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Fatih M. Uckun - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of subchronic 13 week and reproductive toxicity potential of intravaginal gel microemulsion formulation of a dual function Phenyl Phosphate derivative of bromo methoxy zidovudine compound whi 07 in b6c3f1 mice
    Journal of Applied Toxicology, 2000
    Co-Authors: Osmond J Dcruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the USA. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromoPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. In vivo toxicity studies in non-human primates and rodents given WHI-07 (20 mg kg−1) intravenously and intraperitonealy, respectively, had no detectable adverse effects on hematological and clinical chemistry profiles. The 13-week subchronic and reproductive toxicity potential of an intravaginal gel–microemulsion formulation of WHI-07 was studied in mice to support its further development as a dual-function microbicide. Groups of ten female B6C3F1 mice were exposed intravaginally to a gel–microemulsion formulation containing 0, 0.5, 1.0 or 2.0% WHI-07, 5 days a week, for 13 consecutive weeks. On a molar basis, these concentrations represent 1400–5700 times their in vitro spermicidal potency EC50) and 1.4 × 106–5.7 × 106 times their in vitro anti-HIV activity50). After 13 weeks of intravaginal treatment, half of the treated mice were evaluated for toxicity and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. The endpoints that were evaluated included survival, body weight gain, hematological and clinical chemistries, absolute and relative organ weights and histopathology. The WHI-07 applications did not cause weight loss, morbidity, mortality or specific tissue lesions detectable by histopathology. Repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>95%) or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent WHI-07 did not cause significant acute or subchronic toxicity. Copyright © 2000 John Wiley & Sons, Ltd.

  • Evaluation of subchronic (13-week) and reproductive toxicity potential of intravaginal gel–microemulsion formulation of a dual-function Phenyl Phosphate derivative of bromo-methoxy zidovudine (compound whi-07) in B6C3F1 mice
    Journal of applied toxicology : JAT, 2000
    Co-Authors: Osmond J. D'cruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the USA. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromoPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. In vivo toxicity studies in non-human primates and rodents given WHI-07 (20 mg kg−1) intravenously and intraperitonealy, respectively, had no detectable adverse effects on hematological and clinical chemistry profiles. The 13-week subchronic and reproductive toxicity potential of an intravaginal gel–microemulsion formulation of WHI-07 was studied in mice to support its further development as a dual-function microbicide. Groups of ten female B6C3F1 mice were exposed intravaginally to a gel–microemulsion formulation containing 0, 0.5, 1.0 or 2.0% WHI-07, 5 days a week, for 13 consecutive weeks. On a molar basis, these concentrations represent 1400–5700 times their in vitro spermicidal potency EC50) and 1.4 × 106–5.7 × 106 times their in vitro anti-HIV activity50). After 13 weeks of intravaginal treatment, half of the treated mice were evaluated for toxicity and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. The endpoints that were evaluated included survival, body weight gain, hematological and clinical chemistries, absolute and relative organ weights and histopathology. The WHI-07 applications did not cause weight loss, morbidity, mortality or specific tissue lesions detectable by histopathology. Repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>95%) or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent WHI-07 did not cause significant acute or subchronic toxicity. Copyright © 2000 John Wiley & Sons, Ltd.

  • Evaluation of subchronic (13 weeks) and reproductive toxicity potential of intravaginal gel-microemulsion formulation of a dual-function Phenyl Phosphate derivative of bromo-methoxy zidovudine (compound WHI-05) in B6C3F1 mice
    Contraception, 2000
    Co-Authors: Osmond J. D'cruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Abstract Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the United States. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) which exhibit potent anti-HIV and spermicidal activities. This study reports the preliminary preclinical study of our lead compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-methoxyPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. Acute toxicity studies have shown that WHI-05 has no detectable adverse effects on laboratory animals. The 13-week subchronic and reproductive toxicity potential of intravaginal gel-microemulsion formulation of WHI-05 were studied in mice to support its further development as a virucidal spermicide. Groups of 10 female B 6 C 3 F 1 mice were exposed intravaginally to a gel-microemulsion formulation containing 0%, 0.5%, 1.0%, or 2.0% WHI-05, 5 days/week for 13 consecutive weeks. On a molar basis, these concentrations represent 300 to 1200 times their in vitro spermicidal potency, and 1.5 × 10 4 to 6.1 × 10 4 times their in vitro anti-HIV activity. After 13 weeks of intravaginal treatment, one half of treated mice were evaluated for toxicity, and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. Repetitive intravaginal application of WHI-05 to yield a local concentration 6.1 × 10 4 times higher than its in vitro HIV IC 50 value and 1200 times higher than its spermicidal EC 50 value did not cause weight loss, morbidity, mortality, or specific tissue lesions detectable by histopathology. Furthermore, repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>96%), or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent, WHI-05, did not cause significant acute or subchronic and reproductive toxicity under the test conditions.

  • synthesis characterization and preclinical formulation of a dual action Phenyl Phosphate derivative of bromo methoxy zidovudine compound whi 07 with potent anti hiv and spermicidal activities
    Molecular Human Reproduction, 1999
    Co-Authors: Osmond J Dcruz, Chun-lin Chen, Meijue Shih, Fatih M. Uckun
    Abstract:

    In a systematic effort to develop a microbicide contraceptive capable of preventing transmission of human immunodeficiency virus (HIV), as well as providing fertility control, we have previously identified novel Phenyl Phosphate derivatives of zidovudine (ZDV) with 5-halo 6-alkoxy substitutions in the thymine ring and halo substitution in the Phenyl moiety respectively. Here, we describe the synthesis, characterization, and successful preclinical formulation of our lead compound, 5-bromo-6-methoxy-39-azidothymidine-59-(p-bromoPhenyl) methoxyalaninyl Phosphate (WHI-07), which exhibits potent anti-HIV and sperm immobilizing activities. The anti-HIV activity of WHI-07 was tested by measuring viral p24 antigen production and reverse transcriptase activity as markers of viral replication in HIV-1 infected human peripheral blood mononuclear cells (PBMC). WHI-07 inhibited replication of HIV in a concentration-dependent fashion with nanomolar IC50 values. The effects of WHI-07 on human sperm motion kinematics were analysed by computer-assisted sperm analysis (CASA), and its effects on sperm membrane integrity were examined by confocal laser scanning microscopy (CLSM), and high-resolution low-voltage scanning electron microscopy (HR-LVSEM). WHI-07 caused cessation of sperm motility in a concentration- and time-dependent fashion. The in-vitro cytotoxicities of WHI-07 and nonoxynol-9 (N-9) were compared using normal human ectocervical and endocervical epithelial cells by the MTT cell viability assay. Unlike N-9, WHI-07 had no effect upon sperm plasma and acrosomal membrane integrity. N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, whereas WHI-07 was selectively spermicidal. The in-vivo vaginal absorption and vaginal toxicity of 2% gelmicroemulsion of WHI-07 was studied in the rabbit model. The sperm immobilizing activity of WHI-07 was 18-fold more potent than that of N-9. Over a 10 day period, there was no irritation or local toxicity to the vaginal epithelia or systemic absorption of WHI-07. Therefore, as a potent anti-HIV agent with spermicidal activity, and lack of mucosal toxicity, WHI-07 may have the clinical potential to become the active ingredient of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.

  • WHI-05, a novel bromo-methoxy substituted Phenyl Phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activity.
    Contraception, 1999
    Co-Authors: Osmond J. D'cruz, Zhaohai Zhu, Seang Yiv, Chun-lin Chen, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of HIV to women is the fastest-growing mode of transmission. In a systematic effort to develop a microbicide capable of preventing HIV transmission as well as providing fertility control, novel Phenyl Phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) have been identified that exhibit potent anti-HIV and spermicidal activities. This study reports the synthesis, characterization, and preclinical formulation of compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyPhenyl) methoxyalaninyl Phosphate. The anti-HIV activities of WHI-05 and ZDV were compared by measuring p24 antigen production and reverse transcriptase activity as markers of viral replication using human peripheral blood mononuclear cells (PBMC) infected with both ZDV-sensitive and ZDV-resistant strains of HIV. The sperm immobilizing activity (SIA) of WHI-05 was compared with that of ZDV and nonoxynol-9 (N-9) by computer-assisted sperm analysis (CASA). The effect of WHI-05 on sperm membrane integrity was examined by high resolution, low voltage scanning electron microscopy (HR-LVSEM). The in vitro cytotoxicity profile of WHI-05 versus N-9 were compared using normal human vaginal, ectocervical, and endocervical epithelial cells. The in vivo vaginal tolerance, absorption, and toxicity of a 2% WHI-05 gel-microemulsion was tested in the rabbit. Whereas ZDV displayed potent anti-HIV activity but lacked SIA, WHI-05 elicited both potent anti-HIV activity and SIA. WHI-05 inhibited the replication of ZDV-sensitive as well as ZDV-resistant strains of HIV in PBMC. CASA combined with HR-LVSEM demonstrated that WHI-05-induced SIA was not associated with membrane damage. Unlike, N-9, the spermicidal activity of WHI-05 was not associated with cytotoxicity to reproductive tract epithelial cells. Repetitive intravaginal application of a 2% WHI-05 gel-microemulsion did not damage the vaginal epithelium or cause local inflammation in the rabbit model. As a potent anti-HIV agent that has spermicidal activity and is devoid of mucosal toxicity, WHI-05 shows a unique clinical potential to become the active ingredient for a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.

Osmond J. D'cruz - One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of subchronic (13 weeks) and reproductive toxicity potential of intravaginal gel-microemulsion formulation of a dual-function Phenyl Phosphate derivative of bromo-methoxy zidovudine (compound WHI-05) in B6C3F1 mice
    Contraception, 2000
    Co-Authors: Osmond J. D'cruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Abstract Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the United States. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) which exhibit potent anti-HIV and spermicidal activities. This study reports the preliminary preclinical study of our lead compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-methoxyPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. Acute toxicity studies have shown that WHI-05 has no detectable adverse effects on laboratory animals. The 13-week subchronic and reproductive toxicity potential of intravaginal gel-microemulsion formulation of WHI-05 were studied in mice to support its further development as a virucidal spermicide. Groups of 10 female B 6 C 3 F 1 mice were exposed intravaginally to a gel-microemulsion formulation containing 0%, 0.5%, 1.0%, or 2.0% WHI-05, 5 days/week for 13 consecutive weeks. On a molar basis, these concentrations represent 300 to 1200 times their in vitro spermicidal potency, and 1.5 × 10 4 to 6.1 × 10 4 times their in vitro anti-HIV activity. After 13 weeks of intravaginal treatment, one half of treated mice were evaluated for toxicity, and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. Repetitive intravaginal application of WHI-05 to yield a local concentration 6.1 × 10 4 times higher than its in vitro HIV IC 50 value and 1200 times higher than its spermicidal EC 50 value did not cause weight loss, morbidity, mortality, or specific tissue lesions detectable by histopathology. Furthermore, repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>96%), or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent, WHI-05, did not cause significant acute or subchronic and reproductive toxicity under the test conditions.

  • Evaluation of subchronic (13-week) and reproductive toxicity potential of intravaginal gel–microemulsion formulation of a dual-function Phenyl Phosphate derivative of bromo-methoxy zidovudine (compound whi-07) in B6C3F1 mice
    Journal of applied toxicology : JAT, 2000
    Co-Authors: Osmond J. D'cruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the USA. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromoPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. In vivo toxicity studies in non-human primates and rodents given WHI-07 (20 mg kg−1) intravenously and intraperitonealy, respectively, had no detectable adverse effects on hematological and clinical chemistry profiles. The 13-week subchronic and reproductive toxicity potential of an intravaginal gel–microemulsion formulation of WHI-07 was studied in mice to support its further development as a dual-function microbicide. Groups of ten female B6C3F1 mice were exposed intravaginally to a gel–microemulsion formulation containing 0, 0.5, 1.0 or 2.0% WHI-07, 5 days a week, for 13 consecutive weeks. On a molar basis, these concentrations represent 1400–5700 times their in vitro spermicidal potency EC50) and 1.4 × 106–5.7 × 106 times their in vitro anti-HIV activity50). After 13 weeks of intravaginal treatment, half of the treated mice were evaluated for toxicity and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. The endpoints that were evaluated included survival, body weight gain, hematological and clinical chemistries, absolute and relative organ weights and histopathology. The WHI-07 applications did not cause weight loss, morbidity, mortality or specific tissue lesions detectable by histopathology. Repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>95%) or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent WHI-07 did not cause significant acute or subchronic toxicity. Copyright © 2000 John Wiley & Sons, Ltd.

  • WHI-05, a novel bromo-methoxy substituted Phenyl Phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activity.
    Contraception, 1999
    Co-Authors: Osmond J. D'cruz, Zhaohai Zhu, Seang Yiv, Chun-lin Chen, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of HIV to women is the fastest-growing mode of transmission. In a systematic effort to develop a microbicide capable of preventing HIV transmission as well as providing fertility control, novel Phenyl Phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) have been identified that exhibit potent anti-HIV and spermicidal activities. This study reports the synthesis, characterization, and preclinical formulation of compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyPhenyl) methoxyalaninyl Phosphate. The anti-HIV activities of WHI-05 and ZDV were compared by measuring p24 antigen production and reverse transcriptase activity as markers of viral replication using human peripheral blood mononuclear cells (PBMC) infected with both ZDV-sensitive and ZDV-resistant strains of HIV. The sperm immobilizing activity (SIA) of WHI-05 was compared with that of ZDV and nonoxynol-9 (N-9) by computer-assisted sperm analysis (CASA). The effect of WHI-05 on sperm membrane integrity was examined by high resolution, low voltage scanning electron microscopy (HR-LVSEM). The in vitro cytotoxicity profile of WHI-05 versus N-9 were compared using normal human vaginal, ectocervical, and endocervical epithelial cells. The in vivo vaginal tolerance, absorption, and toxicity of a 2% WHI-05 gel-microemulsion was tested in the rabbit. Whereas ZDV displayed potent anti-HIV activity but lacked SIA, WHI-05 elicited both potent anti-HIV activity and SIA. WHI-05 inhibited the replication of ZDV-sensitive as well as ZDV-resistant strains of HIV in PBMC. CASA combined with HR-LVSEM demonstrated that WHI-05-induced SIA was not associated with membrane damage. Unlike, N-9, the spermicidal activity of WHI-05 was not associated with cytotoxicity to reproductive tract epithelial cells. Repetitive intravaginal application of a 2% WHI-05 gel-microemulsion did not damage the vaginal epithelium or cause local inflammation in the rabbit model. As a potent anti-HIV agent that has spermicidal activity and is devoid of mucosal toxicity, WHI-05 shows a unique clinical potential to become the active ingredient for a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.

Seang Yiv - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of subchronic 13 week and reproductive toxicity potential of intravaginal gel microemulsion formulation of a dual function Phenyl Phosphate derivative of bromo methoxy zidovudine compound whi 07 in b6c3f1 mice
    Journal of Applied Toxicology, 2000
    Co-Authors: Osmond J Dcruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the USA. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromoPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. In vivo toxicity studies in non-human primates and rodents given WHI-07 (20 mg kg−1) intravenously and intraperitonealy, respectively, had no detectable adverse effects on hematological and clinical chemistry profiles. The 13-week subchronic and reproductive toxicity potential of an intravaginal gel–microemulsion formulation of WHI-07 was studied in mice to support its further development as a dual-function microbicide. Groups of ten female B6C3F1 mice were exposed intravaginally to a gel–microemulsion formulation containing 0, 0.5, 1.0 or 2.0% WHI-07, 5 days a week, for 13 consecutive weeks. On a molar basis, these concentrations represent 1400–5700 times their in vitro spermicidal potency EC50) and 1.4 × 106–5.7 × 106 times their in vitro anti-HIV activity50). After 13 weeks of intravaginal treatment, half of the treated mice were evaluated for toxicity and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. The endpoints that were evaluated included survival, body weight gain, hematological and clinical chemistries, absolute and relative organ weights and histopathology. The WHI-07 applications did not cause weight loss, morbidity, mortality or specific tissue lesions detectable by histopathology. Repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>95%) or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent WHI-07 did not cause significant acute or subchronic toxicity. Copyright © 2000 John Wiley & Sons, Ltd.

  • Evaluation of subchronic (13 weeks) and reproductive toxicity potential of intravaginal gel-microemulsion formulation of a dual-function Phenyl Phosphate derivative of bromo-methoxy zidovudine (compound WHI-05) in B6C3F1 mice
    Contraception, 2000
    Co-Authors: Osmond J. D'cruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Abstract Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the United States. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) which exhibit potent anti-HIV and spermicidal activities. This study reports the preliminary preclinical study of our lead compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-methoxyPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. Acute toxicity studies have shown that WHI-05 has no detectable adverse effects on laboratory animals. The 13-week subchronic and reproductive toxicity potential of intravaginal gel-microemulsion formulation of WHI-05 were studied in mice to support its further development as a virucidal spermicide. Groups of 10 female B 6 C 3 F 1 mice were exposed intravaginally to a gel-microemulsion formulation containing 0%, 0.5%, 1.0%, or 2.0% WHI-05, 5 days/week for 13 consecutive weeks. On a molar basis, these concentrations represent 300 to 1200 times their in vitro spermicidal potency, and 1.5 × 10 4 to 6.1 × 10 4 times their in vitro anti-HIV activity. After 13 weeks of intravaginal treatment, one half of treated mice were evaluated for toxicity, and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. Repetitive intravaginal application of WHI-05 to yield a local concentration 6.1 × 10 4 times higher than its in vitro HIV IC 50 value and 1200 times higher than its spermicidal EC 50 value did not cause weight loss, morbidity, mortality, or specific tissue lesions detectable by histopathology. Furthermore, repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>96%), or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent, WHI-05, did not cause significant acute or subchronic and reproductive toxicity under the test conditions.

  • Evaluation of subchronic (13-week) and reproductive toxicity potential of intravaginal gel–microemulsion formulation of a dual-function Phenyl Phosphate derivative of bromo-methoxy zidovudine (compound whi-07) in B6C3F1 mice
    Journal of applied toxicology : JAT, 2000
    Co-Authors: Osmond J. D'cruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the USA. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromoPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. In vivo toxicity studies in non-human primates and rodents given WHI-07 (20 mg kg−1) intravenously and intraperitonealy, respectively, had no detectable adverse effects on hematological and clinical chemistry profiles. The 13-week subchronic and reproductive toxicity potential of an intravaginal gel–microemulsion formulation of WHI-07 was studied in mice to support its further development as a dual-function microbicide. Groups of ten female B6C3F1 mice were exposed intravaginally to a gel–microemulsion formulation containing 0, 0.5, 1.0 or 2.0% WHI-07, 5 days a week, for 13 consecutive weeks. On a molar basis, these concentrations represent 1400–5700 times their in vitro spermicidal potency EC50) and 1.4 × 106–5.7 × 106 times their in vitro anti-HIV activity50). After 13 weeks of intravaginal treatment, half of the treated mice were evaluated for toxicity and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. The endpoints that were evaluated included survival, body weight gain, hematological and clinical chemistries, absolute and relative organ weights and histopathology. The WHI-07 applications did not cause weight loss, morbidity, mortality or specific tissue lesions detectable by histopathology. Repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>95%) or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent WHI-07 did not cause significant acute or subchronic toxicity. Copyright © 2000 John Wiley & Sons, Ltd.

  • WHI-05, a novel bromo-methoxy substituted Phenyl Phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activity.
    Contraception, 1999
    Co-Authors: Osmond J. D'cruz, Zhaohai Zhu, Seang Yiv, Chun-lin Chen, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of HIV to women is the fastest-growing mode of transmission. In a systematic effort to develop a microbicide capable of preventing HIV transmission as well as providing fertility control, novel Phenyl Phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) have been identified that exhibit potent anti-HIV and spermicidal activities. This study reports the synthesis, characterization, and preclinical formulation of compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyPhenyl) methoxyalaninyl Phosphate. The anti-HIV activities of WHI-05 and ZDV were compared by measuring p24 antigen production and reverse transcriptase activity as markers of viral replication using human peripheral blood mononuclear cells (PBMC) infected with both ZDV-sensitive and ZDV-resistant strains of HIV. The sperm immobilizing activity (SIA) of WHI-05 was compared with that of ZDV and nonoxynol-9 (N-9) by computer-assisted sperm analysis (CASA). The effect of WHI-05 on sperm membrane integrity was examined by high resolution, low voltage scanning electron microscopy (HR-LVSEM). The in vitro cytotoxicity profile of WHI-05 versus N-9 were compared using normal human vaginal, ectocervical, and endocervical epithelial cells. The in vivo vaginal tolerance, absorption, and toxicity of a 2% WHI-05 gel-microemulsion was tested in the rabbit. Whereas ZDV displayed potent anti-HIV activity but lacked SIA, WHI-05 elicited both potent anti-HIV activity and SIA. WHI-05 inhibited the replication of ZDV-sensitive as well as ZDV-resistant strains of HIV in PBMC. CASA combined with HR-LVSEM demonstrated that WHI-05-induced SIA was not associated with membrane damage. Unlike, N-9, the spermicidal activity of WHI-05 was not associated with cytotoxicity to reproductive tract epithelial cells. Repetitive intravaginal application of a 2% WHI-05 gel-microemulsion did not damage the vaginal epithelium or cause local inflammation in the rabbit model. As a potent anti-HIV agent that has spermicidal activity and is devoid of mucosal toxicity, WHI-05 shows a unique clinical potential to become the active ingredient for a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.

Barbara Waurzyniak - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of subchronic 13 week and reproductive toxicity potential of intravaginal gel microemulsion formulation of a dual function Phenyl Phosphate derivative of bromo methoxy zidovudine compound whi 07 in b6c3f1 mice
    Journal of Applied Toxicology, 2000
    Co-Authors: Osmond J Dcruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the USA. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromoPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. In vivo toxicity studies in non-human primates and rodents given WHI-07 (20 mg kg−1) intravenously and intraperitonealy, respectively, had no detectable adverse effects on hematological and clinical chemistry profiles. The 13-week subchronic and reproductive toxicity potential of an intravaginal gel–microemulsion formulation of WHI-07 was studied in mice to support its further development as a dual-function microbicide. Groups of ten female B6C3F1 mice were exposed intravaginally to a gel–microemulsion formulation containing 0, 0.5, 1.0 or 2.0% WHI-07, 5 days a week, for 13 consecutive weeks. On a molar basis, these concentrations represent 1400–5700 times their in vitro spermicidal potency EC50) and 1.4 × 106–5.7 × 106 times their in vitro anti-HIV activity50). After 13 weeks of intravaginal treatment, half of the treated mice were evaluated for toxicity and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. The endpoints that were evaluated included survival, body weight gain, hematological and clinical chemistries, absolute and relative organ weights and histopathology. The WHI-07 applications did not cause weight loss, morbidity, mortality or specific tissue lesions detectable by histopathology. Repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>95%) or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent WHI-07 did not cause significant acute or subchronic toxicity. Copyright © 2000 John Wiley & Sons, Ltd.

  • Evaluation of subchronic (13 weeks) and reproductive toxicity potential of intravaginal gel-microemulsion formulation of a dual-function Phenyl Phosphate derivative of bromo-methoxy zidovudine (compound WHI-05) in B6C3F1 mice
    Contraception, 2000
    Co-Authors: Osmond J. D'cruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Abstract Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the United States. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) which exhibit potent anti-HIV and spermicidal activities. This study reports the preliminary preclinical study of our lead compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-methoxyPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. Acute toxicity studies have shown that WHI-05 has no detectable adverse effects on laboratory animals. The 13-week subchronic and reproductive toxicity potential of intravaginal gel-microemulsion formulation of WHI-05 were studied in mice to support its further development as a virucidal spermicide. Groups of 10 female B 6 C 3 F 1 mice were exposed intravaginally to a gel-microemulsion formulation containing 0%, 0.5%, 1.0%, or 2.0% WHI-05, 5 days/week for 13 consecutive weeks. On a molar basis, these concentrations represent 300 to 1200 times their in vitro spermicidal potency, and 1.5 × 10 4 to 6.1 × 10 4 times their in vitro anti-HIV activity. After 13 weeks of intravaginal treatment, one half of treated mice were evaluated for toxicity, and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. Repetitive intravaginal application of WHI-05 to yield a local concentration 6.1 × 10 4 times higher than its in vitro HIV IC 50 value and 1200 times higher than its spermicidal EC 50 value did not cause weight loss, morbidity, mortality, or specific tissue lesions detectable by histopathology. Furthermore, repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>96%), or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent, WHI-05, did not cause significant acute or subchronic and reproductive toxicity under the test conditions.

  • Evaluation of subchronic (13-week) and reproductive toxicity potential of intravaginal gel–microemulsion formulation of a dual-function Phenyl Phosphate derivative of bromo-methoxy zidovudine (compound whi-07) in B6C3F1 mice
    Journal of applied toxicology : JAT, 2000
    Co-Authors: Osmond J. D'cruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the USA. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromoPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. In vivo toxicity studies in non-human primates and rodents given WHI-07 (20 mg kg−1) intravenously and intraperitonealy, respectively, had no detectable adverse effects on hematological and clinical chemistry profiles. The 13-week subchronic and reproductive toxicity potential of an intravaginal gel–microemulsion formulation of WHI-07 was studied in mice to support its further development as a dual-function microbicide. Groups of ten female B6C3F1 mice were exposed intravaginally to a gel–microemulsion formulation containing 0, 0.5, 1.0 or 2.0% WHI-07, 5 days a week, for 13 consecutive weeks. On a molar basis, these concentrations represent 1400–5700 times their in vitro spermicidal potency EC50) and 1.4 × 106–5.7 × 106 times their in vitro anti-HIV activity50). After 13 weeks of intravaginal treatment, half of the treated mice were evaluated for toxicity and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. The endpoints that were evaluated included survival, body weight gain, hematological and clinical chemistries, absolute and relative organ weights and histopathology. The WHI-07 applications did not cause weight loss, morbidity, mortality or specific tissue lesions detectable by histopathology. Repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>95%) or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent WHI-07 did not cause significant acute or subchronic toxicity. Copyright © 2000 John Wiley & Sons, Ltd.

  • WHI-05, a novel bromo-methoxy substituted Phenyl Phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activity.
    Contraception, 1999
    Co-Authors: Osmond J. D'cruz, Zhaohai Zhu, Seang Yiv, Chun-lin Chen, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of HIV to women is the fastest-growing mode of transmission. In a systematic effort to develop a microbicide capable of preventing HIV transmission as well as providing fertility control, novel Phenyl Phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) have been identified that exhibit potent anti-HIV and spermicidal activities. This study reports the synthesis, characterization, and preclinical formulation of compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyPhenyl) methoxyalaninyl Phosphate. The anti-HIV activities of WHI-05 and ZDV were compared by measuring p24 antigen production and reverse transcriptase activity as markers of viral replication using human peripheral blood mononuclear cells (PBMC) infected with both ZDV-sensitive and ZDV-resistant strains of HIV. The sperm immobilizing activity (SIA) of WHI-05 was compared with that of ZDV and nonoxynol-9 (N-9) by computer-assisted sperm analysis (CASA). The effect of WHI-05 on sperm membrane integrity was examined by high resolution, low voltage scanning electron microscopy (HR-LVSEM). The in vitro cytotoxicity profile of WHI-05 versus N-9 were compared using normal human vaginal, ectocervical, and endocervical epithelial cells. The in vivo vaginal tolerance, absorption, and toxicity of a 2% WHI-05 gel-microemulsion was tested in the rabbit. Whereas ZDV displayed potent anti-HIV activity but lacked SIA, WHI-05 elicited both potent anti-HIV activity and SIA. WHI-05 inhibited the replication of ZDV-sensitive as well as ZDV-resistant strains of HIV in PBMC. CASA combined with HR-LVSEM demonstrated that WHI-05-induced SIA was not associated with membrane damage. Unlike, N-9, the spermicidal activity of WHI-05 was not associated with cytotoxicity to reproductive tract epithelial cells. Repetitive intravaginal application of a 2% WHI-05 gel-microemulsion did not damage the vaginal epithelium or cause local inflammation in the rabbit model. As a potent anti-HIV agent that has spermicidal activity and is devoid of mucosal toxicity, WHI-05 shows a unique clinical potential to become the active ingredient for a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.

Osmond J Dcruz - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of subchronic 13 week and reproductive toxicity potential of intravaginal gel microemulsion formulation of a dual function Phenyl Phosphate derivative of bromo methoxy zidovudine compound whi 07 in b6c3f1 mice
    Journal of Applied Toxicology, 2000
    Co-Authors: Osmond J Dcruz, Seang Yiv, Barbara Waurzyniak, Fatih M. Uckun
    Abstract:

    Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the USA. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel Phenyl Phosphate derivatives of 3′-azido-3′-deoxythymidine (zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromoPhenyl) methoxyalaninyl Phosphate, for use as a dual-function topical microbicide. In vivo toxicity studies in non-human primates and rodents given WHI-07 (20 mg kg−1) intravenously and intraperitonealy, respectively, had no detectable adverse effects on hematological and clinical chemistry profiles. The 13-week subchronic and reproductive toxicity potential of an intravaginal gel–microemulsion formulation of WHI-07 was studied in mice to support its further development as a dual-function microbicide. Groups of ten female B6C3F1 mice were exposed intravaginally to a gel–microemulsion formulation containing 0, 0.5, 1.0 or 2.0% WHI-07, 5 days a week, for 13 consecutive weeks. On a molar basis, these concentrations represent 1400–5700 times their in vitro spermicidal potency EC50) and 1.4 × 106–5.7 × 106 times their in vitro anti-HIV activity50). After 13 weeks of intravaginal treatment, half of the treated mice were evaluated for toxicity and the other half were mated with untreated males to evaluate potential reproductive and developmental effects. The endpoints that were evaluated included survival, body weight gain, hematological and clinical chemistries, absolute and relative organ weights and histopathology. The WHI-07 applications did not cause weight loss, morbidity, mortality or specific tissue lesions detectable by histopathology. Repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>95%) or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent WHI-07 did not cause significant acute or subchronic toxicity. Copyright © 2000 John Wiley & Sons, Ltd.

  • synthesis characterization and preclinical formulation of a dual action Phenyl Phosphate derivative of bromo methoxy zidovudine compound whi 07 with potent anti hiv and spermicidal activities
    Molecular Human Reproduction, 1999
    Co-Authors: Osmond J Dcruz, Chun-lin Chen, Meijue Shih, Fatih M. Uckun
    Abstract:

    In a systematic effort to develop a microbicide contraceptive capable of preventing transmission of human immunodeficiency virus (HIV), as well as providing fertility control, we have previously identified novel Phenyl Phosphate derivatives of zidovudine (ZDV) with 5-halo 6-alkoxy substitutions in the thymine ring and halo substitution in the Phenyl moiety respectively. Here, we describe the synthesis, characterization, and successful preclinical formulation of our lead compound, 5-bromo-6-methoxy-39-azidothymidine-59-(p-bromoPhenyl) methoxyalaninyl Phosphate (WHI-07), which exhibits potent anti-HIV and sperm immobilizing activities. The anti-HIV activity of WHI-07 was tested by measuring viral p24 antigen production and reverse transcriptase activity as markers of viral replication in HIV-1 infected human peripheral blood mononuclear cells (PBMC). WHI-07 inhibited replication of HIV in a concentration-dependent fashion with nanomolar IC50 values. The effects of WHI-07 on human sperm motion kinematics were analysed by computer-assisted sperm analysis (CASA), and its effects on sperm membrane integrity were examined by confocal laser scanning microscopy (CLSM), and high-resolution low-voltage scanning electron microscopy (HR-LVSEM). WHI-07 caused cessation of sperm motility in a concentration- and time-dependent fashion. The in-vitro cytotoxicities of WHI-07 and nonoxynol-9 (N-9) were compared using normal human ectocervical and endocervical epithelial cells by the MTT cell viability assay. Unlike N-9, WHI-07 had no effect upon sperm plasma and acrosomal membrane integrity. N-9 was cytotoxic to normal human ectocervical and endocervical cells at spermicidal doses, whereas WHI-07 was selectively spermicidal. The in-vivo vaginal absorption and vaginal toxicity of 2% gelmicroemulsion of WHI-07 was studied in the rabbit model. The sperm immobilizing activity of WHI-07 was 18-fold more potent than that of N-9. Over a 10 day period, there was no irritation or local toxicity to the vaginal epithelia or systemic absorption of WHI-07. Therefore, as a potent anti-HIV agent with spermicidal activity, and lack of mucosal toxicity, WHI-07 may have the clinical potential to become the active ingredient of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.