In-vitro inhibitory activities of 2 new orally absorbable imidazole derivatives: BAY n 7133 and BAY 1 9139

The inhibitory activities of 2 new orally absorbed antifungal imidazole derivatives, BAY n 7133 and BAY 1 9139, were compared in vitro with those of ketoconazole and miconazole. Clinical isolates of pathogenic fungi tested included 35 yeasts, 62 dimorphic fungal pathogens, 37 filamentous fungi and 31 dermatophytes. LY 121019, a semisynthetic analog of echinocandin B, was included in tests with the pathogenic yeasts. Both BAY n 7133 and BAY 1 9139 were found to be broad spectrum antifungal agents. The spectra of these newer compounds were comparable to those of ketoconazole and miconazole; however only BAY n 7133 resembled these latter 2 imidazoles quantitatively in terms of the degree of antifungal activity as indicated by measurable MICs. In contrast, the spectrum of LY 121019 appeared to be confirmed only to isolates of Candida.     

球孢子菌病的流行病学、临床表现及诊治进展

球孢子菌病是球孢子菌感染人类所致的疾病。传统认为其流行区域仅限于美洲部分地区,但随着全球人口流动,非疫区的输入性病例报道日渐增多。一些新近研究也对其传统流行病学观念提出了挑战。此外,球孢子菌病的临床表现多样,从轻微的自限性呼吸道感染到严重的全身播散性感染均可发生,给诊断带来了很大的困难。因此,尽管中国并非传统概念上的球孢子菌病疫区,国内感染病工作者仍有必要对其现状有所了解。本文针对球孢子菌病的流行现状及诊疗进展进行综述。     

In-vitro studies with four new antifungal agents: BAY n 7133, bifonazole (BAY h 4502), ICI 153,066 and Ro 14-4767/002

Four new antifungal agents were compared in vitro with miconazole and ketoconazole. The agents were BAY n 7133 and ICI 153,066, two orally active triazoles, and bifonazole (BAY h 4502) and Ro 14-4767/002, both topical agents. While all four were found to be broad spectrum antifungal agents they also demonstrated certain gaps in their spectra. In general, Ro 14-4767/002 was the most active agent tested whereas bifonazole and BAY n 7133 were the least active. Noteworthy activities included that of Ro 14-4767/002 against Candida albicans, the dermatophytes and Sporothrix schenckii and that of ICI 153,066 against Torulopsis glabrata.     

In vitro antifungal activities of Bay n 7133 and Bay L 9139, two new orally absorbed antifungal imidazole derivatives,against pathogenic yeasts

Bay n 7133 and Bay L 9139 (Bayer AG, Wuppertal, Fed. Rep. Germany) are new, orally absorbable, antifungal imidazole derivatives. In vitro, Bay n 7133 was comparable to ketoconazole and miconazole when tested against isolates of Candida albicans and Cryptococcus neoformans. Bay L 9139 also was active against these organisms but to a lesser degree than the other imidazoles. LY 121019, an analog of echinocandin B, was also tested. It proved to be the most active antimycotic against C. albicans but the least active against C. neoformans. Optimal results were obtained in tests employing Kimmig's agar, a medium previously described for use in susceptibility tests with antifungal agents.     

Ketoconazole inhibition and glucocorticoid action in the human lymphoblastic leukemia cell line CEM-C7

The antifungal drug, ketoconazole, was reported to antagonize the induction of the enzyme tyrosine aminotransferase (TAT) by glucocorticoids in hepatoma tissue culture (HTC) cells, and to compete with glucocorticoids for binding to the glucocorticoid receptor. Since glucocorticoids inhibit the growth of the human leukemia cell line CEM-C7, ketoconazole might be expected to reverse this inhibition. Unexpectedly, ketoconazole inhibited CEM-C7 cell growth without utilizing glucocorticoid receptors. This was confirmed by ketoconazole inhibition of the growth of a receptor-less subline of CEM-C7 cells which are insensitive to glucocorticoids. Ketoconazole competed with triamcinolone acetonide (TA) for binding to the glucocorticoid receptor in cell-free supernatant prepared from CEM-C7 cells, but this was greatly reduced if ketoconazole and TA were incubated with intact cells prior to preparation of the cell-free supernatant. Ketoconazole inhibited induction by TA of the enzyme glutamine synthetase only at concentrations of 45-90 microM. We conclude that ketoconazole antagonism of glucocorticoid activity in CEM-C7 cells is probably not of pharmacologic significance due to the large concentrations required, and its reduced interaction with receptors in intact cells. The growth inhibitory activity of ketoconazole may be of interest in cancer chemotherapy.     

CORTISONE IN COCCIDIOIDOMYCOSIS

Cortisone administered orally, in low dosages for brief periods, promptly suppressed the allergic manifestations accompanying primary pulmonary coccidioidomycosis in 19 cases. There was no interference with the coccidioidin skin test reaction or with the usual serologic pattern.Dissemination of the disease as a sequel to the administration of cortisone and/or corticotropin has not been reported. A survey of physicians and of the known instances of disseminated coccidioidomycosis in Kern County failed to reveal any such episode.In none of the cases in which the authors gave cortisone in the presence of coccidioidomycosis was there any complication or undesirable sequel—specifically, no subsequent dissemination of the disease.The data presented are not to be interpreted as a therapeutic recommendation, but as a contribution to the information available concerning the effects of these drugs in infectious diseases.     

Some 3-(4-Aminophenyl)pyrrolidine-2,5-diones as All- trans -retinoic Acid Metabolising Enzyme Inhibitors (RAMBAs)

A series of (±) -3-(4-aminophenyl) pyrrolidin-2,5-diones substituted in the 1-, 3- or 1,3- position with an aryl or long chain alkyl function are weak inhibitors of the metabolism of all-trans retinoic acid (RA) by rat liver microsomes (68-75% inhibition) compared with ketoconazole (85%). Further studies with the 1-cyclohexyl analogue (1) (IC 50 = 98.8 μM, ketoconazole, 22.15 μM) showed that it was not stereoselective in its inhibition. (±) - (1) was not an inhibitor of pig brain microsomal enzyme (ketoconazole, IC 50 = 20.9 μM), had little effect on human liver microsomal enzyme (19.3%, ketoconazole, 81.6%) or human placental microsomal enzyme (9.8%, ketoconazole 73.9%) but was a weak inhibitor of human and rat skin homogenates (52.6% and IC 50 = 211.6 μM respectively; ketoconazole, 38.8% and 85.95 μM). In RA-induced cell cultures of human male genital fibroblasts and HaCat cells, (±) - (1) was a weak inhibitor (c. 53% at 200 μM) whereas ketoconazole showed high potency (c. 65% at 0.625 μM and 0.25 μM respectively). The nature of the induced target enzyme is discussed.     

Some 3-(4-aminophenyl)pyrrolidine-2,5-diones as all-trans-retinoic acid metabolising enzyme inhibitors (RAMBAs)

A series of (+/-)-3-(4-aminophenyl) pyrrolidin-2,5-diones substituted in the 1-, 3- or 1,3-position with an aryl or long chain alkyl function are weak inhibitors of the metabolism of all-trans retinoic acid (RA) by rat liver microsomes (68-75% inhibition) compared with ketoconazole (85%). Further studies with the 1-cyclohexyl analogue (1) (IC50 = 98.8 microM, ketoconazole, 22.15 microM) showed that it was not stereoselective in its inhibition. (+/-)-(1) was not an inhibitor of pig brain microsomal enzyme (ketoconazole, IC50 = 20.9 microM), had little effect on human liver microsomal enzyme (19.3%, ketoconazole, 81.6%) or human placental microsomal enzyme (9.8%, ketoconazole 73.9%) but was a weak inhibitor of human and rat skin homogenates (52.6% and IC50 = 211.6 microM respectively; ketoconazole, 38.8% and 85.95 microM). In RA-induced cell cultures of human male genital fibroblasts and HaCat cells, (+/-)-(1) was a weak inhibitor (c. 53% at 200 microM) whereas ketoconazole showed high potency (c. 65% at 0.625 microM and 0.25 microM respectively). The nature of the induced target enzyme is discussed.     

COCCIDIOIDOMYCOSIS AS A COMPLICATION OF PREGNANCY

Records of 33 cases of coccidioidomycosis occurring during pregnancy were reviewed. In this group the incidence of dissemination of the disease was considerably greater than the reported incidence of dissemination in all cases of coccidioidomycosis.The incidence of dissemination was higher in the patients who contracted coccidioidomycosis late in pregnancy than it was in those in whom onset of the disease occurred earlier in gestation; but dissemination occurred in all Negro patients in the group, regardless of the time of onset during pregnancy.The chief complicating effect when onset was in the first trimester of pregnancy was a tendency to abortion. In cases in which onset was in the third trimester, the incidence of premature labor was extremely high.There was no evidence of congenital infection in any of the babies, but in one case invasion of the placenta by coccidioidal spherules was observed.     

Progress Toward a Human Vaccine Against Coccidioidomycosis

Coccidioidomycosis (San Joaquin Valley fever) is a human respiratory disease caused by a soil-borne mold, and is recognized as an intransigent microbial infection by physicians who treat patients with the potentially life-threatening, disseminated form of this mycosis. Epidemiological studies based on surveys of skin-test reactivity of people who reside in the endemic regions of the Southwestern US have shown that at least 150,000 new infections occur annually. The clinical spectrum of coccidioidomycosis ranges from an asymptomatic insult to a severe pulmonary disease in which the pathogen may spread from the lungs to the skin, bones, brain and other body organs. Escalation of symptomatic infections and increased cost of long-term antifungal treatment warrant a concerted effort to develop a vaccine against coccidioidomycosis. This review examines recently reported strategies used to generate such a vaccine and summarizes current understanding of the nature of protective immunity to this formidable disease.     

Coccidioidomycosis in a California sea otter (Enhydra lutris).

A weak and emaciated California sea otter (Enhydra lutris) was found stranded on Atascadero Beach in Morro Bay, California. It died three weeks after capture. A diagnosis of coccidioidomycosis was confirmed by histology, serology and culture. This is believed to be the first reported case of this disease from the Morro Bay area of San Luis Obispo County, California as well as the first reported case in a free-ranging marine mammal.     

Therapy of Cushing''s syndrome with steroid biosynthesis inhibitors

Several substances with different inhibitory effects on adrenal steroid biosynthesis were investigated in patients with Cushing's syndrome. It has been shown that trilostane, a 3β-hydroxysteroid-dehydrogenase inhibitor, is not potent enough to block cortisol biosynthesis in patients with hypercortisolism. Aminoglutethimide inhibits side chain cleavage of cortisol synthesis, but it has been demonstrated that the blocking effect on cortisol secretion is not strong enough to normalize urinary cortisol excretion in patients with Cushing's disease. For metyrapone, an inhibitor of adrenal 11β-hydroxylase, promising results were reported for the treatment of Cushing's syndrome. However, the drug has several side effects and depending on the definition of the desired reduction of cortisol secretion a true remission was only found in a minority of patients. The antifungal drug ketoconazole in vitro predominantly blocks 17,20-desmolase (IC₅₀ 1 μM) and to a lesser extent 17-hydroxylase (IC₅₀ 10 μM) and 11β-hydroxylase (IC₅₀ 15–40 μM). Therefore, ketoconazole in vivo most potently suppresses androgen secretion and only to a lesser extent cortisol biosynthesis. Several therapeutic trials with ketoconazole treatment in patients with pituitary Cushing's disease showed various remission rates between 30 and 90%. In contrast, in almost all patients with benign, primary adrenal Cushing's syndrome cortisol levels were normalized. In patients with ectopic ACTH syndrome ketoconazole was effective in about 50% of all reported cases, while cortisol hypersecretion due to adrenocortical carcinoma was only rarely inhibited by ketoconazole. The main side effect of ketoconazole treatment was liver toxicity which occurred in 12% of all treated patients. In contrast to ketoconazole, the narcotic drug etomidate shows a strong inhibitory effect on 11β-hydroxylase (IC₅₀ 0.03–0.15 μM) but only a weak inhibition of 17,20 desmolase (IC₅₀ 380 μM). This correlates with in vivo studies where even low, non-hypnotic doses of etomidate induced a pronounced fall in serum cortisol levels in normals and in patients with Cushing's syndrome. However, its clinical use is limited by its mandatory intravenous application and its sedative effects. In conclusion, ketoconazole remains the only available steroid-inhibitory drug for a therapeutic trial in patients with Cushing's syndrome who cannot be treated definitively by surgery.     

Review of human and animal cases of coccidioidomycosis diagnosed in Canada

The first Canadian case of coccidioidomycosis in a human was reported in 1952 and 11 more cases since then. This study provides details of other cases of coccidioidomycosis that have been diagnosed in Canada. Based on clinical details, isolation of Coccidioides immitis, detection of a specific antibody (F band) for coccidioidomycosis by macro- or microimmunodiffusion tests, concurrently used with the complement fixation procedure, and histopathological findings, 116 more cases of this disease were verified. The great majority (94%) of these cases were diagnosed in the western Canadian provinces of British Columbia, Alberta, Saskatchewan and Manitoba, and the others in Quebec, Ontario and Nova Scotia (5,1, and 1 cases, respectively). Available information indicates that the C. immitis infections were contracted during visits to endemic areas in the United States (Arizona, California and New Mexico), Mexico, and Bolivia. Pulmonary infections were the most common type of coccidioidomycosis (93%) followed by the disseminated or meningeal types C. immitis infections occurred in individuals with or without predisposing factor(s) and were more common in males than in females. The exoantigen procedure was very useful and reliable in the accurate and rapid identification of suspected C. immitis isolates. Two cases of coccidioidomycosis were reported in animals in Ontario, Canada.     

The effects of phenobarbital and ketoconazole on the alkaloid biosynthesis in Catharanthus roseus cell suspension cultures

The cytochrome P450 enzyme geraniol 10-hydroxylase plays an important role in the biosynthesis of terpenoid indole alkaloids in suspension cultures of Catharanthus roseus. The activity of this enzyme was induced by the treatment of cells with phenobarbital, and inhibited by treatment with ketoconazole. The alkaloid accumulation increased after phenobarbital treatment whereas it decreased after ketoconazole treatment. Phenobarbital and ketoconazole did not affect the in vivo conversion rate of loganin to secologanin, a reaction proposed to be catalyzed by a cytochrome P450 enzyme.     

Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts

Serologic studies are an important diagnostic tool in the clinical evaluation and follow-up of persons with coccidioidomycosis. Numerous types of serologic tests are available, including immunodiffusion, enzyme immunoassay, and complement fixation. We conducted a retrospective review of the results of 1,797 serologic tests spanning 12 months from the onset of coccidioidomycosis in 298 immunocompetent and 62 immunosuppressed persons with symptomatic infection. Using the onset of symptoms as a reference point, we plotted the positive or negative serologic results over time for both groups. Compared with the immunocompetent group, immunosuppressed persons had lower rates of seropositivity for every type of test during the first year after onset of symptoms for coccidioidomycosis, although many results did not achieve statistical significance. Combining the results of these tests increased the sensitivity of the serologic evaluation in immunocompromised patients. Immunosuppressed persons have the ability to mount a serologic response to coccidioidomycosis, but in some circumstances, multiple methods may be required to improve detection.     

Madurella mycetomatis Is Highly Susceptible to Ravuconazole

The current treatment of eumycetoma utilizing ketoconazole is unsatisfactory because of high recurrence rates, which often leads to complications and unnecessary amputations, and its comparatively high cost in endemic areas. Hence, an effective and affordable drug is required to improve therapeutic outcome. E1224 is a potent orally available, broad-spectrum triazole currently being developed for the treatment of Chagas disease. E1224 is a prodrug that is rapidly converted to ravuconazole. Plasma levels of E1224 are low and transient, and its therapeutically active moiety, ravuconazole is therapeutically active. In the present study, the in vitro activity of ravuconazole against Madurella mycetomatis, the most common etiologic agent of eumycetoma, was evaluated and compared to that of ketoconazole and itraconazole. Ravuconazole showed excellent activity with MICs ranging between ≤0.002 and 0.031 µg/ml, which were significantly lower than the MICs reported for ketoconazole and itraconazole. On the basis of our findings, E1224 with its resultant active moiety, ravuconazole, could be an effective and affordable therapeutic option for the treatment of eumycetoma.     

Hepatic effects of ketoconazole in the male Swiss Webster mouse: temporal changes in drug metabolic parameters

There have been conflicting observations regarding the effects of ketoconazole on hepatic metabolism. The objectives of these studies were to determine whether ketoconazole was an enzyme inducer or inhibitor in the mouse and then to establish the time frame of these ketoconazole-induced enzyme changes. Ketoconazole was administered (150 mg/kg p.o. X 4 days) to male Swiss Webster mice. Biochemical observations over a period of 6 days following treatment indicated that ketoconazole had a temporal biphasic effect on the liver. Although liver weight and microsomal protein were elevated, all other parameters monitored were lower at 2 h following ketoconazole treatment. At 24 h after the last dose of ketoconazole, hepatic biochemical parameters (liver wt., % liver wt./body wt., microsomal protein, and cytochrome P-450) were statistically elevated, while enzyme activities (benzphetamine N-demethylation, 6 beta- and 7 alpha-hydroxylation of testosterone, formation of androstenedione and UDP-glucuronyltransferase) were inhibited. At 72 h the ketoconazole-induced changes in the hepatic biochemical parameters were comparable to those observed at 24 h, and enzymatic parameters generally appeared to be induced by ketoconazole, with the exception of benzphetamine N-demethylase and UDP-glucuronyltransferase, which exhibited lower enzyme activities. Ethoxyresorufin O-deethylase, 7 alpha-hydroxylation of testosterone and glutathione S-transferase, on the other hand, were unaltered by ketoconazole treatment. The opposing effects of ketoconazole on benzphetamine N-demethylase and ethylmorphine N-demethylase at 72 h were further examined. Enzyme kinetics studies indicated that ketoconazole did not effect the Michaelis constants (Km) of the two substrates, but the maximum velocity (Vmax) of the reactions was altered.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cryptococcus neoformans: Comparisons of in vitro antifungal susceptibilities of serotypes AD and BC

Thirty-nine isolates of Cryptococcus neoformans, nineteen serotype AD and twenty serotype BC, were assayed for susceptibility to eight antifungal agents using an in vitro agar dilution assay. Media employed were Kimmig agar and yeast nitrogen base supplemented with 10% glucose. The antifungal agents used were ketoconazole, amphotericin B, 5-fluorocytosine, nystatin, miconazole, BAY N 7133, ICI 153,066, and itraconazole. No clinically significant differences in in vitro minimum inhibitory concentrations were detected between serotypes AD and BC against any of the compounds tested. An adverse medium effect was observed in two of the assays, but the outcome of the AD/BC comparison was not affected. This is the first report in which the in vitro antifungal susceptibilities of Cryptococcus neoformans serotypes are analyzed.     

Disseminated coccidioidomycosis; treatment with ethyl vanillate; a preliminary report

Ethyl vanillate, previously reported to be useful in the treatment of disseminated histoplasmosis, was administered to eight patients with disseminated coccidioidomycosis. Therapeutically effective concentrations of ethyl vanillate were obtained in only three patients, but, in them, the disease was apparently arrested. Failures occurred with patients who were too ill to tolerate the large amounts of ethyl vanillate required to attain a therapeutic concentration in the blood. The principal difficulties of administering ethyl vanillate are (a) the large doses required and (b) the lack of a parenterally administrable form of the drug. Ethyl vanillate, although not universally applicable, may be useful in selected cases of disseminated coccidioidomycosis and should be given further trial.     

Antigens of Coccidioides posadasii as an Important Tool for the Immunodiagnosis of Coccidioidomycosis

Serologic diagnosis has been presented as a safe alternative for coccidioidomycosis. However, commercial kits based on coccidioidal antibodies available in the USA are considered too expensive for laboratories outside that country. In this study, we describe the preparation of antigens for detection of human coccidioidal antibodies by the immunodiffusion test (ID) and enzyme immunoassay (EIA). Antigens were tested against serum samples from patients with coccidioidomycosis, histoplasmosis and paracoccidioidomycosis, as well as healthy individuals. The highest reactivity in the ID tests was seen in the F0-90 antigen. In the EIAs, the best results were obtained with the F60-90 antigen. None of the serum samples from healthy individuals were recognized by any of the antigen extracts tested by ID or EIA. In conclusion, the F0-90 and F60-90 antigens have the potential to be commercially employed in presumptive diagnosis of coccidioidomycosis by ID or EIA, respectively. The tests could improve serological diagnosis of coccidioidomycosis in South America.