Antiretroviral Spermicide WHI-07 Prevents Vaginal and Rectal Transmission of Feline Immunodeficiency Virus in Domestic Cats

D’Cruz, Osmond J.; Waurzyniak, Barbara; Uckun, Fatih M.

doi:10.1128/aac.48.4.1082-1088.2004

Cited by 29 publications

(24 citation statements)

References 57 publications

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“…Spermicidal organometallic complexes of vanadium(IV) with bis(cyclopentadienyl) rings or vanadocenes are a new class of experimental contraceptive agents (D'Cruz and Uckun, 1998;D'Cruz et al, 1998aD'Cruz et al, , 1998b. Among the 45 vanadocene complexes that were synthesized and tested for human spermicidal activity, vanadocene dithiocarbamate (VDDTC) was identified as the lead candidate for preclinical studies (D'Cruz et al, 2001(D'Cruz et al, , 2004cD'Cruz and Uckun, 2001b). Among the 30 thiourea nonnucleoside reverse transcriptase inhibitors (NNRTI) of HIV-1 that were rationally designed, synthesized, and tested for anti-HIV activity, PHI-443 (N -[2-(2-thiophene)ethyl]-N -[2-(5-bromopyridyl)]thiourea), was identified as a broad-spectrum noncontraceptive anti-HIV microbicide (D'Cruz et al, 2000(D'Cruz et al, , 2003(D'Cruz et al, , 2004a.…”

Section: Introductionmentioning

confidence: 99%

A Study of the Potential of the Pig as a Model for the Vaginal Irritancy of Benzalkonium Chloride in Comparison to the Nonirritant Microbicide PHI-443 and the Spermicide Vanadocene Dithiocarbamate

D’Cruz

Erbeck²,

Uckun

2005

Toxicol Pathol

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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.

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Section: Introductionmentioning

confidence: 99%

A Study of the Potential of the Pig as a Model for the Vaginal Irritancy of Benzalkonium Chloride in Comparison to the Nonirritant Microbicide PHI-443 and the Spermicide Vanadocene Dithiocarbamate

D’Cruz

Erbeck²,

Uckun

2005

Toxicol Pathol

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“…These contributions are highlighted by the recent approval of the first animal lentivirus vaccine (Huang et al 2004;Pu et al 2001;Uhl et al 2002). In addition, studies on FIV have contributed to our understanding of the mechanisms of immune suppression (Vahlenkamp et al 2005) and have been used for the evaluation of antiretroviral therapeutics (Arai et al 2002;Bisset et al 2002;de Rozieres et al 2004;Egberink et al 1990;Hartmann et al 1992;Hayes et al 1995), the testing of virus penetration of mucosal barriers (Burkhard et al 2002;Burkhard and Dean 2003;D'Cruz et al 2004;Obert and Hoover 2002), the efficacy of topical antiviral treatments (D'Cruz et al 2004), and the analysis of the efficacy of entry inhibitors (Garg et al 2004). These studies highlight the diverse contributions of FIV to lentiviral pathogenesis, which cannot all be adequately covered in this review.…”

Section: Fiv: a Lentivirus Similar To Hivmentioning

confidence: 99%

Feline Immunodeficiency Virus Neuropathogenesis: From Cats to Calcium

Meeker

2006

Jrnl Neuroimmune Pharm

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Invasion of human immunodeficiency virus (HIV) into the central and peripheral nervous system produces a wide range of neurological symptoms, which continue to persist even with adequate therapeutic suppression of the systemic viremia. The development of therapies designed to prevent the neurological complications of HIV require a detailed understanding of the mechanisms of virus penetration into the nervous system, infection, and subsequent neuropathogenesis. These processes, however, are difficult to study in humans. The identification of animal lentiviruses similar to HIV has provided useful models of HIV infection that have greatly facilitated these efforts. This review summarizes contributions made from in vitro and in vivo studies on the infectious and pathological interactions of feline immunodeficiency virus (FIV) with the nervous system. In vivo studies on FIV have provided insights into the natural progression of CNS disease as well as the contribution of various risk factors. In vitro studies have contributed to our understanding of immune cell trafficking, CNS infection and neuropathogenesis. Together, these studies have made unique contributions to our understanding of (1) lentiviral interactions at the blood-cerebrospinal fluid (CSF) barrier within the choroid plexus, (2) early FIV invasion and pathogenesis in the brain, and (3) lentiviral effects on intracellular calcium deregulation and neuronal dysfunction. The ability to combine in vitro and in vivo studies on FIV offers enormous potential to explore neuropathogenic mechanisms and generate information necessary for the development of effective therapeutic interventions.

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“…Microbicides that are currently being investigated are directed mainly at preventing pregnancy and protection against sexually transmitted HIV-1 (1,(5)(6)(7)(8). However, the availability of a nonspermicidal prophylactic microbicide is equally important for allowing sexually active women to have children while protecting both mother and child from HIV-1 infection and for the prevention of transmission of HIV-1 by semen, especially for HIV-1 serodiscordant couples, before assisted reproductive technology (ART) procedures.…”

mentioning

confidence: 98%

Mucosal safety of PHI-443 and stampidine as a combination microbicide to prevent genital transmission of HIV-1

D’Cruz

Uckun

2007

Fertility and Sterility

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Antiretroviral Spermicide WHI-07 Prevents Vaginal and Rectal Transmission of Feline Immunodeficiency Virus in Domestic Cats

Cited by 29 publications

References 57 publications

A Study of the Potential of the Pig as a Model for the Vaginal Irritancy of Benzalkonium Chloride in Comparison to the Nonirritant Microbicide PHI-443 and the Spermicide Vanadocene Dithiocarbamate

A Study of the Potential of the Pig as a Model for the Vaginal Irritancy of Benzalkonium Chloride in Comparison to the Nonirritant Microbicide PHI-443 and the Spermicide Vanadocene Dithiocarbamate

Feline Immunodeficiency Virus Neuropathogenesis: From Cats to Calcium

Mucosal safety of PHI-443 and stampidine as a combination microbicide to prevent genital transmission of HIV-1

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