Vol. 36, No. 1
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1992, p. 217-219
0066-4804/92/010217-03$02.00/0 Copyright © 1992, American Society for Microbiology
Comparison of SCH 39304 and Its Isomers, RR 42427 and SS 42426, for Treatment of Murine Cryptococcal and Coccidioidal Meningitis R.
ALLENDOERFER,1 2* R. R. YATES,' A. J. MARQUIS,' D. LOEBENBERG,3
M. G. RINALDI,2'4 AND J. R. GRAYBILL" 2 Departments of Medicine' and Pathology,4 University of Texas Health Science Center at San Antonio, and Audie L. Murphy V. A. Hospital,2 San Antonio, Texas 78284, and Schering Plough Research Corp., Bloomfield, New Jersey 070033
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.
were suspended in 0.3% Noble agar and administered per os by gavage in a volume of 0.2 ml per dose. To assess mortality, treatment against both infections was initiated 24 h postinfection and was given for 10 consecutive days. The doses for 304 were chosen on the basis of our previous studies of efficacy; the doses for the isomers were chosen according to the manufacturer's recommendation. The following dosages were given once daily to treat cryptococcal meningitis: for 304, 0.2, 0.5, 1, and 5 mg/kg of body weight; for 427, 0.05, 0.1, 0.2, and 0.5 mg/kg; and for 426, 5, 10, 20, and 50 mg/kg). The dosages used to treat coccidioidal meningitis were as follows: for 304, 1, 5, 10, and 20 mg/kg; for 427, 0.5, 1, 5, and 10 mg/kg; and for 426, 5, 10, 20, and 50 mg/kg. The controls received the drug vehicle. Mice were observed daily until day 30 postinfection. On day 18 postinfection, 50% protective doses (PD50s) were calculated by probit analysis. For quantitative tissue cultures, animals (five to eight per group) were treated for 4 days (C. neoformans) with the PD5Os or 5 days (C. immitis) with the PD25s. 48 h after the last dose, animals were sacrificed by cervical dislocation, and their brains were removed, homogenized, and serially diluted in saline. Homogenates and dilutions were plated on SDA (C. neoformans) or Mycosel agar (C. immitis) and incubated for 72 h at 37°C or 7 days at 25°C, respectively. CFU were then enumerated, and the number of colonies per gram of tissue was calculated. Azole concentrations in serum were determined by a modified gas liquid chromatography assay (9) after a single oral dose of 0.5 mg of 427 per kg, 5 mg of 304 per kg, and 50 mg of 426 per kg. The levels of 304 and 426 in serum peaked at 2 h, with 2.93 and 14.8 ,ug/ml, respectively. The peak of 427 was at the 6-h level with 0.61 pug/ml, indicating an even longer half-time in serum than that for 304. Mortality data were analyzed by probit procedure and Mantel Haenszel survival analysis. Newman Keuls multiple comparison was used to analyze quantitative culture studies. A P value less than 0.05 was considered significant. Table 1 demonstrates percent mortality after infection with C. neoformans. The highest dosages of 304 (5 mg/kg) and 426 (50 mg/kg) showed significant protection compared
Cryptococcal and coccidioidal meningitis are severe systemic fungal infections with high mortality and relapse rates after completion of treatment (1, 16). The standard treatment for both infections is amphotericin B plus additional flucytosine for cryptococcal meningitis. The major toxicities associated with this polyene (5, 12) have led to the development of new antifungal agents, most recently the triazoles, some of which are now clinically available. SCH 39304 (304) and its isomers, RR 42427 (427) and SS 42426 (426), are N-substituted triazole antifungal compounds. 304 is well absorbed after oral administration, has an extended half-life in serum and penetrates well into the cerebrospinal fluid (11). The compound possesses potent activity against a broad spectrum of fungi (10). 304 has been shown to be effective in the treatment of experimental cryptococcal and coccidioidal meningitis (3, 11). Because little is known about the efficacy of the isomers, we compared treatment with 304, 427, and 426 in cryptococcal and coccidioidal meningitis. ICR outbred mice (Harlan Sprague-Dawley), 6 to 8 weeks of age and weighing 30 g, were used for all experiments. The organisms utilized for infection were Cryptococcus neoformans variety neoformans (R-8998) and Coccidioides immitis (C735), which were maintained in stock cultures at 4°C on Sabouraud dextrose agar (SDA) slants or glucose yeast extract, respectively, until used. For infection, C. neoformans was cultured at 37°C for 72 h on SDA. Yeast cells were collected, washed twice with 0.9% saline, quantitated by using a hemacytometer, and adjusted to a concentration of 150 to 300 CFU/0.06 ml in saline. The endospores of C. immitis were prepared as previously described (8) and adjusted to 200 endospores per 0.06 ml in phosphate-buffered saline. Viable counts for both organisms were confirmed by quantitative culture. The above inocula were delivered to mice through a 26.5-gauge needle after puncturing the cranium midline. The azoles 304, 427, and 426 were provided by Schering Plough Research Corp., Bloomfield, N.J. The compounds *
Corresponding author. 217
Downloaded from http://aac.asm.org/ on March 8, 2015 by UCSF Library & CKM
Received 29 July 1991/Accepted 1 November 1991
218
NOTES
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. Efficacy between 304, 427, and 426 in treatment of cryptococcal meningitisa % Mortality at the following day postchallenge:
Azole and dose
(mg/kg)
14
16
18
20
22
24
26
28
30
427 0.05 0.1 0.2 0.5
10 30 0 0
40 30 0 0
70 40 10 0
80 40 40 10
80 60 50 40
80 60 80 40
80 70 80 50
90 70 80 50
90 70 90 50
90 80 90 80
304 0.2 0.5 1 5
10 10 0 0
30 10 0 0
50 40 10 0
70 60 40 0
80 70 70 10
80 90 80 30
80 90 90 30
80 90 90 40
80 90 90 50
80 90 90 50
426 1 5 25 50
40 30 0 0
70 50 20 0
80 70 60 10
90 70 60 30
90 80 80 40
100 80 100 60
80
80
80
90
60
70
70
80
None (control)
30
60
70
80
100
a The mice were challenged with 150 to 300 CFU per mouse (10 mice per group), treatment per os was given once daily for 10 days, and probit analysis was done on day 18. The PD50s were 0.11 mg/kg for 427, 0.56 mg/kg for 304, and 23.5 mg/kg for 426.
with controls at day 20 of infection. Isomer 427, however, provided protection even at 0.1 mg/kg. The PD50s were 0.56 mg/kg for 304, 23.5 mg/kg for 426, and 0.11 mg/kg for 427. By day 26 of infection, the effect of treatment with 5 mg of 304 per kg and 0.5 mg of 427 per kg was still apparent, because mortality rates were significantly lower than the mortality rate for the controls. Table 2 provides mortality rates of mice after infection with C. immitis. All animals in the control group succumbed by day 16 of infection. No dosages employed with 426 provided significant protection compared with controls. However, the other isomer, 427, delayed mortality significantly compared with controls (P < 0.05) at the higher
dosages administered (5 and 10 mg/kg), as did 304 at high doses of 10 and 20 mg/kg. Mortality was delayed more by 5 mg of 427 per kg than 5, 10, or even 20 mg of 304 per kg. Nevertheless, none of the compounds provided total protection, because nearly all mice succumbed by day 30 of infection. The PD5Os calculated for the compounds were 2.1 mg/kg for 427, 10.8 mg/kg for 304, and 200 mg/kg for 426. The tissue burden with C. neoformans after treatment with the compounds corresponding to the PD50s demonstrated a significant (P < 0.05) reduction of yeast cells comparing all treatment groups to controls (427 (0.4 0.3) x 107; 304, (0.1 0.1) x 107; 426, (0.4 0.3) x 107; control, (3.0 3.6) x 107). The brain burden with C. immitis after ±
±
±
±
TABLE 2. Efficacy between 304, 427, and 426 in treatment of murine coccidioidal meningitisa % Mortality at the following day postchallenge:
Azole and dose
(mg/kg)
12
14
16
18
20
22
24
26
28
30
427 0.5 1 5 10
40 20 0 0
50 30 0 0
80 50 11 0
80 70 22 20
80 80 33 20
80 80 33 20
80 90 55 30
90 90 55 30
90 90 77 70
90 90 88 80
304 1 5 10 20
22 10 0 0
66 30 0 10
100 50 33 30
100 70 55 30
100 70 55 50
70 77 80
80 88 90
80 88 90
80 88 90
80 88 90
426 5 10 20 50
50 40 66 30
100 60 88 60
100 90 88 70
100 90 88 80
100 90 88 80
90 88 80
90 88 90
90 88 90
90 88 90
90 88 90
None (control)
60
90
100
100
a The mice were challenged with 200 endospores per mouse (9 to 10 mice per group), treatment per os was given once daily for 10 days, and probit analysis was done on day 18. The PD5Os were 2.1 mg of 427 per kg, 10.8 mg of 304 per kg, and 200 mg of 426 per kg.
Downloaded from http://aac.asm.org/ on March 8, 2015 by UCSF Library & CKM
12
VOL. 36, 1992
This work was in part supported by a grant from Schering Plough Corp. REFERENCES 1. Bouza, E., J. S. Dreyer, W. L. Hewitt, and R. D. Meyer. 1981. Coccidioidal meningitis. An analysis of thirty-one cases and review of the literature. Medicine (Baltimore) 60:139-172. 2. Clemons, K. V., L. H. Hanson, A. M. Perlman, and D. A. Stevens. 1990. Efficacy of SCH 39304 and fluconazole in a murine model of disseminated coccidioidomycosis. Antimicrob. Agents Chemother. 35:928-930. 3. Defaveri, J., S. H. Sun, and J. R. Graybill. 1990. Treatment of murine coccidioidal meningitis with SCH39304. Antimicrob. Agents Chemother. 34:663-664. 4. Dismukes, W., G. Cloud, S. Thompson, A. Sugar, C. Tuazon, C. Kaufmann, M. Grieco, J. Jacobson, W. Powderly, and P. Robinson. 1989. Fluconazole versus amphotericin B therapy of acute cryptococcal meningitis, abstr. 1065. Program Abstr. 29th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, D.C. 5. Drutz, D. J. 1983. Amphotericin B in the treatment of coccidi-
219
oidomycosis. Drugs 26:337-346. 6. Galgiani, J. N., A. Catanzaro, J. R. Graybill, R. A. Larson, W. E. Dismukes, G. A. Cloud, and others of the NIAID Mycoses Study Group. 1990. Fluconazole therapy for coccidioidomycosis, abstr. 574. Program Abstr. 30th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, D.C. 7. Galgiani, J. N., J. Hostetler, A. Catanzaro, J. R. Graybill, R. A. Larson, R. Tucker, D. A. Stevens, and others of the NIAID Mycoses Study Group. 1991. Coccidioidal infections treated with SCH 39304, abstr. 3.107. Program Abstr. 11th Congress of the International Society for Human and Animal Mycology. International Society for Human and Animal Mycology, Montreal, Canada. 8. Graybill, J. R., S. H. Sun, and J. Ahrens. 1986. Treatment of murine coccidioidal meningitis with fluconazole (UK 49,858). J. Med. Vet. Mycol. 24:113-119. 8a.Graybill, J. R. Unpublished data. 9. Harris, S. C., J. E. Wallace, G. Foulds, and M. G. Rinaldi. 1989. Assay of fluconazole by megabore capillary gas liquid chromatography with nitrogen-selective detection. Antimicrob. Agents Chemother. 33:714-716. 10. McIntyre, K. A., and J. N. Galgiani. 1989. In vitro susceptibilities of yeasts to a new antifungal triazole, SCH 39304: effects of test conditions and relation to in vivo efficacy. Antimicrob. Agents Chemother. 33:1095-1100. 11. Perfect, J. R., K. A. Wright, M. M. Hobbs, and D. T. Durack. 1989. Treatment of cryptococcal meningitis and disseminated candidiasis with SCH 39304. Antimicrob. Agents Chemother. 33:1735-1740. 12. Stamm, A. M., R. B. Diasio, W. E. Dismukes, S. Shadomy, G. A. Cloud, C. A. Bowles, G. H. Karam, A. Espinel-Ingroff, and Additional members of the National Institute of Allergy and Infectious Diseases Mycoses Study Group. 1987. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am. J. Med. 83:236-242. 13. Tanio, T., K. Ichise, T. Nakajima, and T. Okuda. 1990. In vivo efficacy of SM-8668 (SCH 39304), a new oral triazole antifungal agent. Antimicrob. Agents Chemother. 34:980-984. 14. Tucker, R. M., D. W. Denning, B. Dupont, and D. A. Stevens. 1990. Itraconazole therapy for chronic coccidioidal meningitis. Ann. Intern. Med. 112:108-112. 15. Tucker, R. M., J. N. Galgiani, D. W. Denning, L. H. Hanson, J. R. Graybill, K. Sharkey, M. R. Eckman, C. Salemi, R. Libke, R. A. Klein, and D. A. Stevens. 1990. Treatment of coccidioidal meningitis with fluconazole. Rev. Infect. Dis. 12(Suppl. 3):380389. 16. Zugar, A., E. Louie, R. S. Holzman, M. S. Simberkoff, and J. J. Rahal. 1986. Cryptococcal disease in patients with the acquired immunodeficiency syndrome: diagnostic features and outcome of treatment. Ann. Intern. Med. 104:234-240.
Downloaded from http://aac.asm.org/ on March 8, 2015 by UCSF Library & CKM
treatment with the corresponding PD25 was not significantly different than those for the controls (427, (0.7 ± 6.8) x 106; 304, (7 + 2.3) x 106; 426, (3.7 + 1.7) x 106; control, (5 + 3.9) x 106). Currently, one alternative oral antifungal agent to amphotericin B (the standard treatment of coccidioidal meningitis) is itraconazole, which has been shown to be effective in a small series of patients with this disease (14) and exhibits relatively mild toxicities in contrast to ketoconazole. Fluconazole is active against cryptococcal meningitis (4) and is already widely used for maintenance therapy. It is also effective in coccidioidal meningitis (6, 15). Little is known about the potency of the isomers of 304. The present study demonstrates that both isomers are effective therapeutic agents against experimental cryptococcal meningitis, but only isomer 427 (at the dosages used) is efficacious against coccidioidal meningitis. Isomer 427 is far more active (at least 50 times) than 426 and approximately 5 times more potent than 304. Results of previous animal models with 304 were encouraging, because the compound was found to be more active in vivo against C. immitis and C. neoformans than fluconazole (2, 13). 304 had been introduced into clinical trials and appeared effective against several systemic fungal infections (7, 8a); however, its oncogenicity in rats will limit its clinical use to compassionate therapy.
NOTES
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1992, p. 217-219
0066-4804/92/010217-03$02.00/0 Copyright © 1992, American Society for Microbiology
Comparison of SCH 39304 and Its Isomers, RR 42427 and SS 42426, for Treatment of Murine Cryptococcal and Coccidioidal Meningitis R.
ALLENDOERFER,1 2* R. R. YATES,' A. J. MARQUIS,' D. LOEBENBERG,3
M. G. RINALDI,2'4 AND J. R. GRAYBILL" 2 Departments of Medicine' and Pathology,4 University of Texas Health Science Center at San Antonio, and Audie L. Murphy V. A. Hospital,2 San Antonio, Texas 78284, and Schering Plough Research Corp., Bloomfield, New Jersey 070033
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.
were suspended in 0.3% Noble agar and administered per os by gavage in a volume of 0.2 ml per dose. To assess mortality, treatment against both infections was initiated 24 h postinfection and was given for 10 consecutive days. The doses for 304 were chosen on the basis of our previous studies of efficacy; the doses for the isomers were chosen according to the manufacturer's recommendation. The following dosages were given once daily to treat cryptococcal meningitis: for 304, 0.2, 0.5, 1, and 5 mg/kg of body weight; for 427, 0.05, 0.1, 0.2, and 0.5 mg/kg; and for 426, 5, 10, 20, and 50 mg/kg). The dosages used to treat coccidioidal meningitis were as follows: for 304, 1, 5, 10, and 20 mg/kg; for 427, 0.5, 1, 5, and 10 mg/kg; and for 426, 5, 10, 20, and 50 mg/kg. The controls received the drug vehicle. Mice were observed daily until day 30 postinfection. On day 18 postinfection, 50% protective doses (PD50s) were calculated by probit analysis. For quantitative tissue cultures, animals (five to eight per group) were treated for 4 days (C. neoformans) with the PD5Os or 5 days (C. immitis) with the PD25s. 48 h after the last dose, animals were sacrificed by cervical dislocation, and their brains were removed, homogenized, and serially diluted in saline. Homogenates and dilutions were plated on SDA (C. neoformans) or Mycosel agar (C. immitis) and incubated for 72 h at 37°C or 7 days at 25°C, respectively. CFU were then enumerated, and the number of colonies per gram of tissue was calculated. Azole concentrations in serum were determined by a modified gas liquid chromatography assay (9) after a single oral dose of 0.5 mg of 427 per kg, 5 mg of 304 per kg, and 50 mg of 426 per kg. The levels of 304 and 426 in serum peaked at 2 h, with 2.93 and 14.8 ,ug/ml, respectively. The peak of 427 was at the 6-h level with 0.61 pug/ml, indicating an even longer half-time in serum than that for 304. Mortality data were analyzed by probit procedure and Mantel Haenszel survival analysis. Newman Keuls multiple comparison was used to analyze quantitative culture studies. A P value less than 0.05 was considered significant. Table 1 demonstrates percent mortality after infection with C. neoformans. The highest dosages of 304 (5 mg/kg) and 426 (50 mg/kg) showed significant protection compared
Cryptococcal and coccidioidal meningitis are severe systemic fungal infections with high mortality and relapse rates after completion of treatment (1, 16). The standard treatment for both infections is amphotericin B plus additional flucytosine for cryptococcal meningitis. The major toxicities associated with this polyene (5, 12) have led to the development of new antifungal agents, most recently the triazoles, some of which are now clinically available. SCH 39304 (304) and its isomers, RR 42427 (427) and SS 42426 (426), are N-substituted triazole antifungal compounds. 304 is well absorbed after oral administration, has an extended half-life in serum and penetrates well into the cerebrospinal fluid (11). The compound possesses potent activity against a broad spectrum of fungi (10). 304 has been shown to be effective in the treatment of experimental cryptococcal and coccidioidal meningitis (3, 11). Because little is known about the efficacy of the isomers, we compared treatment with 304, 427, and 426 in cryptococcal and coccidioidal meningitis. ICR outbred mice (Harlan Sprague-Dawley), 6 to 8 weeks of age and weighing 30 g, were used for all experiments. The organisms utilized for infection were Cryptococcus neoformans variety neoformans (R-8998) and Coccidioides immitis (C735), which were maintained in stock cultures at 4°C on Sabouraud dextrose agar (SDA) slants or glucose yeast extract, respectively, until used. For infection, C. neoformans was cultured at 37°C for 72 h on SDA. Yeast cells were collected, washed twice with 0.9% saline, quantitated by using a hemacytometer, and adjusted to a concentration of 150 to 300 CFU/0.06 ml in saline. The endospores of C. immitis were prepared as previously described (8) and adjusted to 200 endospores per 0.06 ml in phosphate-buffered saline. Viable counts for both organisms were confirmed by quantitative culture. The above inocula were delivered to mice through a 26.5-gauge needle after puncturing the cranium midline. The azoles 304, 427, and 426 were provided by Schering Plough Research Corp., Bloomfield, N.J. The compounds *
Corresponding author. 217
Downloaded from http://aac.asm.org/ on March 8, 2015 by UCSF Library & CKM
Received 29 July 1991/Accepted 1 November 1991
218
NOTES
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. Efficacy between 304, 427, and 426 in treatment of cryptococcal meningitisa % Mortality at the following day postchallenge:
Azole and dose
(mg/kg)
14
16
18
20
22
24
26
28
30
427 0.05 0.1 0.2 0.5
10 30 0 0
40 30 0 0
70 40 10 0
80 40 40 10
80 60 50 40
80 60 80 40
80 70 80 50
90 70 80 50
90 70 90 50
90 80 90 80
304 0.2 0.5 1 5
10 10 0 0
30 10 0 0
50 40 10 0
70 60 40 0
80 70 70 10
80 90 80 30
80 90 90 30
80 90 90 40
80 90 90 50
80 90 90 50
426 1 5 25 50
40 30 0 0
70 50 20 0
80 70 60 10
90 70 60 30
90 80 80 40
100 80 100 60
80
80
80
90
60
70
70
80
None (control)
30
60
70
80
100
a The mice were challenged with 150 to 300 CFU per mouse (10 mice per group), treatment per os was given once daily for 10 days, and probit analysis was done on day 18. The PD50s were 0.11 mg/kg for 427, 0.56 mg/kg for 304, and 23.5 mg/kg for 426.
with controls at day 20 of infection. Isomer 427, however, provided protection even at 0.1 mg/kg. The PD50s were 0.56 mg/kg for 304, 23.5 mg/kg for 426, and 0.11 mg/kg for 427. By day 26 of infection, the effect of treatment with 5 mg of 304 per kg and 0.5 mg of 427 per kg was still apparent, because mortality rates were significantly lower than the mortality rate for the controls. Table 2 provides mortality rates of mice after infection with C. immitis. All animals in the control group succumbed by day 16 of infection. No dosages employed with 426 provided significant protection compared with controls. However, the other isomer, 427, delayed mortality significantly compared with controls (P < 0.05) at the higher
dosages administered (5 and 10 mg/kg), as did 304 at high doses of 10 and 20 mg/kg. Mortality was delayed more by 5 mg of 427 per kg than 5, 10, or even 20 mg of 304 per kg. Nevertheless, none of the compounds provided total protection, because nearly all mice succumbed by day 30 of infection. The PD5Os calculated for the compounds were 2.1 mg/kg for 427, 10.8 mg/kg for 304, and 200 mg/kg for 426. The tissue burden with C. neoformans after treatment with the compounds corresponding to the PD50s demonstrated a significant (P < 0.05) reduction of yeast cells comparing all treatment groups to controls (427 (0.4 0.3) x 107; 304, (0.1 0.1) x 107; 426, (0.4 0.3) x 107; control, (3.0 3.6) x 107). The brain burden with C. immitis after ±
±
±
±
TABLE 2. Efficacy between 304, 427, and 426 in treatment of murine coccidioidal meningitisa % Mortality at the following day postchallenge:
Azole and dose
(mg/kg)
12
14
16
18
20
22
24
26
28
30
427 0.5 1 5 10
40 20 0 0
50 30 0 0
80 50 11 0
80 70 22 20
80 80 33 20
80 80 33 20
80 90 55 30
90 90 55 30
90 90 77 70
90 90 88 80
304 1 5 10 20
22 10 0 0
66 30 0 10
100 50 33 30
100 70 55 30
100 70 55 50
70 77 80
80 88 90
80 88 90
80 88 90
80 88 90
426 5 10 20 50
50 40 66 30
100 60 88 60
100 90 88 70
100 90 88 80
100 90 88 80
90 88 80
90 88 90
90 88 90
90 88 90
90 88 90
None (control)
60
90
100
100
a The mice were challenged with 200 endospores per mouse (9 to 10 mice per group), treatment per os was given once daily for 10 days, and probit analysis was done on day 18. The PD5Os were 2.1 mg of 427 per kg, 10.8 mg of 304 per kg, and 200 mg of 426 per kg.
Downloaded from http://aac.asm.org/ on March 8, 2015 by UCSF Library & CKM
12
VOL. 36, 1992
This work was in part supported by a grant from Schering Plough Corp. REFERENCES 1. Bouza, E., J. S. Dreyer, W. L. Hewitt, and R. D. Meyer. 1981. Coccidioidal meningitis. An analysis of thirty-one cases and review of the literature. Medicine (Baltimore) 60:139-172. 2. Clemons, K. V., L. H. Hanson, A. M. Perlman, and D. A. Stevens. 1990. Efficacy of SCH 39304 and fluconazole in a murine model of disseminated coccidioidomycosis. Antimicrob. Agents Chemother. 35:928-930. 3. Defaveri, J., S. H. Sun, and J. R. Graybill. 1990. Treatment of murine coccidioidal meningitis with SCH39304. Antimicrob. Agents Chemother. 34:663-664. 4. Dismukes, W., G. Cloud, S. Thompson, A. Sugar, C. Tuazon, C. Kaufmann, M. Grieco, J. Jacobson, W. Powderly, and P. Robinson. 1989. Fluconazole versus amphotericin B therapy of acute cryptococcal meningitis, abstr. 1065. Program Abstr. 29th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, D.C. 5. Drutz, D. J. 1983. Amphotericin B in the treatment of coccidi-
219
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treatment with the corresponding PD25 was not significantly different than those for the controls (427, (0.7 ± 6.8) x 106; 304, (7 + 2.3) x 106; 426, (3.7 + 1.7) x 106; control, (5 + 3.9) x 106). Currently, one alternative oral antifungal agent to amphotericin B (the standard treatment of coccidioidal meningitis) is itraconazole, which has been shown to be effective in a small series of patients with this disease (14) and exhibits relatively mild toxicities in contrast to ketoconazole. Fluconazole is active against cryptococcal meningitis (4) and is already widely used for maintenance therapy. It is also effective in coccidioidal meningitis (6, 15). Little is known about the potency of the isomers of 304. The present study demonstrates that both isomers are effective therapeutic agents against experimental cryptococcal meningitis, but only isomer 427 (at the dosages used) is efficacious against coccidioidal meningitis. Isomer 427 is far more active (at least 50 times) than 426 and approximately 5 times more potent than 304. Results of previous animal models with 304 were encouraging, because the compound was found to be more active in vivo against C. immitis and C. neoformans than fluconazole (2, 13). 304 had been introduced into clinical trials and appeared effective against several systemic fungal infections (7, 8a); however, its oncogenicity in rats will limit its clinical use to compassionate therapy.
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