| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Endocrinology, William Harvey Research Institute, Queen Mary, University of London (C.C.-H., H.L.S., F.M.-M., M.O.S.), London EC1M 6BQ, United Kingdom; Department of Pediatrics, Birmingham Heartland Hospital (S.R.), Birmingham B9 5SS, United Kingdom; Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health (M.A.P.), London WC1N 1EH, United Kingdom; Insmed, Inc. (M.S., A.R., G.A., A.S.), Glen Allen, Virginia 23060; Department of Endocrinology and Metabolism and Center of Excellence for Biomedical Research, University of Genoa (F.M.), Genoa I-16132, Italy; and Medical Research Laboratories and Medical Department, Nørrebrogade, Aarhus University Hospital (J.F.), Aarhus DK-8000, Denmark
Address all correspondence and requests for reprints to: Dr. Cecilia Camacho-Hübner, Department of Endocrinology, William Harvey Research Institute, John Vane Science Building, First Floor, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail: c.camacho-hubner{at}qmul.ac.uk.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
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 µg/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.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Long-term studies have demonstrated that patients receiving rhIGF-I therapy greatly benefited demonstrating sustained catch-up growth and improvement of height SD scores (SDS) from –6.5 to –4.2 and from –5.6 to –4.2 after 5 and 7.5 yr of treatment, respectively (10, 11, 12). The clinical benefit of rhIGF-I therapy outweighed the adverse side effects of this drug, which were primarily pain at the injection site, headaches, and hypoglycemia usually occurring during the first months of treatment (10, 11, 12). Other adverse events were observed with chronic treatment, such as lipohypertrophy at the injection site and rarely papilledema, related to benign intracranial hypertension. In the latter case the symptoms improved after interrupting the treatment and did not recur when IGF-I was restarted at a lower dose. The adverse events may have been related to high levels of free IGF-I, which occur after rhIGF-I administration (10, 11, 12). However, it is important to emphasize that one of the most limiting factors for the clinical use of rhIGF-I, as discovered in the early clinical studies in the late 1980s, has been a shortage of supplies of the drug.
Recently, a new rhIGF-I compound has been developed which contains a 1:1 molar complex of rhIGF-I and rhIGFBP-3 (Insmed, Inc., Glen Allen, VA). rhIGF-I/rhIGFBP-3 is IGF-I derived from Escherichia coli containing the human gene for IGF-I coupled to IGFBP-3 derived from E. coli containing the human gene for IGFBP-3. After extensive in vitro and animal studies, it was shown that rhIGF-I/rhIGFBP-3 mimics the physiological effects of IGF-I, with a more favorable pharmacokinetic profile (16). In animal studies, rhIGF-I/rhIGFBP-3 has biological effects similar to or enhanced compared with those observed with administration of rhIGF-I alone (17). Upon entering the circulation, rhIGF-I/rhIGFBP-3 binds to acid-labile subunit (ALS) to form the ternary complex that represents the natural form of circulating IGF-I (18). These experimental studies were followed by phase 1 and 2 clinical trials, which demonstrated its safety and efficacy in adult healthy volunteers and subjects with type 1 and 2 diabetes mellitus or patients recovering from osteoporotic hip fracture (19, 20, 21).
In a study conducted in severely burned children, rhIGF-I/rhIGFBP-3 improved the catabolic state with similar efficacy to rhIGF-I alone, but without serious acute side events (22). This led us to hypothesize that administration of rhIGF-I/rhIGFBP-3 to children with GHIS would be safe and effectively improve the pharmacokinetics of the increased levels of circulating IGF-I. We, therefore, performed a pharmacokinetic study in which we administered rhIGF-I/rhIGFBP-3 sc in increasing doses to four subjects with the genetic form of GHIS. Participants were monitored for effects on serum levels of IGF-I, IGFBP-3, and ALS as well as levels of blood glucose and other clinical and laboratory markers of safety. As a secondary outcome variable, effects on tolerability were also measured.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Screening visit
After taking a full medical history and performing a physical examination, an electrocardiograph was performed. Five milliliters of blood was drawn for differential cell count, liver function tests, urea, electrolytes, calcium, phosphorus, and levels of total serum IGF-I, IGFBP-3, and ALS. Major medical problems were excluded. The screening visit was conducted while the patients were receiving compassionate treatment with rhIGF-I (Pharmacia Biotech, Stockholm, Sweden). Normal clinical examination, with the exception of the clinical features corresponding to GHIS, normal electrocardiograph and general biochemistry, and willingness to participate led to inclusion in the study.
Study drug
The protein complex rhIGF-I/rhIGFBP-3 (Insmed, Inc.) was manufactured by fermentation (each protein separately) of rhIGF-I and nonglycosylated rhIGFBP-3 in genetically engineered E. coli bacteria containing the DNA encoding for each of the human proteins. The purification of both proteins was achieved by column chromatography. The rhIGF-I/rhIGFBP-3 complex is formed in a 1:1 molar ratio of rhIGF-I to rhIGFBP-3, corresponding to the naturally occurring protein complex. Cation exchange column chromatography was used to purify the complex.
The formulation buffer for rhIGF-I/rhIGFBP-3 was 50 mM sodium acetate and 105 mM sodium chloride (pH 5.5). The enclosure system consisted of a 2-ml USP type I glass vial with a 13-mm opening, a 13-mm Flurotec stopper (Daiko Sieko Ltd., Tokyo, Japan), and a 13-mm flip-off seal. The formulated complex was aseptically filled under general medical practice conditions and released according to Insmed specifications.
Study design
Four adolescent subjects (three males and one female; mean age, 14.9 ± 0.9 yr) with a confirmed diagnosis of GHIS were studied. All subjects participated in this clinical study, which took place at Royal London Hospital (London, UK). Each subject was first studied while receiving his or her last week of treatment with rhIGF-I at a dose of 80 µg/kg given by sc injection twice daily; this treatment was stopped due to lack of drug supply. After an approximately 3-month washout period, each subject was readmitted for the phase 1 clinical study using rhIGF-I/rhIGFBP-3 treatment at 0.5 and at 1.0 mg/kg·dose (corresponding to 0.1 and 0.2 mg/kg·dose of rhIGF-I alone, respectively). The study drug was administered by sc injection, rotating the site of injection.
The participants were admitted for 2 d while receiving their regular treatment with rhIGF-I after 24 h of stopping their medication with rhIGF-I. Before breakfast, a venous catheter was placed in the forearm, and they were allowed to walk in the ward. Standardized meals were served at 0800, 1200, and 1800 h. Extra snacks were freely available.
The patients received two doses of rhIGF-I at their established therapeutic dose (80 µg/kg, sc, twice daily), given after breakfast and after the evening meal, as part of their last week of medical treatment with this drug.
The children’s well-being and vital signs were monitored throughout the study. Glucose levels were measured at hourly intervals from 0900–2100 h, then every 4 h during the night after injection, and then twice daily throughout the study period in all four subjects. Serum electrolytes, phosphate, and magnesium concentrations were determined daily. Blood was drawn for measurements of IGF-I, IGFBP-3, IGF-II, and ALS levels as well as biochemical parameters. Marked lipohypertrophy was observed on the legs in all patients. Only the arms were used for injecting rhIGF-I during this study day, and no local reactions at the injection sites were observed.
Blood samples were obtained at 60-min intervals from 0800 h just before breakfast until 2100 h; the last sample was obtained the following morning at 0800 h. No overnight sampling was performed, but glucose monitoring was carried out during the night. The patients were discharged home after lunch.
After a washout period of 3 months in which the subjects did not receive any medication, they were readmitted to the Royal London Hospital for the phase 1 clinical study using rhIGF-I/rhIGFBP-3.
The study protocol was as follows. An indwelling catheter was placed in the forearm before breakfast, and baseline blood samples were obtained. After a standard breakfast, a single dose of rhIGF-I/rhIGFBP-3 (0.5 mg/kg·dose, equivalent to 100 µg/kg rhIGF-I) was given by sc injection at 0830 h. Serial blood samples were drawn at the following time points: baseline and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 24, 28, and 48 h after treatment. At 72 h after first dose of 0.5 mg/kg, a blood sample was taken, and the second dose of rhIGF-I/rhIGFBP-3 (1.0 mg/kg·dose, equivalent to 200 µg/kg rhIGF-I) was administered by sc injection (Fig. 1
). No overnight sampling was performed, but glucose monitoring was carried out during the night.
|
Biochemical analysis
All samples from the same subject were analyzed within the same assay in duplicate unless otherwise stated. Plasma glucose was determined immediately after blood sampling (Beckman Instruments, Palo Alto, CA)
Total IGF-I and IGF-II. IGF-I and IGF-II were measured using commercial immunoassays (Diagnostic Systems Laboratories, Webster, TX) with a lower limit of sensitivity of less than 1 ng/ml for IGF-I. The interassay coefficients of variation for IGF-I and IGF-II were 6.8% and 8.9%, respectively.
Free IGF-I. Free IGF-I levels were determined using ultrafiltration by centrifugation (23). The detection limit of ultrafiltered free IGF-I was 0.025 ng/ml. The intraassay coefficient of variation averaged 15%.
IGFBP-3, IGFBP-2, and ALS. Serum IGFBP-3 and ALS levels were determined using commercially available immunoassays (Diagnostic System Laboratories). Serum IGFBP-3 levels were measured using an ELISA kit with a detection limit of 0.04 ng/ml. The interassay coefficient of variation was 8.3%. The normal reference value for 13–17 yr olds (mean ± SD) is 3.9 ± 0.9 mg/liter.
Serum ALS levels were measured with a commercial ELISA (Diagnostic System Laboratories) with a detection limit of 0.7 ng/ml absolute concentration and an interassay coefficient of variation of 8%. The normal reference value for 13–17 yr olds (mean ± SD) is 26.7 ± 3.7.
IGFBP-2 was measured using an RIA kit (Diagnostic System Laboratories) with an assay sensitivity of 0.5 ng/ml and an interassay coefficient of variation of 4.9%.
Immunoblot analysis of IGFBP-3
Characterization of IGFBP-3 was performed on serum samples (5 µl) obtained at baseline and 8 and 24 h after rhIGF-I/rhIGFBP-3 injections at low and high doses. Briefly, samples were denatured and fractionated under nonreducing conditions on 12.5% SDS-PAGE, then transferred to Hybond C-Extra nitrocellulose membranes (Amersham Biosciences, Arlington Heights, IL). After transfer, nonspecific binding sites were blocked using Tris-buffered saline-Tween [0.02 mol/liter Tris base, 0.137 mol/liter NaCl, and 0.5% Tween 20 (pH 7.6) with 1 mol/liter HCl] containing 10% nonfat dry milk (Bio-Rad Laboratories, Inc., Hercules, CA) for 1 h at room temperature on an orbital shaker. The membranes were washed with Tris-buffered saline-Tween, and then incubated at 4 C overnight with a 1:2000 dilution of anti-IGFBP-3 antiserum (Upstate Biotechnology, Inc., Lake Placid, NY). After washing, the membranes were incubated with antirabbit secondary antibody conjugated to horseradish peroxidase at a 1:8000 dilution for 1 h at room temperature. The bands were visualized using an enhanced chemiluminescence detection system (ECL, Amersham Biosciences, Little Chalfont, UK).
Calculations for pharmacokinetic modeling
Pharmacokinetic parameters were derived from measurements of serum IGF-I and were calculated with a model-independent approach using the program WinNonlin (version 3.2, Pharsight Corp., Mountain View, CA). The following pharmacokinetic variables were estimated: observed maximum IGF-I concentration, volume of distribution, observed time for maximum IGF-I concentration, and elimination half-life, calculated as ln(2)/Kel.
Statistics
All data are expressed as the mean ± SD. Only descriptive statistics are presented. It was not appropriate to perform statistical hypothesis testing due to the small sample size.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
. Three subjects were progressing normally through puberty. It is worth noting that only subject 2 had a clinical facial phenotype of classical Laron syndrome and a molecular defect in the extracellular domain of the GHR (splice site mutation in intron 2 of the GHR). The other three subjects had mild clinical facial features or no dysmorphic features associated with different molecular defects in the GHR (Table 2) and were considered to have nonclassical or an atypical form of GHIS. Biochemical investigations and molecular analysis of the GHR in each subject are described in Table 2.
|
|
Baseline biochemical characteristics
Baseline samples were obtained at entry into this study after a 3-month washout period from the end of their prolonged rhIGF-I therapy (Table 2
). The serum IGF-I and IGFBP-3 values obtained at this time were higher than the values reported at diagnosis, but all of them were less than –2 SDS. The main clinical difference was that at the time of this clinical study, three of the subjects were progressing through puberty. Only subject 3 was prepubertal at the time of this study.
Adverse events
Throughout the study, all subjects remained euglycemic, hemodynamically stable, and with normal vital signs. No signs or symptoms of anaphylaxis, allergic, or local reactions at injection site were observed. All subjects had evidence of lipohypertrophy on the legs due to their previous long-term treatment with rhIGF-I alone. Therefore, the treatment injections were given in the upper arms, rotating the injection site for each study drug treatment dose. All subjects experienced some pain with injections of combined therapy. One subject (subject 1) experienced nausea 14 h after administration of 0.5 mg/kg·dose rhIGF-I/rhIGFBP-3, but this symptom was not associated with hypoglycemia or changes in vital signs.
IGF-I exposure
To obtain an estimate of IGF-I exposure, all subjects were investigated for 24 h while receiving their standard treatment with rhIGF-I (80 µg/kg given by twice daily sc injections). A 24-h washout preceded the sampling protocol. The daily (24-h) exposure to IGF-I was estimated in the four subjects by calculating the area under the serum concentration vs. time curve (AUC) after the two injections of rhIGF-I were given.
Three months after stopping rhIGF-I treatment, the subjects were admitted to determine rhIGF-I/rhIGFBP-3 pharmacokinetics and safety. The AUC was used as a measure of total exposure. AUC(0-inf) values for single doses of rhIGF-I/rhIGFBP-3 are approximately three times higher than the values for the 80 µg/kg twice-daily treatment of rhIGF-I based on the data obtained at the subjects’ first admission to the hospital while receiving rhIGF-I treatment (Table 3). These data confirm that once-daily administration of rhIGF-I/rhIGFBP-3 provides adequate exposure, during a 24-h period, compared with twice-daily dosing of rhIGF-I.
|
Figure 2 shows the time course of total IGF-I (circulating bound to IGFBPs plus circulating free), total IGF-II, IGFBP-3, ALS, and glucose levels in the four subjects when they received 0.5 mg/kg and, 3 d later, 1.0 mg/kg rhIGF-I/rhIGFBP-3. The serum IGF-I profiles obtained with the low dose and high doses (0.5 and 1.0 mg/kg, respectively) were similar, although a discrete dose-dependent increase in circulating IGF-I levels was observed, and this was associated with a discrete dose-dependent decrease in circulating IGF-II levels (Fig. 2). An approximately 40% increase in serum IGFBP-3 was observed after treatment.
|
). All glucose determinations carried out during the study period were normal.
Selected serum samples from each subject were subjected to IGFBP-3 immunoblot analysis. A discrete band at approximately 30 kDa corresponding to nonglycosylated IGFBP-3 was found. This band appears to correspond to the study drug (nonglycosylated rhIGFBP-3); it was found 2 h after rhIGF-I/rhIGFBP-3 injection and remained until 8 h after injection, disappearing from the circulation by 24 h. This could be due to rapid clearance or increased proteolysis of nonglycosylated IGFBP-3 (Fig. 3).
|
After the injections of rhIGF-I/rhIGFBP-3, the concentrations of total IGF-I increased in all treated subjects. Maximum levels were increased to approximately 3- to 4-fold baseline IGF-I concentrations when receiving the low or high dose of rhIGF-I/rhIGFBP-3. Levels reached a maximum between 19 ± 8.3 and 15 ± 6.2 h for the low and high doses, respectively. The serum IGF-I profiles obtained with the low and high doses (0.5 and 1.0 mg/kg, respectively) were similar, although a discrete dose-dependent increase in circulating IGF-I levels was observed.
The maximum total IGF-I levels and the times at which these levels were observed are shown in Fig. 2 and are summarized in Table 3.
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, based on the baseline-corrected data and calculated as ln(2)/Kel, where Kel is the linear portion of the log concentration vs. time curve. The half-life is markedly longer than that previously reported in adults with GHIS after a dose of rhIGF-I (26).
Steady-state level
One subject received daily sc injections of rhIGF-I/rhIGFBP-3 at a dose of 1 mg/kg·d after breakfast for 5 consecutive days (Fig. 4). The serum IGF-I concentrations remained more or less unchanged from d 2–6, indicating no accumulation of IGF-I between doses.
|
To determine the effect of rhIGF-I/rhIGFBP-3 administration on free IGF-I, this was measured at all time points. Free IGF-I appeared to be reasonably constant (less than 10% of the total IGF-I during treatment with rhIGF-I/rhIGFBP-3) as shown in Fig. 5.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Our results demonstrate that the combination of rhIGF-I and rhIGFBP-3 administered in a single sc injection increased circulating IGF-I levels into the normal physiological range in four adolescents with genetic GHIS while maintaining normal blood glucose levels. Because these patients had significantly low endogenous IGFBP-3 and ALS concentrations, their ability to maintain IGF-I levels for 24 h or more is evidence of the effect of using combined rhIGF-I and rhIGFBP-3 therapy.
The majority of naturally circulating IGF-I exists in the form of a ternary complex consisting of equimolar amounts of IGF-I, IGFBP-3, and ALS. IGF-I binds IGFBP-3 and the binary complex, in turn, binds ALS, regulating IGF-I half-life and bioavailability (18). IGF-I carried within the ternary complex has a half-life of more than 15 h (26, 27).
A study of the pharmacokinetics of rhIGF-I (40 µg/kg single dose) administered sc to young adults with GHIS and normal subjects demonstrated clearance and half-life in GHIS subjects to be 0.60 ml/min·kg and 5.7 ± 2.4 h, respectively, compared with 0.20 ml/min·kg and 17 ± 8.8 h in healthy subjects (26). In GHIS patients, the rapid clearance of rhIGF-I is related to decreased production of IGFBP-3 and ALS.
GH stimulates IGFBP-3 and ALS in GH-deficient subjects. Lee et al. (28) reported the effect of a single sc dose of rhGH given to untreated GH-deficient subjects leading to an increase in serum IGF-I 3 h after treatment coincident with peak GH concentrations. The rise in IGF-I levels preceded that in IGFBP-3, the major carrier for IGFs. ALS is a glycoprotein with an almost exclusively hepatic origin; therefore, it may reflect hepatic GH responsiveness better than IGF-I and/or IGFBP-3, which are produced in many tissues (18).
ALS levels have not been determined systematically in GHIS patients. A previous study using ALS immunoblot demonstrated significant low ALS levels in patients with classical GHIS (29), and similar findings were described for a prepubertal patient with classical Laron syndrome before and after rhIGF-I treatment (30).
In our study GHIS subjects demonstrated that rhIGF-I/rhIGFBP-3, or possibly the limited amounts of endogenous glycosylated IGFBP-3, displaced from IGF-II, can bind to the endogenous ALS that is produced, extending the half-life of IGF-I (26). Although it appears that the injected nonglycosylated rhIGFBP-3 (from rhIGF-I/rhIGFBP-3) may clear rapidly after delivering IGF-I. Immunoblot analysis indicates that treatment with rhIGF-I/rhIGFBP-3 resulted in the appearance of a distinct band of approximately 30 kDa corresponding to nonglycosylated IGFBP-3, but that this protein disappears by 24 h after injection of study drug. The net effects of rhIGF-I/rhIGFBP-3 administration are an increase in serum IGF-I, a decrease in serum IGF-II, and a discrete increase in serum IGFBP-3.
It is possible that ternary complex is formed with the small amounts of ALS present in three of these subjects, as shown in Fig. 2.
The concentrations of endogenous IGFs, IGFBP-3, and ALS were all less than –2 SD below the mean of reference values for age, sex, and stage of puberty and therefore were deemed insufficient to allow normal growth velocity in affected individuals.
In GHIS, the rhIGF-I/rhIGFBP-3 complex has theoretical advantages over rhIGF-I alone. Firstly, GHIS patients have severe deficiency of the three peptides of the ternary complex. Consequently, IGF-I has a significantly reduced half-life of approximately 6 h in patients with GHIS compared with over 15 h in normal adults (26), making twice-daily injections of IGF-I preferable. A longer half-life of IGF-I was observed in the four subjects treated with rhIGF-I/rhIGFBP-3 in this study, and this could reduce the frequency of injections during treatment. In a single patient, sampling for IGF-I after consecutive daily injections of rhIGF-I/rhIGFBP-3 suggested that there was no additional accumulation of serum IGF-I.
Adverse effects related to rhIGF-I therapy are likely to be linked to high concentrations of free IGF-I after sc injection. These could be reduced if the rhIGF-I/rhIGFBP-3 complex were associated with physiological circulating levels, especially of free IGF-I. To some extent, this was the case, as reported in this study with determination of free IGF-I levels at various time points.
Treatment with rhIGF-I/rhIGFBP-3 was well tolerated by all subjects. None of the subjects experienced local reaction to the injections, and no symptoms or signs of anaphylaxis were noted after its administration. The development of this new compound will allow future studies to evaluate the long-term safety and efficacy in GHIS patients. Treatment of GHIS with rhIGF-I/rhIGFBP-3 could provide a means of administering large doses of IGF-I without the generation of substantial quantities of free IGF-I. Thus, rhIGF-I/rhIGFBP-3 has the potential to minimize acute insulin-like side effects that are thought to be due to the interaction of therapeutic quantities of IGF-I with the insulin receptor. Finally, the implications of the long-term safety of rhIGF-I/rhIGFBP-3 administration are important if this form of treatment is to enter clinical practice for GHIS patients as well as for other pediatric patients suffering from diseases associated with IGF-I deficiency.
In conclusion, the rhIGF-I/rhIGFBP-3 complex was effective in increasing levels of circulating total and free IGF-I into the normal range for a prolonged period after a single sc administration. The drug was well tolerated and did not cause acute side effects. Therefore, rhIGF-I/rhIGFBP-3 warrants additional evaluation in phase II/III clinical studies for the treatment of IGF-I deficiency caused by genetic defects of the GHR or to acquired severe GH resistance and in syndromes of severe insulin resistance.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
The authors have no conflict of interest.
First Published Online January 10, 2006
Abbreviations: ALS, Acid-labile subunit; AUC, area under the serum concentration vs. time curve; GHIS, GH insensitivity syndrome; GHR, GH receptor; rhIGF-I, recombinant human IGF-I; rhIGFBP-3, recombinant human IGF-binding protein-3; SDS, SD score.
Received May 6, 2005.
Accepted January 4, 2006.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  R. G Rosenfeld IGF-I therapy in growth disorders Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S57 - S60. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
) or high dose (1.0 mg/kg·dose; 
).
