A porcine model was established to test the mucosal toxicity potential of a thiophene thiourea (PHI-443)-based anti-HIV microbicide and a vanadocene-based spermicide, vanadocene dithiocarbamate (VDDTC) in comparison to benzalkonium chloride (BZK). Nine domestic pigs (Duroc) in nonestrus stage received a single intravaginal application of 2% BZK, 2% PHI-443, or 0.1% VDDTC-containing gel. At various times after gel application, cell differentials and levels of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, IL-18, IFN-γ , and TNF-α) in cervicovaginal lavage (CVL) fluid were monitored by flow cytometry and ELISA, respectively. Eight pigs were exposed intravaginally to a gel with and without BZK or VDDTC for 4 consecutive days and vaginal tissues were scored histologically for inflammation using a new scoring system. Only CVL fluid from pigs exposed to BZK showed a significant increase of IL-1β, IL-8, and also IL-18 production when compared to the controls, PHI-443 or VDDTC-treated groups. Maximum levels of BZK-induced IL-1β (100-fold), IL-8 (2,500-fold), IL-18 (80-fold), and IFN-γ (10-fold) were found at 24 hours. In the in vivo porcine vaginal irritation model, increased levels of vaginal IL-1β, IL-8, and IL-18 were associated with histological changes consistent with vaginal inflammation. These results demonstrate that key cervicovaginal inflammatory cytokines are useful in vivo biomarkers for predicting the mucosal toxicity potential of vaginal products in the physiologically relevant and sensitive porcine model.
The in vivo toxicity and pharmacokinetics of stampidine (CAS 217178-62-6), an aryl phosphate derivative of stavudine (CAS 3056-17-5) under development as a new anti-human immunodeficiency virus (anti-HIV) agent, were studied in mice and rats. Stampide was very well tolerated by both mice and rats without any toxicity at cumulative dose levels > 1 g/kg. Therapeutic micromolar plasma concentrations of stampidine and its active metabolites ala-STV-MP (CAS 180076-92-0) and STV were rapidly achieved and maintained several hours after i.p. administration of the nontoxic 25-50 mg/kg bolus doses of stampidine. The remarkable in vivo safety of stampidine warrants the further development of this promising new antiviral agent for possible clinical use in HIV-infected patients.
The leflunomide (CAS 75706-12-6) metabolite (LFM) analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, DDE-28, CAS 244240-24-2) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK). LFM-A13 exhibited favorable pharmacokinetics in CD-1 mice, BALB/c mice, rats, and dogs. The intraperitoneal bioavailability was estimated to be -100%, while the oral bioavailability was -30%. LFM-A13 enters, but does not bind to multiple tissues followed by a rapid elimination from most of the tissues. Limited distribution of LFM-A13 to extravascular tissues and its corresponding low volume of distribution could be attributed to its plasma protein binding. LFM-A13 was not toxic to mice, rats, or dogs at daily dose levels as high as 100 mg/kg. LFM-A13 formulated as a suspension and hard gelatin capsules for oral administration showed a rapid absorption and favorable pharmacokinetic features. These preclinical research studies provide the basis for future pre-IND studies and clinicaldevelopment of LFM-A13 as an intravenously or orally administered new anti-leukemia agent targeting BTK.
N'-[2-(2-Thiophene)ethyl]-N'-[2-(5bromopyridyl)]thiourea (CAS 258340-15-7, HI-443) is a potent non-nucleoside inhibitor of HIV reverse transcriptase (NNRTI) that was rationally designed as a candidate anti-HIV agent. The purpose of the present study was to examine the in vivo pharmacokinetics, metabolism, toxicity, and anti-HIV activity of HI-443. HI-443 was very well tolerated in CD-1 mice and Lewis rats without any detectable toxicity at single parenteral bolus dose levels as high as 80 mg/kg. Intraperitoneally administered HI-443 exhibited anti-HIV activity in the Hu-PBL-SCID mouse surrogate model for hunnan AIDS at a non-toxic daily dose level of 10-20 mg/kg. These preclinical research studies provide the basis for future preclinical studies and clinical development of HI-443 as a new NNRTI candidate.
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