to Candida spp., one was due to Trichosporon spp. and in one, both Candida and Trichosporon and an unidentified acid-fast bacillus were isolated. Clinical features of fungal peritonitis and bacterial peritonitis were the same. A direct comparison with patients without fungal peritonitis failed to reveal an increased incidence of diabetes mellitus. However, a history of recent bacterial peritonitis and antibiotic treatment was frequently obtained. We found that the combination of oral ketoconazole and intraperitoneal miconazole is successful in treating fungal peritonitis complicating peritoneal dialysis but catheter removal and replacement is often necessary. Analysis of the relationship between clinical outcome and various treatment strategies in cases reported in the literature and in our own showed that an initial trial of antifungal drugs consisting of oral ketoconazole and i.p. 5-fluorocytosine or miconazole is warranted in most cases before contemplating catheter removal.

A comparison of fluconazole and ketoconazole in the oral treatment of vaginal candidiasis; report of a double-blind multicentre trial

One hundred and eighty three patients with vaginal candidiasis were randomly allocated to treatment with either fluconazole in a single oral 150 mg dose, or ketoconazole, 200 mg twice daily for 5 days. Favourable clinical responses were obtained in 92% of the patients in the fluconazole group and in 89% of those in the ketoconazole group after 5–16 days. Long-term evaluation at 27–62 days showed favourable clinical responses in 86 and 88%, respectively. Candida was eradicated from the vagina in 77% of both treatment groups at the long-term evaluation. The relapse or reinfection rate was similar for both groups, ranging between 4–8%. One hundred and thirty two of the 160 patients who had rectal swabs cultured for yeast at baseline, gave positive results. Of the 27 patients in the fluconazole group whose rectal cultures remained negative at the long-term evaluation, 26 maintained mycological cure of their vaginal candidiasis. In contrast, patients with positive rectal cultures at this time were much less frequently associated with mycological cure. The results were similar for the patients in the ketoconazole group. Treatment-related side effects in both groups were few and minor. This double-blind multicentre study showed that a single oral 150 mg dose of fluconazole was as effective as 5 days of oral ketoconazole medication in the treatment of vaginal candidiasis.