Effectiveness of dehydroepiandrosterone in reduction of cryptosporidial activity in immunosuppressed rats

Rasmussen, Kathleen R.; Arrowood, Michael J.; Healey, Mark C.

doi:10.1128/aac.36.1.220

Cited by 38 publications

(19 citation statements)

References 10 publications

(9 reference statements)

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“…The steroid hormone DHEA has been shown to be effective against Cryptosporidium infections in immunosuppressed rats (13,14). When administered subcutaneously twice a day (120 mg/kg/day) for 8 days, this hormone significantly lowered the pocyst excretion score for a group of animals that had been infected 5 weeks earlier, but it failed to significantly reduce the score for animals that had been infected more than 3 months earlier (Fig.…”

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“…Steroid-immunosuppressed rats and mice have been extensively used in drug evaluation studies, and several agents have been found to be effective with such animal models (3,4,8,9,(13)(14)(15)(16). Such studies have been undertaken with short-term infections (3 weeks or less), with the agents often being administered a few hours before or after the inoculation of infecting oocysts or prior to the time of maximum oocyst excretion.…”

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“…Splenectomized animals could be infected with a smaller number of oocysts and generally had a higher oocyst excretion score than did intact animals. Splenectomy has been used to exacerbate parasitic infections (7) and in tumor transplantation studies to reduce residual immunity in nude mice (20).In the present study, agents were used that had been demonstrated to possess anticryptosporidial activity with immunosuppressed rat and mouse models (3,4,8,9,13,14). Three agents were tested here, the ionophore lasalocid, the steroid hormone dehydroepiandrosterone (DHEA), and the natural nucleoside antibiotic sinefungin.…”

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“…In the present study, agents were used that had been demonstrated to possess anticryptosporidial activity with immunosuppressed rat and mouse models (3,4,8,9,13,14). Three agents were tested here, the ionophore lasalocid, the steroid hormone dehydroepiandrosterone (DHEA), and the natural nucleoside antibiotic sinefungin.…”

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Putative anticryptosporidial agents tested with an immunodeficient mouse model

Leitch

1994

Antimicrob Agents Chemother

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Lasalocid, sinefungin, and dehydroepiandrosterone were tested for anticryptosporidial activity with an immunodeficient mouse model at doses that have been reported effective when tested with immunosuppressed rodent models. Small but significant reductions in oocyst excretion were only observed under some conditions with lasalocid and dehydroepiandrosterone, but sinefungin had no elfect.Cryptosporidiosis is an enteric protozoan parasitic disease of animals and humans that is self-limiting in the immunocompetent host, but it may cause persistent diarrhea and severe malabsorption in the immunodeficient host (5, 17). Chronic cryptosporidiosis makes a contribution to the morbidity and mortality of a significant number of AIDS patients (10), with the result that finding effective anticryptosporidial chemotherapeutic agents has become a major priority. In spite of a number of promising preliminary clinical reports (1,12), no effective agent has been found (17).Several immunodeficient and immunosuppressed animal models have been employed to study the pathophysiology of the Cryptosporidium infection and to evaluate the efficacies of potential antiparasitic agents (3, 4, 8, 9, 11, 13-16, 18, 19). Steroid-immunosuppressed rats and mice have been extensively used in drug evaluation studies, and several agents have been found to be effective with such animal models (3,4,8,9,(13)(14)(15)(16). Such studies have been undertaken with short-term infections (3 weeks or less), with the agents often being administered a few hours before or after the inoculation of infecting oocysts or prior to the time of maximum oocyst excretion. The present study compares the anticryptosporidial effects of such agents by using a chronic immunodeficient mouse model rather than an immunosuppressed rodent model.Immunodeficient mouse model. Young adult intact or splenectomized male athymic nude mice were purchased from Harlan Sprague-Dawley Inc. (Indianapolis, Ind.). Cryptosporidium parvum, originally of calf origin, has been carried in a colony of these animals for over 2 years. Oocysts were isolated from the feces of infected mice (2) and administered per os. Oocyst excretion was monitored by collecting five fresh fecal pellets, macerating them in 2 ml of neutral formalin, and counting the number of oocysts visualized in a 10-,ul sample of this homogenate by a commercially available immunofluorescent assay (Meridian Diagnostics Inc., Cincinnati, Ohio). The following oocyst excretion score was developed: based on the oocyst counts of the 10-,ul samples, 0, no oocysts; 1, <10 oocysts; 2, 11 to 50 oocysts; 3, 51 to 100 oocysts; 4, >100 oocysts.When a histological study was performed with chronically (>3 months) infected nude mice, linear relationships were found between the oocyst excretion score (y) and the percentage of infected ileal villus cells (x1), described by the equation 755-7318. y = 0.76 + 0.092x1 (r = 0.888), and between the oocyst excretion score and the percentage of infected ileal crypt cells (x2), described by the equation y = 0.06...

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Putative anticryptosporidial agents tested with an immunodeficient mouse model

Leitch

1994

Antimicrob Agents Chemother

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“…Among a series of data showing its inhibitory effect on breast cancer, DHEA blocked the stimulatory effect of N-nitroso-N-methylurea on mammary tumor development in the rat by a p16-dependent mechanism (Shilkaitis et al 2005). DHEA has also been shown to have immunomodulatory effects in vitro (Suzuki et al 1991) and in vivo in fungal and viral diseases (Rasmussen et al 1992). On the other hand, a stimulatory effect of DHEA on the immune system has been described in postmenopausal women (Casson et al 1993).…”

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Future perspectives of selective estrogen receptor modulators used alone and in combination with DHEA

Labrie

2006

Endocr Relat Cancer

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Breast cancer is the most frequently diagnosed and the second cause of cancer death in women, thus making breast cancer a most feared disease. Since breast cancer metastasizes early and it is unlikely that improvements in the treatment of metastatic disease could permit a cure in most cases in the foreseeable future, it is clear that prevention is essential in order practically to eliminate deaths from breast cancer. Tamoxifen is the only selective estrogen receptor modulator (SERM) currently registered for use in breast cancer prevention; the tamoxifen versus raloxifene study should indicate the efficacy of this compound compared with raloxifene. The recent benefits of aromatase inhibitors over tamoxifen indicate the advantages of a blockade of estrogens more complete than the one achieved with tamoxifen, a SERM having some estrogenic activity in the mammary gland and an even higher estrogenic action in the uterus. However, it is unlikely that the general estrogen ablation achieved with aromatase inhibitors will be acceptable for the long-term use required for prevention. It is thus important to develop SERMs with highly potent and pure antagonistic activity in the mammary gland and uterus while possessing estrogen-like activity in tissues of particular importance for women's health, namely the bones and the cardiovascular system. However, it is expected that a SERM alone will not meet all the requirements of women's health at the postmenopause when ovarian estrogen secretion has ceased and peripheral formation of androgens and estrogens from DHEA by intracrine mechanisms is decreased by 60% or more. One possibility is to combine a SERM with DHEA, a precursor of sex steroids that permits, somewhat like SERMs, tissue-specific formation of androgens and/or estrogens according to the level of expression of the steroidogenic and steroid-inactivating enzymes. DHEA could thus compensate for the important loss of androgens that accompanies aging and could also permit sex steroid formation and action in the brain while breast cancer prevention would be achieved by the SERM.

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