Oleanolic acid displayed anti-inflammatory activity in carrageenan and dextran-induced oedema in rats. It elicited marked anti-arthritic action in adjuvant-induced polyarthritis in rats and mice and in formaldehyde-induced arthritis in rats. Oleanolic acid checked the inflammation-induced increased serum transaminase levels. It reduced exudate volume and inhibited leucocyte infiltration in carrageenan-induced pleurisy in rats. It is devoid of any analgesic, antipyretic or ulcerogenic action. Oleanolic acid did not affect the parturition time in pregnant rats or castor oil-induced diarrhoea in rats. Oral LD50 was found to be greater than 2 g kg-1 in mice and rats.
Pharmacological evaluation of alcoholic extract of salai guggal (AESG) has been carried out in experimental animals. AESG displayed marked anti-inflammatory activity in carrageenan induced oedema in rats and mice and dextran oedema in rats. It was equally effective in adrenalectomised rats. In formaldehyde and adjuvant arthritis, AESG produced prominent anti-arthritic activity but no significant effect was observed in cotton pellet-induced granuloma test. It inhibited inflammation induced increase in serum transaminase levels and leucocyte counts but lacked any analgesic or anti-pyretic effects. The gestation period or parturition time in pregnant rats or onset time of castor oil-induced diarrhoea was unaffected by AESG and no significant effect was seen on cardiovascular, respiratory and central nervous system functions. No ulcerogenic effects were found in the rat stomach. The oral and intraperitoneal LD50 was greater than 2 g/Kg in mice and rats.
Suspensions of rat peritoneal polymorphonuclear leukocytes (PMNL) elicited with glycogen were stimulated by calcium and ionophore to produce leukotrienes and 5-HETE from endogenous arachidonic acid (AA). We investigated the effect of ethanolic extracts of the gum resin exudate of Boswellia serrata. A concentration-dependent inhibition of LTB4 and 5-HETE production by different charges of exudate extracts were found. All products of the 5-lipoxygenase (5-LOx) from endogenous arachidonic acid (AA) in PMNL were reduced to the same extent by the extracts tested. The ethanolic extract of the gum resin also decreased 5-LOx mediated metabolisation of exogenously added AA to LTB4 and 5-HETE. Since steroidal-type anti-inflammatory drugs do not exert an immediate effect in the test system used, we conclude that the activity of the 5-LOx itself represents the side of inhibition by the gum resin extract. Therefore, an inhibition of 5-LOx catalysed mediator synthesis might be involved in the previously reported anti-inflammatory activity in vivo.
Studies were done to develop a murine model that mimics the pattern of mucosal candidiasis followed by disseminated disease seen in patients given cytotoxic chemotherapy. Developmental studies showed that suppression of mice with 5-fluorouracil beginning 3 days prior to infection and given every 7 days thereafter necessitated antibacterial treatment but resulted in a reproducible model. Candida albicans given in the drinking water resulted in oral infection by day 3 that significantly increased from days 10 to 15 and mucosal infection with 4 to 7 log 10 Candida CFU in the esophagus, stomach, small intestine, and cecum. Dissemination to livers occurred and was 100% on days 5 to 15; fewer animals had kidney infection. The median kidney or liver CFU were 2 or 3 log 10 CFU, respectively, on day 15; despite this, mortality was low through 21 days of infection. As a demonstration of the utility of the model to test antifungal activity, daily treatment with 10 or 50 mg/kg itraconazole significantly reduced dissemination to the liver and kidneys and reduced tongue CFU compared to controls. Overall, these studies indicate that a nonlethal model of oral and gastrointestinal mucosal candidiasis with dissemination can be established in mice. Drug efficacy in treating localized infection and in preventing or treating disseminated infection can be studied.Candidiasis of the oral mucosal surfaces and the intestinal tract is problematic for a variety of patient populations. Those at the highest risk include those with AIDS and those on immunosuppressive therapy (e.g., cancer chemotherapy or high-dose steroids). We previously reported a model of orogastrointestinal mucosal candidiasis that closely mimics the clinical manifestations observed in AIDS patients and demonstrated its utility for the study of therapeutics (5, 7). Although quite useful, this model does not result in the translocation of Candida albicans across the intestinal mucosa to cause disseminated disease (5, 7). Disseminated candidiasis in cancer chemotherapy patients is thought to arise from the translocation of C. albicans across gut mucosa damaged from chemotherapy treatment. A murine model of gastrointestinal candidiasis mimicking this situation and resulting in systemic dissemination and death has been previously reported (35). However, our attempts to replicate this model resulted in minimal dissemination and little to no lethality due to Candida albicans. In addition, others have previously reported inconsistent or no dissemination from gut tissues in similar models (3,9,10,34,45,46). The goal of the present studies was to further develop and standardize a model of disseminated disease arising from translocation from gut colonization, induce oral mucosal disease, and determine the utility of this model for the study of therapeutic intervention.
MATERIALS AND METHODSMice. Female CD-1 mice (Charles River Laboratories, Portage, Mich.) were used in all studies. Animals were 7 weeks of age in experiment 1 and 5 weeks of age in other experiments. Mice were cage...
We have reported previously that prolonged caspofungin (CAS) dosing enhances survival in a murine model of central nervous system aspergillosis. In this study we determined by quantitative PCR (qPCR) and CFU enumeration whether CAS could reduce fungal burdens, prior to the deaths of untreated animals, and also assessed progressive infection in untreated mice. Mice were infected intracranially and treated for 4 days with CAS (1, 5, or 10 mg/kg of body weight/day) or amphotericin B (AMB) (3 mg/kg/day) starting 1 day postinfection. Fungal burdens in brains and kidneys of untreated controls were determined on days 1, 3, and 5 to assess progressive infection; burdens in treated animals were determined on day 5. qPCR showed higher burdens than CFU enumeration in all comparisons. In untreated animals, qPCR showed transiently increased burdens in brains, while CFU enumeration showed a decrease. qPCR showed increased burdens in kidneys, but CFU enumeration did not. Neither method indicated drug efficacy in the brain. Both methods showed AMB efficacy in the kidneys, and qPCR demonstrated CAS efficacy at all doses. Spearman correlations of qPCR and CFU determination results showed a significant correlation for most untreated groups; results correlated well for kidneys (P < 0.03) but not for brains in treated mice. Regression analyses of qPCR and CFU groups indicated different slopes for progressive infection in untreated animals but the same slopes for CAS dose-response efficacy. qPCR appeared to better reflect the progression of untreated infection. The lack of demonstration of efficacy in the brain suggests that longer dosing is necessary to cause burden reduction. These results also suggest that, when there is drug efficacy in a therapeutic study, either method appears to be useful for determining Aspergillus fumigatus burdens.
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