Search PubMed⌕ Search

Biomedical subjects

J R Graybill

Publications and source records attributed to J R Graybill.

At least 19 recordsLinked to original sources
PubMed1992

A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group.

BACKGROUND: After primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse. METHODS: We conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (greater than or equal to 15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture. RESULTS: Of 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the remaining 189 patients, after a median follow-up of 286 days 14 of 78 receiving amphotericin B (18 percent) and 2 of 111 assigned to fluconazole (2 percent) had relapses of symptomatic cryptococcal disease (P less than 0.001 by Fisher's exact test). There was a difference of 19 percent in the estimated probability of remaining relapse-free at one year between the fluconazole group (97 percent) and the amphotericin B group (78 percent) (95 percent confidence interval, 7 percent to 31 percent; P less than 0.001). Serious drug-related toxicity was more frequent in the amphotericin B group (P = 0.02), as were bacterial infections (P = 0.004) and bacteremia (P = 0.002). CONCLUSIONS: Fluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Comparison of amphotericin B lipid complex with amphotericin B and SCH 39304 in the treatment of murine coccidioidal meningitis.

To assess the efficacy of amphotericin B lipid complex (ABLC) in the treatment of coccidioidal meningitis, we compared a wide range of doses (0.35-15 mg kg-1, intravenously (IV)) of ABLC with amphotericin B deoxycholate (AmB) (0.3-7 mg kg-1, intraperitoneally (IP)) and (IV) and a new triazole, SCH 39304 (SCH), in an experimental murine model. Survival data showed high dose ABLC to be of equal efficacy to IV and high dose IP AmB and SCH. Quantitative studies confirmed this outcome. No acute toxicity with ABLC, at the doses employed, was found. We conclude that ABLC is effective in the treatment of murine coccidioidal meningitis.

Amphotericin B↗
PubMed1992

Fluconazole.

Explore the source record for details and available documents.

Animals↗
PubMed1992

Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations.

Twelve patients receiving therapy with an azole agent (ketoconazole, itraconazole, and/or fluconazole) for systemic mycoses experienced drug interactions with rifampin, phenytoin, and/or carbamazepine resulting in substantial decreases in azole concentrations in serum. All four patients receiving azoles and concurrent phenytoin and/or carbamazepine failed to respond to treatment or suffered a relapse of their fungal infection. Four of five patients with cryptococcosis who received itraconazole and rifampin responded despite decreases in their serum itraconazole concentrations; synergy between itraconazole and rifampin was documented by in vitro analysis of inhibition and of killing of Cryptococcus neoformans isolates from all patients receiving this combination. In contrast, two patients with coccidioidomycosis failed to respond to itraconazole/rifampin. Moreover, two patients with cryptococcosis suffered a relapse or persistence of seborrheic dermatitis while receiving itraconazole/rifampin. The latter combination showed synergy in vitro in the inhibition of the mycelial phase of Coccidioides immitis and, to a lesser extent, of the pathogenic spherule phase of this fungus; synergy in the killing of C. immitis was not noted, nor was synergy seen against Malassezia furfur, the purported etiologic agent of seborrheic dermatitis. These findings illustrate several drug interactions that may affect clinical outcome and that must be considered in the management of antifungal therapy.

Adult↗
PubMed1992

Future directions of antifungal chemotherapy.

The number of recognized fungal pathogens and the alternatives for treatment of infections due to these organisms have increased dramatically in the 1980s. Use of the traditional agent, amphotericin B, has been hampered by severe dose-limiting toxicity and variable efficacy, and flucytosine is characterized by a narrow spectrum, rapid emergence of resistance, and significant dose-limiting toxicities. In recent years, the appearance of a variety of azole antifungal drugs has permitted exploration of the use of different agents in a wide range of dosages for treatment of a variety of fungal infections. Even so, the azoles are often ineffective or cannot be used, and major therapeutic gaps still remain, particularly for patients with AIDS and those with severe neutropenia. For those with acute, life-threatening disease, the use of amphotericin B-lipid complex or ampholiposomes offers the potential of delivering much higher doses of amphotericin B safely. However, the efficacy of these formulations compared with that of amphotericin B is as yet uncertain. In addition to treatment of established disease, there has been interest in using antifungal azoles for prophylaxis for mucocutaneous candidiasis and systemic mycoses in patients who are predisposed to these conditions. Recently completed large-scale studies suggest that antifungal prophylaxis can be accomplished with use of azoles; however, the cost versus benefits of the prophylactic use of these agents is not yet defined. The 1990s will see consolidation of the uses of antifungals presently available, exploration of the use of much higher doses of amphotericin B (perhaps other polyenes as well in liposomal form), and perhaps the use of azoles in combination as well as alone or sequentially in the form of polyene/azole antifungal therapy. New entries may include beta-1,3-glucan inhibitors in the mid-1990s and other classes of drugs toward the end of the decade.

Antifungal Agents↗
PubMed1992

Comparison of SCH 39304 and its isomers, RR 42427 and SS 42426, for treatment of murine cryptococcal and coccidioidal meningitis.

SCH 39304 (304) and its isomers, SCH 42426 (426) and SCH 42427 (427), are new orally administered antifungal azole derivatives. In this study, we compared the efficacy of 304 with that of 426 and 427 in murine models of cryptococcal and coccidioidal meningitis. On day 18 postinfection with Cryptococcus neoformans, controls showed 80% mortality. The 50% protective doses calculated at this day were 0.56 mg of 304 per kg of body weight, 23.5 mg of 426 per kg, and 0.11 mg of 427 per kg. Controls with coccidioidal meningitis all succumbed, and treated mice at the same time point showed 50% protective doses of 10.8 mg/kg for 304, 200 mg/kg for 426, and 2.1 mg/kg for 427. We conclude that isomer 427 is five times as potent, whereas 426 is 1/50th as potent as 304 in these experimental mycoses.

Administration, Oral↗
PubMed1992

Pharmacokinetics of SCH-39304 in human immunodeficiency virus-infected patients following chronic oral dosing.

The pharmacokinetics of SCH-39304, an investigational, orally active, broad-spectrum antifungal agent, were evaluated in 17 adult, human immunodeficiency virus-positive males. Patients were studied on days 1 and 16 and were divided into the following three treatment groups: (i) patients with culture-proven oropharyngeal candidiasis who were not receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 6); (ii) patients with culture-proven oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 50 mg of SCH-39304 daily (n = 5); and (iii) patients with or without oropharyngeal candidiasis who were receiving concurrent zidovudine therapy and who were treated with 200 mg of SCH-39304 daily (n = 6). All patients received a single daily dose of the study medication for 16 days. Plasma samples for SCH-39304 concentration measurement were collected for 6 h following the initial dose and for 504 h following the day 16 dose. Urine was collected for 24 h following SCH-39304 administration on days 1 and 16. All samples were assayed for SCH-39304 by gas chromatography. Wide intersubject variations in SCH-39304 plasma concentration-versus-time profiles were observed on each study day. Absorption appeared to be slow, with mean day 1 peak plasma SCH-39304 concentrations of 1.2 micrograms/ml at 2.1 h (50 mg) and 3.9 micrograms/ml at 4.0 h (200 mg) after drug administration. Mean peak plasma SCH-39304 concentrations on day 16 were 7.6 micrograms/ml at 4.3 h (50 mg) and 17.2 micrograms/ml at 3.2 h (200 mg) after drug administration. Mean elimination half-lives on day 16 for the 50- and 200-mg daily dosages were 100 and 89 h, respectively. SCH-39304 was cleared primarily unchanged in the urine. Mean areas under the plasma concentration-versus-time curve (from 0 to 24 h) on day 16 reflect a lower than expected increase with the 200-mg/day regimen (314.5 microgram.h/ml) compared with that for the 50-mg/day regimen (139.9 microgram.h/ml), suggesting the potential for reduced bioavailability at higher dosages. No significant effect of concurrent zidovudine therapy on the kinetics of SCH-39304 was observed.

Administration, Oral↗
PubMed1992

Use of high-dose fluconazole as salvage therapy for cryptococcal meningitis in patients with AIDS.

Eight patients with AIDS were treated orally with 800 mg of fluconazole daily for cryptococcal meningitis for a mean duration of 4.5 months. Previous antifungal treatment had failed for all of the patients. No major toxicity was observed. Three patients died from cryptococcal infection. High-dose fluconazole may be effective salvage therapy for cryptococcal meningitis.

Acquired Immunodeficiency Syndrome↗
PubMed1991

High-dose itraconazole in the treatment of severe mycoses.

Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (less than 2.5 micrograms/ml) in both patients. All other patients had mean trough levels in serum above 5 micrograms/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Combined therapy with fluconazole and flucytosine in murine cryptococcal meningitis.

To assess the possible beneficial effects of combined therapy (fluconazole and flucytosine) in the treatment of cryptococcal meningitis in the immunocompromised host, we compared therapy with fluconazole and flucytosine, individually and combined, in the experimental murine model. BALB/c athymic (nu/nu) mice were infected intracerebrally with 150 to 300 CFU of Cryptococcus neoformans. In mortality studies, treatment was initiated 24 h postinfection and continued for 10 to 14 days with either fluconazole (1 to 15 mg/kg of body weight per day), flucytosine (60 to 120 mg/kg/8 h), both drugs, or 0.3% Noble agar (control). Combined therapy delayed mortality significantly when compared with controls and single-drug regimens. This was observed over a broad range of doses. Quantitative determinations of CFU in brain tissue demonstrated a significantly lower burden of C. neoformans in mice receiving combined therapy. The results indicate that combined therapy with fluconazole and flucytosine is superior to single-drug therapy.

Amphotericin B↗
PubMed1991

Treatment of murine cryptococcal meningitis with an SCH 39304-amphotericin B combination.

Cryptococcal meningitis was induced in BALB/c mice by intracerebral infection with Cryptococcus neoformans. Drug therapy was initiated 1 day later, with mice receiving amphotericin B (AMB), SCH 39304, combination therapy, or no drug therapy (controls). Most, but not all, combinations showed additive benefits, significantly prolonging survival and reducing organism counts in tissues compared with those in controls and groups which received the drugs independently. Optimum protection was obtained when a single dose of 10 mg of AMB per kg of body weight was combined with a fairly narrow SCH 39304 dose range. AMB antagonism did not occur with any regimen tested. AMB-azole combinations may be reasonable alternatives for patients who fail standard cryptococcosis therapeutic regimens.

Amphotericin B↗
PubMed1991

Immunohistopathology of murine pulmonary histoplasmosis during normal and hypersensitive conditions.

Pulmonary histoplasmosis was induced in nonimmunized and immunized Balb-C nu/+ mice. The lung tissue burden of H. capsulatum, histopathology, the size of the inflammatory area, and the numbers of total T lymphocytes and subtypes in situ were evaluated serially after challenge. Over 3 days previously immunized mice developed a large lymphocyte/macrophage inflammatory response. This rapidly decreased in the next 2 wk. In contrast, the nonimmunized control mice developed a predominantly polymorphonuclear infiltrate that evolved more slowly over the first week of infection. This initial response was nonspecific but, after the first week, shifted to lymphocytes and granuloma formation. The lymphocyte infiltration in both immunized and nonimmunized mice was predominantly CD4. Previously immunized mice had a rapid decrease in tissue counts of H. capsulatum after Day 3, but nonimmunized mice continued to have increased counts through Day 7 after infection. These studies reproduce in the mouse model a host response similar to acute reinfection histoplasmosis in the human. In this condition an intense cell-mediated inflammatory response is thought to be elicited by fungal antigens and to represent host reaction rather than fungal replication. Our experimental model added new information relevant to the understanding of the pathogenesis of this process.

Alveolitis, Extrinsic Allergic↗
PubMed1990

Itraconazole treatment of coccidioidomycosis. NAIAD Mycoses Study Group.

PURPOSE: The purpose of this study was to assess the tolerance and efficacy of itraconazole in the treatment of coccidioidomycosis. PATIENTS AND METHODS: Fifty-one patients with nonmeningeal coccidioidomycosis were considered for treatment with intraconazole. Forty-nine patients who met study criteria were treated with itraconazole given orally in doses of 100 to 400 mg/day for periods up to 39 months. Of these patients, 12 had osteoarticular disease, 23 had chronic pulmonary disease, and 14 had skin or soft tissue disease. Clinical response was evaluated using a scoring system accounting for lesion number and size, symptoms, culture, and serologic titer. Remission was defined as reduction of the pretreatment score by 50% or more. RESULTS: Patients with osteoarticular, chronic pulmonary, and soft tissue disease improved at similar rates. Because two patients had no scoring assessment for efficacy, they were considered inassessable for efficacy. Forty-seven patients are evaluable. Of these patients, 44 have completed therapy, and three are still receiving itraconazole. Of the 44 patients no longer receiving therapy, 25 (57%) achieved remission. Of the 25 patients achieving remission, four later experienced a relapse. Therapy failed in 19 patients (43%). Of these cases, 16 (36%) were clinical failures and three (7%) developed drug intolerance that precluded continuation of treatment. Evaluation of culture conversions was of limited value in the osteoarticular patients, fewer than half of whom had follow-up biopsies. However, culture conversions were a useful index of response in patients with chronic pulmonary disease. During the course of treatment, serologic titers declined in the two groups with extrapulmonary disease, but not in patients with pulmonary coccidioidomycosis. Possible toxicities were generally mild. CONCLUSION: Itraconazole appears efficacious and very well tolerated in patients with coccidioidomycosis.

Adolescent↗
PubMed1990

Itraconazole treatment of phaeohyphomycosis.

Nineteen patients with phaeohyphomycosis were treated with itraconazole. Of these, 17 were assessable for clinical outcome. Of these, two had received no prior therapy, five had failed amphotericin B therapy, four had failed ketoconazole or miconazole therapy, and five had failed both amphotericin B and azole therapy. One patient had received only prior surgical intervention. Fungi of seven different genera caused disease of the skin in nine patients, soft tissue in nine, sinuses in eight, bone in five, joints in two, and lungs in two. Itraconazole was given in dosages ranging from 50 to 600 mg/day for 1 to 48 months. Clinical improvement or remission occurred in nine patients. Two patients have had stabilization of disease. Six patients failed treatment, one had a relapse after initially successful treatment. Itraconazole appears to be highly effective in some patients with phaeohyphomycosis, including patients refractory to other antifungal agents.

Adult↗
PubMed1990

Tumor necrosis factor-alpha plays a role in host defense against Histoplasma capsulatum.

Tumor necrosis factor-alpha was detected in supernatants collected from BALB/c mouse peritoneal macrophages incubated continuously with Histoplasma capsulatum. The levels of TNF alpha measured by actinomycin D bioassay peaked within hours after exposure and then greatly declined by 24 h. TNF alpha was also measured in bronchoalveolar lavage fluid from BALB/c mice challenged intranasally with H. capsulatum. Lavage fluid TNF alpha levels exhibited the same pattern as the in vitro supernatants; they peaked within hours after challenge and lower levels were detected at 24 h. Treatment of mice with anti-TNF alpha antibody accelerated mortality in response to systemic infection and significantly increased tissue colony counts in the liver and spleen. In the murine model, TNF alpha is produced in response to H. capsulatum and appears to play some role in host defense to infection.

Animals↗
PubMed1990

Treatment of murine coccidioidal meningitis with SCH39304.

The triazole SCH39304 was compared with itraconazole and fluconazole for treatment of murine coccidioidal meningitis. Mice were treated for 30 days with 1, 5, 10, or 30 mg of each drug per kg of body weight. Survival and brain tissue counts were measured. At equivalent doses, SCH39304 was more effective than the other triazoles.

Animals↗