Treatment Of Superficial Fungal Infections Research Articles

Comparsion ofin vitro activities of antifungal drugs and propolis against yeasts isolated from patients with superficial mycoses

Thein vitro susceptibilities of propolis and antifungal drugs were determined against some yeasts isolated from patients with superficial mycoses. The agents tested included fluconazole, itraconazole, ketoconazole, terbinafine and propolis. MICs were determined by the broth microdilution technique following National Committee for Clinical Laboratory Standards document M27-P. For allCandida albicans isolates from the patients with superficial mycoses, ketoconazole presented higher (P<0.05) efficiency than that of the other antifungal agents tested. The geometric mean MIC values of antifungal drugs and propolis against the yeasts tested ranged from 0.087 to 12.69 μg/mL and 0.4–0.6 μg/mL, respectively. Propolis also showed an important antifungal activity against the yeasts tested, MIC ranges of the propolis were between 0.01–1.65 μg/mL. Based on these results, propolis requires further investigation as a potential agent for the treatment of superficial mycoses.

Advances in Topical and Systemic Antifungals

Topical antifungal agents are generally used for the treatment of superficial fungal infections unless the infection is widespread, involves an extensive area, or is resistant to initial therapy. Systemic antifungals are often reserved for the treatment of onychomycosis, tinea capitis, superficial and systemic candidiasis, and prophylaxis and treatment of invasive fungal infections. With the development of resistant fungi strains and the increased incidence of life-threatening invasive fungal infections in immunocompromised patients, some previously effective traditional antifungal agents are subject to limitations including multidrug interactions, severe adverse effects, and their fungistatic mechanism of actions. Several new antifungal agents have demonstrated significant therapeutic benefits and have broadened clinicians' choices in the treatment of superficial and systemic invasive fungal infections.

Preliminary crystallographic characterization of PrnB, the second enzyme in the pyrrolnitrin biosynthetic pathway.

Pyrrolnitrin is the active ingredient of drugs for the treatment of superficial fungal infections and was used as a lead structure for the development of fludioxonil. It is an effective agent for plant diseases caused by the fungal pathogen Rhizoctonia solani. Pyrrolnitrin is made in four steps, the second of which, catalyzed by PrnB, is a novel chemical rearrangement of 7-chlorotryptophan. PrnB was overproduced in Pseudomonas fluorescens (BL915) and well diffracting crystals were obtained of a triple cysteine-to-serine mutant by sitting-drop vapour diffusion. Crystals grown in the presence of L-7-chlorotryptophan, D-tryptophan and L-tryptophan are reported. Data sets for each are reported with high-resolution limits of 2.0, 1.75 and 1.75 A, respectively. Two crystals (PrnB in the presence of D-tryptophan and L-7-chlorotryptophan) belong to space group C2 with similar unit-cell parameters (a = 68.6, b = 79.5, c = 92.7 A, alpha = gamma = 90.0, beta = 103.8 degrees). Crystals grown in the presence of L-tryptophan belong to space group C222(1) and have unit-cell parameters a = 67.7, b = 80.1, c = 129.5 A. All crystals contain a monomer in the asymmetric unit.

Itraconazole in the Treatment of Fungal Infection in Children

伊曲康唑为新一代三唑类广谱抗真菌药,虽然目前尚未被美国食品药品管理局批准在儿童使用,但临床已经应用于儿童浅部真菌及系统性真菌感染.多数临床研究认为,伊曲康唑每天5mg/kg,对儿童多种真菌病有很好的疗效,不良反应少.在治疗儿童浅部真菌感染性疾病中,间歇冲击疗法能缩短疗程、减少不良反应.伊曲康唑在儿童中使用的不良反应与成人基本一致,但更轻微和短暂.与伊曲康唑有相互作用的药物应注意避免在儿童同时使用。

Review of in vitro activity of sertaconazole nitrate in the treatment of superficial fungal infections

The evaluation of susceptibility patterns of clinical and laboratory isolates of dermatophytes and Candida to sertaconazole nitrate has been determined using macrodilution and microdilution test methods in laboratories worldwide. Antimycotics that have been compared to sertaconazole nitrate include itraconazole, clotrimazole, miconazole, and terbinafine. A comparison of the minimum inhibitory concentrations clearly shows differences in potency and spectrum among the various agents. This article reviews the antifungal activity of sertaconazole nitrate against major fungal pathogens that cause and complicate tinea pedis. In light of the new topical formulation of sertaconazole nitrate, this compilation of data from the literature is helpful for relating in vitro data to the tissue concentrations required for effective eradication of cutaneous fungal infections.

Dermatophytosis: The Management of Fungal Infections

Dermatophytosis is an infection of the hair, skin, or nails caused by a dermatophyte, which is most commonly of the Trichophyton genus and less commonly of the Microsporum or Epidermophyton genera. Tinea capitis, tinea pedis, and onychomycosis are common dermatologic diseases that may result from such an infection. The treatment of fungal infections caused by a dermatophyte has been successful when treated with oral or topical antifungal agents. Terbinafine, itraconazole, and fluconazole are oral antimycotics that are effective in the treatment of superficial mycoses, although, depending on the severity of the infection, a topical antifungal may be sufficient.

Involvement of proapoptotic Bcl-2 family members in terbinafine-induced mitochondrial dysfunction and apoptosis in HL60 cells

Terbinafine (TB, lamisil ®), a promising world widely used oral-anti-fungal agent, has been used in the treatment of superficial mycosis. In this study, we found that apoptosis but not cell growth arrest was induced by TB (1 μM, for 24 h) in human promyelocytic leukemia (HL60) cells. The apoptotic effect induced by TB in the HL60 cell was not through the general differentiation mechanisms evidenced by evaluation of three recognized markers, including CD11b, CD33, and morphological features. In addition, our results also revealed that TB-induced apoptosis was not through the cellular surface CD 95 receptor-mediated signaling pathway. We found that the mitochondria membrane in the TB-treated HL60 cells was dissipated by decreasing of the electrochemical gradient (Δ Ψ m) led to leakage of cytochrome c from mitochondria into cytosol. Such effects were completely blocked by in vitro transfection of the HL60 cells with Bcl-2 overexpression plasmid (HL60/Bcl-2). However, our data found that TB-mediated apoptosis could not be completely prevented in the Bcl-2 over expressed (HL60/Bcl-2) cells. Such results implied that additional mediators (such as caspase-9) other than mitochondria membrane permeability might contribute to the TB-induced cellular apoptosis signaling. This hypothesis was supported by the evidence that administration of caspases-9 specific inhibitor (z-LEHD-fmk) blocked the TB-induced apoptosis. Our studies highlight the molecular mechanisms of TB-induced apoptosis in human promyelocytic leukemia (HL60) cells.

Sertaconazole: updated review of a topical antifungal agent

Sertaconazole is an imidazole-type antifungal agent that has shown considerable in vitro activity against pathogenic fungi. Various studies carried out in animal models, clinical and toxicologic trials have confirmed the value of sertaconazole in the topical treatment of superficial mycoses in dermatology and gynecology. After several years of clinical experience in the topical treatment of dermatophytosis and Tinea versicolor, the substance has been approved for gynecologic candidiasis in Europe. Sertaconazole has a wide action spectrum that includes yeasts and dermatophyte fungi, and it is also active against bacteria, mainly Gram-positive cocci, making it highly efficient in the treatment of polymicrobial infections. The recent approval of the molecule by the US Food and Drug Administration, and the appearance of a new formulation of sertaconazole for the treatment of onychomycoses on a weekly administrative basis, are all data relevant to the process of marketing the product.

Molecular mechanisms of econazole-induced toxicity on human colon cancer cells: G0/G1 cell cycle arrest and caspase 8-independent apoptotic signaling pathways

Econazole (Eco), a potent broad-spectrum anti-fungal agent, has been used in the treatment of superficial mycosis. Eco is a store-operated Ca 2+ channel antagonist which induces cytotoxic cell death of leukemia. However, little is known about its cytotoxic effect upon solid tumor cells. The purpose of this study is to investigate both the in vitro and in vivo molecular mechanisms of Eco-induced toxicity on colon cancer cells. We used COLO 205 cell line and nude mice xenograft model to investigate the cytotoxic effect of Eco. We demonstrated that lower doses Eco (5–20 μM) arrested human colon cancer cells at the G0/G1 phase of the cell cycle. The protein levels of p53, p21/Cip1, and p27/Kip1 were significantly elevated while CDK2 and CDK4 kinase activity were significantly suppressed by Eco treatment in COLO 205 cells. At higher doses (40–60 μM), Eco induced COLO 205 cells apoptosis evidenced by ladder formation in DNA fragmentation assay and sub-G1 peak in flow cytometry analysis. Western blot analysis showed that caspases 3, 9 but not 8 were activated by high dose Eco treatment to the COLO 205 cells accompanied with cytochrome c and apoptosis-inducing factor (AIF) translocation. Significant anti-tumorigenesis effect was further demonstrated in vivo by treating nude mice bearing COLO 205 tumor xenografts with Eco 50 mg/kg intraperitoneally. Our findings highlight the molecular mechanisms underlying the Eco-induced toxicity on colon cancer cells.

Diagnose und Therapie von Pilzinfektionen und der Pneumozystis-Pneumonie bei Kindern und Jugendlichen mit neoplastischen Erkrankungen

Invasive fungal infections are important causes of morbidity and mortality in pediatric cancer patients with hematological malignancies and following allogeneic hematopoietic stem cell transplantation. This article provides the recommendations of the Infectious Diseases Working Party of the German Society for Pediatric Infectious Diseases (DGPI) and the German Society for Pediatric Hematology/Oncology (GPOH) for diagnosis and treatment of fungal infections including Pneumocystis jiroveci. They are based on specific pediatric pharmacological and regulatory considerations and on the results of clinical trials, case series and expert opinions using the evidence criteria set forth by the Infectious Diseases Society of America (IDSA). Recommendations for the most frequent clinical entities are summarized here. Options for initial therapy of uncomplicated candidemia include deoxycholate amphotericin B (DAMB), fluconazole (FLC), liposomal amphotericin B (LAMB), the combination of DAMB plus FLC as well as voriconazole (VCZ) for patients > 11 years. For acute disseminated candidiasis, the combination of DAMB plus flucytosine is recommended. Indwelling central venous catheters serve as infectious nidus and should be removed whenever feasible. First-line therapy for presumed or proven invasive Aspergillus infections in patients 12 years and older is VCZ with DAMB and LAMB serving as alternatives. Choices for patients < 12 years of age are essentially limited to DAMB and LAMB. Due to the yet lacking evidence for enhanced antifungal efficacy and the ongoing dosage finding of caspofungin (CAS) in pediatric patients, combination therapies (LAMB plus CAS or VCZ plus CAS) should only be considered for fulminant or massive, life threatening infections. In granulocytopenic patients, adjunctive therapy with colony-stimulating factors (G-CSF) is recommended. In patients under immunosuppressive therapy, glucocorticosteroids ought to be reduced or discontinued, if feasible. Surgical interventions are restricted to specific indications. Zygomyces infections are an indication for high-dose LAMB. The combination of DAMB plus flucytosine is the initial treatment of choice of cryptococcal mengoencephalitis, and for treatment of Pneumocystis jiroveci pneumonitis, trimethoprim/sulfamethoxazol or intravenous pentamidine is recommended. Beyond the listed entities, the article provides a brief review on the pharmacokinetics and dosing of antifungal agents in children and adolescents as well as detailed discussions and evidence-based recommendations for empirical antifungal therapy, diagnosis and treatment of superficial fungal infections, of invasive infections by previously rare fungal pathogens and endemic moulds and for adjunctive immunomodulatory and surgical interventions.

Inhibition of human vascular endothelial cells proliferation by terbinafine.

We have demonstrated previously that terbinafine (TB), an oral antifungal agent used in the treatment of superficial mycosis, suppresses proliferation of various cultured human cancer cells in vitro and in vivo by inhibiting DNA synthesis and activating apoptosis. In our study, we further demonstrated that TB at a range of concentrations (0-120 microM) dose-dependently decreased cell number in cultured human umbilical vascular endothelial cells (HUVEC). Terbinafine was not cytotoxic at a concentration of 120 microM, indicating that it may have an inhibitory effect on the cell proliferation in HUVEC. The TB-induced inhibition of cell growth rate is reversible. [(3)H]thymidine incorporation revealed that TB reduced the [(3)H]thymidine incorporation into HUVEC during the S-phase of the cell-cycle. Western blot analysis demonstrated that the protein levels of cyclin A, but not cyclins B, D1, D3, E, CDK2 and CDK4, decreased after TB treatment. The TB-induced cell-cycle arrest in HUVEC occurred when the cyclin-dependent kinase 2 (CDK2) activity was inhibited just as the protein level of p21 was increased and cyclin A was decreased. Pretreatment of HUVEC with a p21 specific antisense oligonucleotide reversed the TB-induced inhibition of [(3)H]thymidine incorporation. Taken together, these results suggest an involvement of the p21-associated signaling pathway in the TB-induced antiproliferation in HUVEC. Capillary-like tube formation and chick embryo chorioallantoic membrane (CAM) assays further demonstrated the anti-angiogenic effect of TB. These findings demonstrate for the first time that TB can inhibit the angiogenesis.

A current appraisal of drug interactions of significance in clinical practice: focus on antifungal therapeutic agents used in the treatment of superficial mycoses

The subject of drug-drug interactions has continued to expand in terms of understanding its mechanisms, with potentially significant interactions based on advances in evaluating metabolic pathways and enhanced recognition of the importance of pharmacogenomics. Within dermatology, the clinical significance of drug interactions has been made evident by the withdrawal from the marketplace of the “nonsedating” antihistamines, terfenadine and astemizole, due to the increased propensity for prolongation of the QTc interval with subsequent ventricular arrhythmia when these agents were coadministered with erythromycin, ketoconazole or itraconazole. This “hallmark interaction” association is directly related to inhibition of the cytochrome (CYP) 3A4 metabolic pathway by several macrolide antibiotics and azole antifungal agents. Due to the predominant role of CYP 3A4 in the metabolism of approximately half of currently available drugs, the potential for widespread impact related to CYP3A4 inhibition, as well as other less predominant CYP metabolic isoenzymes, has received significant notoriety. In the US, between 1987 and 1991, 98 drugs received approval for use with 32 inclusive of drug interaction studies. Between 1992 and 1997, although the number of approved drugs doubled, the number of associated drug interaction studies more than tripled. Several warnings and contraindications have emerged related to drug interactions, such as recommendations to avoid coadministration of some macrolide antibiotics or azole antifungal agents with HMG-CoA reductase inhibitors, some benzodiazepines and some cardiac drugs, including digoxin. Considering the widespread prevalence of superficial mycotic infections and associated oral antifungal use, it is rational to periodically revisit the subject of potential drug interactions and oral antifungal agents. Due to variations in metabolic pathways, significant differences in the potential for interactions have been established when comparing griseofulvin, terbinafine, ketoconazole and the triazoles, itraconazole and fluconazole. Overall, compared to other oral antifungal agents, terbinafine is associated with the most favorable safety profile with regard to clinically significant drug interactions. This poster provides an overview and update on potential drug interactions related to the selection of specific oral antifungal agents. Emphasis will be placed on supportive data, clinical significance, and management suggestions for the clinician.

Optimal management of fungal infections of the skin, hair, and nails.

Superficial fungal infections are chronic and recurring conditions. Tinea capitis is a scalp infection, primarily affecting prepubescent children. Ringworm infections, such as tinea corporis and tinea cruris, involve the glabrous skin. Tinea nigra is a rare mycotic infection that may be related to travel abroad. Piedra, black or white, is limited to the hair shaft without involvement of the adjacent skin. Pityriasis (tinea) versicolor and seborrheic dermatitis are dermatoses associated with yeasts of the genus Malassezia that affect the lipid-rich areas of the body. The taxonomy of the Malassezia yeasts has been revised to include nine species, eight of which have been recovered from humans. Tinea pedis, an infection of the feet and toes, is one of the most common forms of dermatophytosis. Onychomycosis is a fungal infection affecting the nail bed and nail plate; it may be chronic and can be difficult to treat. In instances where the superficial fungal infection is severe or chronic, an oral antifungal agent should be considered. Terbinafine, itraconazole, and fluconazole are oral antifungals that are effective in the treatment of superficial mycoses.

Itraconazole (Sporanox®) in superficial and systemic fungal infections

Itraconazole (Sporanox®) is a triazole antifungal agent with a broad activity spectrum and favorable pharmacokinetic and safety profiles. Numerous clinical trials have established the efficacy and safety of itraconazole in the treatment of superficial fungal infections. In this field, full exploitation of its pharmacokinetics in keratinized tissues has led to the development of intermittent (pulse) treatment regimens that allow similar efficacy with lower overall drug exposure as well as a reduction in treatment costs. The additional anti-inflammatory action of itraconazole also makes it suitable for application in difficult-to-treat inflammatory skin disorders, such as seborrheic dermatitis. Recently, a new oral liquid formulation and an intravenous formulation have been developed, extending the therapeutic application of itraconazole to systemic fungal infections. Due to its broad activity spectrum and excellent tolerability, itraconazole is a valuable addition to the antifungal armamentarium used for prophylactic and empiric treatment in immunocompromised hosts.

In vitro and in vivo studies of the anticancer action of terbinafine in human cancer cell lines: G0/G1 p53-associated cell cycle arrest.

Terbinafine (TB) (Lamisil), a promising oral antifungal agent used worldwide, has been used in the treatment of superficial mycosis. In our study, we demonstrated that TB dose-dependently decreased cell number in various cultured human malignant cells. Flow cytometry analysis revealed that TB interrupts the cell cycle at the G0/G1 transition. The TB-induced cell cycle arrest in colon cancer cell line (COLO 205) occurred when the cyclin-dependent kinase (cdk) system was inhibited just as the levels of p53, p21/Cip1 and p27/Kip1 proteins were augmented. In the TB-treated COLO 205, the binding between p53 protein and p53 consensus binding site in p21/Cip1 promoter DNA probe was increased. Pretreatment of COLO 205 with p53-specific antisense oligodeoxynucleotide decreased the TB-induced elevations of p53 and p21/Cip1 proteins, which in turn led to arrest in the cell cycle at the G0/G1 phase. Moreover, in the p53 null cells, HL60, TB treatment did not induce cell cycle arrest. Taken together, these results suggest an involvement of the p53-associated signaling pathway in the TB-induced antiproliferation in COLO 205. We further examined whether administration of TB could affect the growth of tumors derived from human colon cancer cells in an in vivo setting. COLO 205 cells implanted subcutaneously in nude mice formed solid tumor; subsequent intraperitoneal injections of TB (50 mg/kg) led to obvious decline in tumor size, up to 50-60%. In these tumors, increases in the p21/Cip1, p27/Kip1 and p53 proteins and the occurrence of apoptosis were observed. Combined treatment with TB and nocodazole (ND), a clinically used anticancer agent, potentiated the apoptotic effect in COLO 205. These findings demonstrate for the first time that TB can inhibit the proliferation of tumor cells in vitro and in vivo.

Persistent and Recurrent Tinea Corporis in Children Treated With Combination Antifungal/ Corticosteroid Agents

Combination antifungal/corticosteroid preparations are widely used by nondermatologists in the treatment of superficial fungal infections in patients of all ages. Over half of the prescriptions written for the most commonly used combination agent clotrimazole 1%/betamethasone diproprionate 0.05% cream (Lotrisone, Schering, Kenilworth, NJ) were prescribed for children younger than 4 years old. Our pediatric dermatology division has recently encountered a series of children with recurrent or persistent tinea corporis, especially tinea faciei, treated initially with combination antifungal/corticosteroid cream. All children evaluated for tinea corporis in a university hospital pediatric dermatology clinic from January through June 2001 were identified from the clinic registry for a retrospective chart review. Response to therapy was confirmed by telephone survey and/or follow-up visits at least 1 month after clearing of infection. Six children ranging in age from 4 to 11 years were evaluated for tinea corporis in a pediatric dermatology clinic at our institution during the 6-month period. All 6 children were diagnosed clinically by their pediatrician with tinea corporis and initially treated with clotrimazole 1%/betamethasone diproprionate 0.05% cream for 2 to 12 months. In our pediatric dermatology clinic, patients had their diagnosis confirmed with a positive potassium hydroxide preparation and were treated with one of several oral or topical antifungal agents with clearing of all tinea infections. The use of combination clotrimazole 1% cream/betamethasone diproprionate 0.05% cream (Lotrisone) for the treatment of tinea corporis may be associated with persistent/recurrent infection.

Hepatic Safety of Itraconazole

Background: As the use of the newer oral antifungal agents for the treatment of superficial fungal infections becomes more widespread, the issue of safety surrounding their use is becoming an increasingly important consideration. Itraconazole is effective and well tolerated, with most side effects being minor and reversible. The most common adverse events are gastrointestinal upset, headache, and transient skin reaction. There have also been rare reports of hepatitis. Objective: To assess the hepatic safety of pulse and continuous itraconazole in the treatment of onychomycosis. Methods: An analysis was performed on all itraconazole clinical trials sponsored by Janssen Research Foundation in the treatment of onychomycosis, where there was an assessment of laboratory safety. A review of the published literature was also undertaken to assess the hepatic safety of itraconazole in common practice. Results: The data indicate that itraconazole pulse treatment is safe, with no significant differences in the number of code 4 abnormalities (baseline value is in the normal range and at least two values, or the last testing in the observation period, exceed twice the upper limit of normal) in the liver function parameters studied: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin. The incidence of all the code 4 abnormalities was below 2%. In the literature there are reports of symptomatic hepatitis with itraconazole continuous therapy but no published report of symptomatic hepatotoxicity using the pulse regimen. Conclusions: Itraconazole pulse therapy for onychomycosis appears to be safe, especially from the perspective of potential liver damage. In the itraconazole package insert liver function tests are recommended for patients receiving continuous itraconazole for periods of time exceeding 1 month. There is no such monitoring requirement for the pulse regimen unless the patient has a history of underlying hepatic disease, the liver function tests are abnormal at baseline, or at any time that there is the development of signs or symptoms suggestive of liver dysfunction.

Hepatic safety of itraconazole.

As the use of the newer oral antifungal agents for the treatment of superficial fungal infections becomes more widespread, the issue of safety surrounding their use is becoming an increasingly important consideration. Itraconazole is effective and well tolerated, with most side effects being minor and reversible. The most common adverse events are gastrointestinal upset, headache, and transient skin reaction. There have also been rare reports of hepatitis. To assess the hepatic safety of pulse and continuous itraconazole in the treatment of onychomycosis. An analysis was performed on all itraconazole clinical trials sponsored by Janssen Research Foundation in the treatment of onychomycosis, where there was an assessment of laboratory safety. A review of the published literature was also undertaken to assess the hepatic safety of itraconazole in common practice. The data indicate that itraconazole pulse treatment is safe, with no significant differences in the number of code 4 abnormalities (baseline value is in the normal range and at least two values, or the last testing in the observation period, exceed twice the upper limit of normal) in the liver function parameters studied: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin. The incidence of all the code 4 abnormalities was below 2%. In the literature there are reports of symptomatic hepatitis with itraconazole continuous therapy but no published report of symptomatic hepatotoxicity using the pulse regimen. Itraconazole pulse therapy for onychomycosis appears to be safe, especially from the perspective of potential liver damage. In the itraconazole package insert liver function tests are recommended for patients receiving continuous itraconazole for periods of time exceeding 1 month. There is no such monitoring requirement for the pulse regimen unless the patient has a history of underlying hepatic disease, the liver function tests are abnormal at baseline, or at any time that there is the development of signs or symptoms suggestive of liver dysfunction.

Antitumor Effects of Miconazole on Human Colon Carcinoma Xenografts in Nude Mice through Induction of Apoptosis and G0/G1 Cell Cycle Arrest

Miconazole (MIC), a promising oral antifungal agent, has been used worldwide in the treatment of superficial mycosis. In this study, we demonstrated that MIC dose dependently arrested various human cancer cells at the G0/G1 phase of the cell cycle. The protein levels of p53, p21/Cip1, and p27/Kip1 were significantly elevated by MIC treatment in COLO 205 cells. Electrophoretic mobility gel shift assays showed that the nuclear extracts of the MIC-treated COLO 205 cells exerted a significant binding between wild-type p53 and its consensus-binding site present in the p21/Cip1 promoter. These results suggested that the p53-associated signaling pathway is involved in the regulation of MIC-induced cancer cell growth arrest. By immunoblot analysis, we demonstrated that cyclin D3 and cyclin-dependent kinase-4 (CDK4) protein levels were inhibited by MIC treatment in the cancer cells. Significant therapeutic effect was further demonstrated in vivo by treating nude mice bearing COLO 205 tumor xenografts with MIC (50 mg/kg ip). The protein expression of p53 was significantly increased in MIC-treated tumor tissues by immunohistochemical staining and Western blotting analysis. DNA fragmentation and TUNEL assay were performed and demonstrated that apoptosis occurred in tumor tissues treated with MIC. Our study provides the novel mechanisms of antitumor effects of MIC and such results may have significant applications for cancer chemotherapy.

Pharmacology of itraconazole.

Itraconazole is a triazole antifungal agent that has a broad spectrum of activity and is well tolerated. Itraconazole is highly efficacious, particularly because its main metabolite, hydroxy-itraconazole, also has considerable antifungal activity. The original capsule formulation of itraconazole may lead to variability in absorption and the plasma concentration. For the treatment of superficial fungal infections, this is not problematical because itraconazole accumulates at the infection site, making consistently high plasma concentrations unnecessary -- a characteristic that has been exploited in the development of a pulse regimen. Because consistent plasma concentrations are critical for the more serious systemic fungal infections, variable absorption of itraconazole from the capsules limits their application. Moreover, underlying disease processes and medical interventions can reduce absorption from the capsules in some patients with systemic fungal infections. To widen the beneficial application of itraconazole to include such patients, an oral solution and an intravenous formulation were developed. These formulations combine lipophilic itraconazole with hydroxypropyl-beta-cyclodextrin, a ring of substituted glucose molecules, which improves the solubility of itraconazole. The enhanced absorption and bioavailability of itraconazole from these new formulations make them ideal for the treatment of systemic fungal infections in a wide range of patient populations. The additional flexibility offered by the different routes of administration also means that itraconazole can be used in patients at high risk, such as children or those requiring intensive care, for whom the capsule formulation may be impractical.