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O. J. D’CRUZ AND F. M. UCKUN
WHI-07.4 Furthermore, repeated intravaginal application
of 0.5–2.0% WHI-07 for 13 weeks did not result
in systemic toxicity and no specific target organs
were identified.6 No statistically significant treatment-
related effects on survival, growth, hematological, and
clinical chemistries, absolute or relative organ weights or
histopathology were noted.6 These studies demonstrated
that WHI-07 has low potential to produce systemic
toxicity after intravaginal application, and WHI-07 is not
toxic to the female genital tract. In the present study, no
evidence of fetal toxicity or teratogenicity was observed
when pregnant mice were treated intravaginally with
2% WHI-07 during the period of major organogenesis.
The low incidence of external anomalies or skeletal
malformations observed in this study was evident in
both gel–microemulsion control and WHI-07-exposed
superovulated mice. Based on our preclinical studies
performed in mice and rabbits, intravaginal application of
WHI-07 when used as a topical dual-function microbicide
during pregnancy is unlikely to cause adverse systemic or
local side-effects.
or developmental measurements. In humans, oral ZDV
therapy during pregnancy has been shown to reduce peri-
natal HIV transmission from an infected woman to her
infant by nearly 70%.18 Epidemiological data have since
confirmed the efficacy of ZDV for reduction of perinatal
transmission and have extended this efficacy to children of
women with advanced disease, low CD4+ T-lymphocyte
counts and prior ZDV therapy. Children exposed to ZDV
in utero, during labor and delivery and also as newborns
for 6 weeks showed no adverse health effects when fol-
lowed up for as long as 5.6 years.18
In conclusion, repeated intravaginal administration of
up to 2.0% WHI-07 via a gel–microemulsion formulation
given to CD-1 mice during ovulation, in in vivo fertil-
ization or before or during pregnancy had no adverse
effect on fertility. Compound WHI-07 was not terato-
genic in mice. Repeated intravaginal exposure of mice
to WHI-07 for 13 weeks had no adverse effects on subse-
quent reproductive performance, neonatal survival or pup
development. Compound WHI-07 shows unique clinical
potential as a safe dual-function vaginal contraceptive for
curbing mucosal and perinatal HIV transmission.
Currently, ZDV is being used clinically during preg-
nancy.16 Oral administration of ZDV has been evaluated
for adverse effect on reproduction and fetal development
in animal test species.17 In both the reproduction/fertility
study and a peri- and postnatal study in rats, liveborn
offspring showed no adverse effects on survival, growth
Acknowledgements
This work was supported in part by National Institutes of Health
Grant HD 37357 and American Foundation for AIDS Research Grant
02667.
REFERENCES
10. Toltzis P, Mourton T, Magnuson T. Effect of zidovudine
on preimplantation murine embryos. Antimicrob. Agents
Chemother. 1993; 37: 1610–1613.
1. Quinn TC. Global burden of the HIV pandemic. Lancet 1996;
348: 99–106.
2. Uckun FM, D’Cruz OJ. Prophylactic contraceptives for HIV/
AIDS. Hum. Reprod. Update 1999; 5: 506–514.
11. Jan S-T, Shih M-J, Venkatachalam TK, D’Cruz OJ, Chen C-L,
Uckun FM. Synthesis of dual function (5R,6R)- and (5S,6S)-5-
bromo-6-methoxy-5,6-dihydro-AZT-5ꢀ-(para-bromophenyl
methoxyalaninyl phosphate) as novel spermicidal and anti-
HIV agents. Antiviral Chem. Chemother. 1999; 10: 39–46.
12. Klug S, Lewandowski C, Merker HJ, Stahlmann R, Wildt L,
Neubert D. In vitro and in vivo studies on the prenatal toxicity
of five virustatic nucleoside analogues in comparison to
aciclovir. Arch. Toxicol. 1991; 65: 283–291.
13. Sieh E, Coluzzi ML, De Angelis MG, Mezzogiorno A,
Floridia M, Canipari R, Cossu G, Vella S. The effects of AZT
and DDI on pre- and postimpantation mammalian embryos:
an in vivo and in vitro study. AIDS Res. Hum. Retrovir. 1992;
8: 639–649.
14. Toltzis P, Mourton T, Magnuson T. Comparative embryonic
cytotoxicity of antiretroviral nucleosides. J. Infect. Dis. 1994;
169: 1100–1102.
15. Rosiak K, Li M-H, Degitz SJ, Skalla DW, Chu I, Francis BM.
Maternal and developmental toxicity of polychlorinated
diphenyl ethers (PCDEs) in Swiss-Webster mice and
Sprague-Dawley rats. Toxicology 1997; 121: 191–204.
16. Fowler MG, Simonds RJ, Roongpisuthipong A. Update on
perinatal HIV transmission. Pediatr. Clin. North Am. 2000;
47: 21–38.
17. Greene JA, Ayers KM, Tucker WE Jr, de Miranda P. Nonclin-
ical toxicology studies with zidovudine: reproductive toxicity
studies in rats and rabbits. Fundam. Appl. Toxicol. 1996; 32:
140–147.
18. Culnane M, Fowler M, Lee SS, McSherry G, Brady M, O’Don-
nell K, Mofenson L, Gortmaker SL, Shapiro DE, Scott G,
Jimenez E, Moore EC, Diaz C, Flynn PM, Cunningham B,
Oleske J. Lack of long-term effects of in utero exposure
to zidovudine among uninfected children born to HIV-
infected women. Pediatric AIDS Clinical Trials Group Proto-
col 219/076 Teams. J. Am. Med. Assoc. 1999; 281: 151–157.
3. D’Cruz OJ, Venkatachalam TK, Zhu Z, Shih M-L, Uckun FM.
Bromo-methoxy and aryl phosphate derivatives of azi-
dothymidine are dual function spermicides with potent
anti-HIV activity. Biol. Reprod. 1998; 59: 503–515.
4. D’Cruz OJ, Shih M-J, Yiv SH, Chen CL, Uckun FM. Synthesis,
characterization and preclinical formulation of
a novel
phenyl phosphate derivative of bromo-methoxy zidovudine
(compound WHI-07) with potent anti- HIV and spermicidal
Activities. Mol. Hum. Reprod. 1999; 5: 421–432.
5. D’Cruz OJ, Venkatachalam TK, Uckun FM. Structural require-
ments for potent human spermicidal activity of dual-
function aryl phosphate derivative of bromo-methoxy
zidovudine (compound WHI-07). Biol. Reprod. 2000; 63:
37–44.
6. D’Cruz OJ, Waurzyniak B, Yiv SH, Uckun FM. Evaluation of
subchronic (13 weeks) and reproductive toxicity potential
of intravaginal gel–microemulsion formulation of a dual-
function phenyl phosphate derivative of bromomethozy-
zidovudine (compound WHI-07) in B6C3F1 mice. J. Appl.
Toxicol. 2000; 20: 319–325.
7. D’Cruz OJ, Venkatachalam TK, Uckun FM. Thymidine kinase-
independent intracellular delivery of bioactive nucleotides
by aryl phosphate derivatives of bromo-methoxy zidovudine
(compounds WHI-05 and WHI-07) in normal human female
genital tract epithelial cells and sperm. Biol. Reprod. 2001;
64: 51–59.
8. D’Cruz OJ, Zhu Z, Yiv SH, Chen CL, Waurzyniak B, Uckun
FM. WHI-05, a novel bromo-methoxy substituted phenyl
phosphate derivative of zidovudine, is a dual-action sper-
micide with potent anti-HIV activity. Contraception 1999; 59:
319–331.
9. Toltzis P, Marx CM, Kleinman N, Levine EM, Schmidt EV.
Zidovudine-associated embryonic toxicity in mice. J. Infect.
Dis. 1991; 163: 1212–1218.
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J. Appl. Toxicol. 21, 317–322 (2001)