Administration of 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta)

Safety and efficacy studies

Alice F Tarantal, Marta Marthas, Jing Ping Shaw, Ken Cundy, Norbert Bischofberger

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) significantly inhibits viral reverse transcription and has been reported to sustain low virus load in SIV-infected rhesus monkeys. Based on these findings, studies were conducted to assess the safety, efficacy, and placental transfer of PMPA when administered once daily subcutaneously to gravid rhesus monkeys during the second and third trimesters and their offspring (30 mg/kg/day). Fetuses (SIV- infected, N = 6; noninfected, N = 6) were monitored sonographically, and maternal/fetal blood samples were collected at select time points for hematologic, clinical chemical, virologic, immunologic, and pharmacologic assessments. Newborns were delivered by cesarean section at term and nursery reared for postnatal studies. Infants were administered PMPA once daily beginning on day 2 of life until 9 months postnatal age. Results of these studies have shown significant placental transport of PMPA, with peak fetal levels at 1 to 3 hours post-maternal administration; a significant and sustained reduction in viral load in SIV-infected fetuses and infants; and marked improvements in outcome (e.g., survival, growth, health) in SIV- infected offspring. However, decreased infant body weights and alterations of select serum biochemical parameters (e.g., decreased phosphorus levels, elevated alkaline phosphatase) have been shown to occur in ~67% of PMPA- treated infants, with severe growth restriction and bone-related toxicity in ~25% of animals studied. These data suggest that although PMPA holds great promise for HIV-infected patients, there is the potential for bone-related toxicity at chronic, high dosages, particularly in infants.

Original languageEnglish (US)
Pages (from-to)323-333
Number of pages11
JournalJournal of Acquired Immune Deficiency Syndromes and Human Retrovirology
Volume20
Issue number4
StatePublished - Apr 1 1999

Fingerprint

Adenine
Macaca mulatta
Safety
Fetus
Mothers
Nurseries
Bone Development
Third Pregnancy Trimester
Second Pregnancy Trimester
Viral Load
Fetal Blood
Cesarean Section
Phosphorus
Reverse Transcription
Alkaline Phosphatase
Body Weight
HIV
Newborn Infant
Viruses
Bone and Bones

Keywords

  • Bone toxicity
  • Fetus
  • Monkey
  • Placental transport
  • PMPA
  • Pregnancy
  • SIV

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Virology

Cite this

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title = "Administration of 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta): Safety and efficacy studies",
abstract = "9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) significantly inhibits viral reverse transcription and has been reported to sustain low virus load in SIV-infected rhesus monkeys. Based on these findings, studies were conducted to assess the safety, efficacy, and placental transfer of PMPA when administered once daily subcutaneously to gravid rhesus monkeys during the second and third trimesters and their offspring (30 mg/kg/day). Fetuses (SIV- infected, N = 6; noninfected, N = 6) were monitored sonographically, and maternal/fetal blood samples were collected at select time points for hematologic, clinical chemical, virologic, immunologic, and pharmacologic assessments. Newborns were delivered by cesarean section at term and nursery reared for postnatal studies. Infants were administered PMPA once daily beginning on day 2 of life until 9 months postnatal age. Results of these studies have shown significant placental transport of PMPA, with peak fetal levels at 1 to 3 hours post-maternal administration; a significant and sustained reduction in viral load in SIV-infected fetuses and infants; and marked improvements in outcome (e.g., survival, growth, health) in SIV- infected offspring. However, decreased infant body weights and alterations of select serum biochemical parameters (e.g., decreased phosphorus levels, elevated alkaline phosphatase) have been shown to occur in ~67{\%} of PMPA- treated infants, with severe growth restriction and bone-related toxicity in ~25{\%} of animals studied. These data suggest that although PMPA holds great promise for HIV-infected patients, there is the potential for bone-related toxicity at chronic, high dosages, particularly in infants.",
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author = "Tarantal, {Alice F} and Marta Marthas and Shaw, {Jing Ping} and Ken Cundy and Norbert Bischofberger",
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AU - Marthas, Marta

AU - Shaw, Jing Ping

AU - Cundy, Ken

AU - Bischofberger, Norbert

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