ABSTRACT
CONTEXT: GH insensitivity syndrome (GHIS), Laron syndrome, is characterized by severe short stature, high serum GH levels, and very low serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels associated with a genetic defect of the GH receptor. Recombinant human (rh) IGF-I treatment at doses of 80-120 microg/kg given sc twice daily is effective in promoting growth in these patients. We have investigated a newly developed drug, rhIGF-I/rhIGFBP-3, a 1:1 molar complex of rhIGF-I and rhIGFBP-3. OBJECTIVES: The objectives of the study were to determine IGF-I pharmacokinetics after the administration of rhIGF-I/rhIGFBP-3 in adolescents with GHIS and to evaluate its safety and tolerability. DESIGN: This was an open-label clinical study. SETTING: The study was conducted in a general pediatric ward of a university teaching hospital. PARTICIPANTS: Four patients (one female and three males; mean age, 14.9 yr; mean height sd score, -4.9) with confirmed molecular diagnosis of GHIS agreed to participate in the study. INTERVENTION: rhIGF-I/rhIGFBP-3 was administered in a single sc injection at 0.5 and 1.0 mg/kg.dose (equivalent to 100 and 200 microg/kg rhIGF-I) after breakfast with a 2-d interval between doses. RESULTS: IGF-I levels reached a maximum between 19 +/- 8.3 and 15 +/- 6.2 h for the low and high doses, respectively. The circulating IGF-I levels obtained with the low and high doses were similar, although a discrete dose-dependent increase in circulating IGF-I levels was observed. The IGF-I half-life in four subjects after a dose of 0.5 mg/kg rhIGF-I/rhIGFBP-3 was estimated to be 21+/- 4 h. There were no acute adverse events reported, and all blood glucose measurements were normal. CONCLUSION: These data demonstrated that the rhIGF-I/rhIGFBP-3 complex was effective in increasing levels of circulating total and free IGF-I into the normal range for a 24-h period after a single sc administration in patients with GHIS, and that administration of rhIGF-I/rhIGFBP-3 was safe and well tolerated.
Subject(s)
Human Growth Hormone/physiology , Insulin-Like Growth Factor Binding Protein 3/pharmacokinetics , Insulin-Like Growth Factor I/pharmacokinetics , Laron Syndrome/metabolism , Adolescent , Blood Glucose/metabolism , Blotting, Western , Body Mass Index , Carrier Proteins/metabolism , Dose-Response Relationship, Drug , Female , Glycoproteins/metabolism , Humans , Insulin-Like Growth Factor Binding Protein 3/administration & dosage , Insulin-Like Growth Factor Binding Protein 3/adverse effects , Insulin-Like Growth Factor I/administration & dosage , Insulin-Like Growth Factor I/adverse effects , Insulin-Like Growth Factor II/metabolism , Male , Models, Statistical , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/pharmacokineticsABSTRACT
Bis(boronates) that utilize internal photoinduced electron transfer (PET) quenching mechanisms can specifically signal the binding of chiro-inositol without responding to its epimer, myo-inositol.
