Current Clinical Trials with Authentic Recombinant Human Growth Hormone in Japan

ABSTRACT. Daily injections of methionine-free, recombinant hGH (rhGH), 8IU, were administered in six healthy volunteers. Non-esterified fatty acid levels increased significantly from 0.45 ± 0.06 to 1.08 ± 0.05 mEq/litre (mean ± SEM) at 4 hours after the first injection of rhGH (p < 0.001). Plasma IGF-1 levels increased significantly at 24 hours after each of the four daily injections of rhGH (basal, 0.80 ± 0.06 units/ml; 24 hours, 1.72 ± 0.21 units/ml; 48 hours, 3.22 ± 0.42 units/ml; 72 hours, 3.17 ± 0.49 units/ml; 96 hours, 3.63 ± 0.32 units/ml; p < 0.001). Eleven patients with hGH deficiency were treated with rhGH, 0.5 IU/kg/week for 3 months. Their heights increased by between 1.1 cm and 4.1 cm during the 3 months of treatment, which was calculated to be equivalent to 4.4–16.4 cm/year, with a mean height velocity of 8.6 ±1.1 cm/year. Anti-hGH antibody was observed in one patient treated with rhGH and had a titre of 10.     

Growth Hormone Treatment in Turner's Syndrome

ABSTRACT. A total of 21 patients with Turner's syndrome were treated with pituitary hGH and/or somatrem for 1–2 years. Plasma non-esterified fatty acid increased significantly from 0.52 ± 0.06 to 1.30 ± 0.09 mEq/litre at 4 hours after injection of hGH, 4 IU (mean ± SEM, p < 0.001). Basal plasma IGF-1 levels were within the normal range; however, they increased significantly at 24 hours after the first three daily injections of hGH, 4 IU (basal, 0.92 ± 0.14 units/ml; 24 hours, 1.39 ± 0.16 units/ml; 48 hours, 1.68 ± 0.19 units/ml; 72 hours, 1.91 ± 0.22 units/ml; p < 0.001). For long-term treatment, patients were given hGH, 4–16 IU for 1–2 years. Their height velocity increased to 5.5 ± 1.2 cm/year and 5.1 ± 0.6 cm/year in the first and second year of the treatment, respectively. These values were greater than the pretreatment value of 3.6 ± 0.8 cm/year (p < 0.001). Antibody against hGH was observed in 60% of the patients at the end of 12 months of somatrem treatment. Otherwise there were no significant changes in physical, blood or urine examinations. These results indicate that hGH treatment is useful for the acceleration of growth velocity in patients with Turner's syndrome.     

Clinical Trial with Authentic Recombinant Somatropin in Sweden and Finland

A total of 47 prepubertal children with hGH deficiency were treated for up to 6 months with recombinant somatropin. All the children markedly increased their growth rate; 21 of them were naive (not previously treated with hGH), and increased their growth rate from 4.2 ± 0.2 cm/year to 13.9 ± 0.9 cm/year (calculated from growth data after 6 months'treatment, n = 11). Of the 47 children, 26 had been previously treated for 2 ± 0.3 years (range 0.3 - 8.3 years) with pituitary hGH. After a period of 0.9 ± 0.03 years (range 5–15 months) without any hGH therapy, their growth rate increased from 2.9 cm/year to 11.1 cm/year on recombinant somatropin therapy (calculated from growth data after 6 months'treatment, n = 10). One child reacted with temporary local erythema at the injection site. Anti-hGH antibodies, with a binding capacity of 0.02 mg/litre, were detected in 1 of the 16 children after 6 months of therapy. No adverse effect on her growth rate was seen. No changes in levels of antibodies to Escherichia coli proteins were detected. No other allergic manifestations or systemic side-effects were demonstrable.     

Current Clinical Trials with Authentic Recombinant Somatropin in Japan

Hibi, I., Takano, K. and Shizume, K. (National Children's Hospital and Tokyo Women's Medical College, Institute of Clinical Endocrinology, Tokyo, Japan). Current clinical trials with authentic recombinant somatropin in Japan. Acta Paediatr Scand [Suppl] 337:141, 1987.
A total of 25 children with hGH deficiency were treated with recombinant somatropin, 0.5 IU/kg/week i.m. for approximately 12 months in a multicentre study. Sixteen patients were previousky untreated with any hGH preparation (naïve group) and 9 patients had been treated with pituitary hGH for 4–42 months (previously treated group). The height gain after 12 months with the present treatment was 7.7 ± 1.8 cm/year in the naive group and 5.8 ± 1.0 cm/year in the previously treated group. Using the criteria proposed by the Foundation for Growth Science in Japan, recombinant somatropin treatment was effective in 15 of 16 patients (93.8%) of the naive group and in all of the 9 patients (100%) in the switched group. Anti-hGH antibody was observed in none of 9 patients in the previously treated group throughout the study period. It was observed in only 2 of 16 patients after 6 months of treatment and 1 of 16 patients after 12 months of treatment in the naïve group. No side-effects or abnormalities in laboratory findings were observed.     

Preliminary Results of Authentic Recombinant Somatropin Treatment in Human Growth Hormone Deficient Children. French Collaborative Study

A total of 50 children with hGH deficiency have been enrolled in a multicentre open trial of recombinant somatropin in France. Recombinant somatropin, 0.2 IU/kg s.c, was administered 3 times/week (0.6 IU/kg/week). Results are available after 3 months'treatment for 24 of the patients (11 prepubertal, 13 pubertal). The mean growth rate increased from 3.8 ± 1.5 cm/year to 9.9 ± 3.6 cm/year. Only one child developed anti-hGH antibodies with a very low binding capacity of 0.02 mg/litre; adverse events were uncommon and probably unrelated to treatment.     

Effect of combined treatment with gonadotropin releasing hormone analogue and growth hormone in patients with central precocious puberty who had subnormal growth velocity and impaired height prognosis

Growth hormone-insulin-like growth factor-I status and response to growth hormone therapy (0.6 IU/kg/week sc, six times a week for 12 months) were evaluated in 12 girls (chronological age 9.4 ± 1.6 years) suffering from central precocious puberty with growth velocity less than 4 cm/year and no substantial increase or decrease in predicted adult height during gonadotropin releasing hormone (Gn-RH) analogue treatment (D-Trp⁶-LH-RH, 60 μg/kg im/28 days). At baseline, large variations were observed in nocturnal growth hormone (GH) means (pathological values (< 3.6μg/l) 33.3%), stimulated levodopa GH peaks (pathological values (<10.0 μg/I) 28.6%) and serum insulin-like growth factor-I (IGF-I) levels. Neither GH nor IGF-I levels were correlated with growth velocity. During recombinant GH therapy, growth velocity increased significantly (baseline 3.0 ± 0.9 cm/year; 6 months 6.4 ± 1.9cm/year, p < 0.001 versus baseline; 12 months 6.0 ± 1.3cm/year, p < 0.001 versus baseline). There was a significant increase in height SDS for bone age (baseline –1.6 ±0.5 SDS; 12 months -1.04 ± 0.6SDS; p < 0.002) and in predicted adult height (baseline 152.0 ± 3.6cm; 12 months 155.9 ± 3.4cm; p < 0.002). Our results suggest that combined therapy with Gn-RH analogues and recombinant GH can improve growth velocity and predicted adult height in girls with central precocious puberty and impaired height prognosis during Gn-RH analogue treatment.     

Treatment of Growth Hormone Deficient Patients with Recombinant Somatropin for 1 year: Results of a Chinese Multicentre Trial

ABSTRACT. Fifty-nine patients with idiopathic growth hormone deficiency were included in a Chinese multicentre trial of recombinant somatropin, 0.5-0.7 IU/kg/week s.c. given in six or seven divided doses. The height velocity increased from 2.8 ±1.0 cm/year to 13.1 ± 2.5 cm/year during 1 year of treatment, and typical catch-up growth was observed. The increase in height SDS for chronological age was significant, but the increase in height SDS for bone age was not statistically significant. No adverse reactions to the treatment were recorded. Recombinant somatropin was shown to be very effective and safe during the first year of therapy in patients with growth hormone deficiency.     

Clinical Experience with Authentic Recombinant Somatropin – German Collaborative Study

A multicentre clinical trial with recombinant somatropin was initiated in West Germany in early 1986. Acceptance of patients to the study was determined according to criteria outlined in a detailed study protocol. To the present time, 41 patients with hGH deficiency not previously treated (naive) and 28 patients previously treated with pituitary hGH have been admitted. Recombinant somatropin is given, 12 IU/m²/week s.c, divided into six doses. Height velocities during treatment rose dramatically for naive patients from 3.5 cm/year (n = 40, before treatment), to 15.0 cm/year (n = 19, calculated at 3 months), and 13.3 cm/year (n = 8, calculated at 6 months). For previously treated patients, the increase in height velocity was from 5.8 cm/year (n = 20) to 9.2 cm/year (n = 19, after 3 months) and 8.6 cm/year (n = 9) at 6 months. Tolerance of recombinant somatropin was good, and no anti-hGH antibodies were detected in any of the patients.     

An Attempt to Assess the Replacement Dose of Human Growth Hormone in the Treatment of Growth Hormone Deficient Children

Hibi, I., Tanaka, T., Yano, H., Umezawa, S., Kagawa, J., Tanae, A. and Ishikawa, E. (National Children's Medical Research Center, Tokyo, the National Children's Hospital, Tokyo and the Department of Biochemistry, Miyazaki Medical College, Miyazaki, Japan). Acta Paediatr Scand [Suppl] 337:87, 1987.
In 25 patients with hGH deficiency, who had been treated long-term with hGH, the mode of hGH administration was switched from the conventional method (0.3–0.5 IU/kg/week, in two or three divided doses, intramuscularly) to daily subcutaneous injection at 1900–2100 hours with a dose of 0.46 ± 0.07 IU/kg/week (equivalent to 14.7 ± 2.0 IU/m²/week). After 1–3 months of this new mode of hGH administration, blood and urine were sampled at 0900 hours after overnight fasting. Blood glucose, plasma insulin, plasma IGF-1 and plasma total IGF (after extraction) were analysed in blood samples. IGF-1 and hGH were measured in urine samples. These measurements indicated that the dose studied was close to a replacement one, but might be slightly higher than the exact replacement dose.     

Clinical Experience with Genotropin in Growth Hormone Deficient Children

The efficacy of Genotropin (recombinant somatropin, KabiVitrum AB, Sweden) was analysed in 194 children with GH deficiency, comprising a combined series of four multicentre trials. The linear height velocity increased from 3.3±1.4 to 9.3±2.6 cm/year in 149 prepubertal children with 12 months'data available. In 18 pubertal children the pretreatment height velocity was 4.0±1.2, and increased to 8.4±1.7 cm/year during 12 months of treatment. There was a positive correlation between the gain in height velocity and the weekly dose of Genotropin. Covariance analysis revealed significantly greater height velocity with 6-7 injections/week compared to 2-3 injections/week; corrections for chronological age, bone age, height SD score and dose were made. On average, a regimen of 6-7 injections/week was 25% more effective than one of 2-3 injections/week corresponding to an extra gain in height velocity of 1.8±0.6 cm/year. At 12 months, only 0.9% of the children had developed anti-GH antibodies. Very few side-effects have been reported from more than 1000 children on Genotropin.     

HYPOCALCEMIA IN INFANTS OF DIABETIC MOTHERS

ABSTRACT. Twenty-two infants of diabetic mothers (IDM) were studied and were divided into two groups: a first group of 14 IDM did not receive vitamin D3 and was studied at birth and at 2, 24, 48 and 120 hours; a second group was given daily dosage of 60 μg of vitamin D3 from 3 hours to 120 hours and was studied at 2 hours and 120 hours.
In the first group, serum calcium levels decreased markedly during the first 24 hours of life (mean ± SD: 1.77±0.3 mmol/1, p <0.01) and remained low at 5 days. Serum phosphorus levels remained normal but serum magnesium levels decreased significantly at 24 hours (mean ± SD: 0.64±0.108 mmol/1, p <0.01) and returned to normal at 5 days. Serum immunoreactive parathormone levels increased consistently to high levels at 24 hours and remained elevated at 120 hours ( p <0.001). Serum immunoreactive calcitonin levels increased at 24 hours ( p <0.001) and decreased at 120 hours to low or undetectable values in all infants.
In group II, serum 25O-HD levels and 1.25 OH₂ D levels increased significantly ( p <0.001) respectively to 27.2±2.7 ng/ml and 114±20 pg/ml at 5 days. The results of this study show hypocalcemia to be a common event in IDM during the first days of life and furthermore hypophosphatemia, hypoparathyroidism, hypomagnesemia or defect of vitamine D metabolism would not seem to be the main etiological factors.     

PASSAGE OF CEPHALOSPORINS AND AMOXICILLIN INTO THE BREAST MILK

ABSTRACT. Kafetzis, D. A., Siafas C. A., Georgakopoulos P. A., and Papadatos C. J. (Second Department of Pediatrics University of Athens, and Third Department of Obstetrics and Gynecology, Maternity Hospital "Marika Iliadi", Athens, Greece). Passage of cephalosporins and amoxicillin into the breast milk. Acta Paediatr Scand, 70:285, 1981.–The concentrations of five cephalosporins and amoxicillin in breast milk were studied in 42 voluntarily participating lactating mothers using standard assay methods. Each mother received one single dose of 1 g of either an orally or intravenously administered antibiotic. Amoxicillin, cephalexin , and cefadroxil were given orally, and peak milk concentrations averaged 0.81±0.33 µg/ml at 5 hours, 0.50±0.23 ug/ml at 4 hours, and 1.64±0.73 µg/ml at 6 hours, respectively. Cephalothin, cephapirin and cefotaxime were given as an i.v. bolus injection, and peak milk concentrations at 2 hours averaged 0.47±0.14 ug/ml, 0.43±0.16 µg/ml and 0.32±0.09 ug/ml, respectively. The high concentrations of cefadroxil can be explained by its low rate of elimination and higher fat solubility. Milk/serum ratios for all antibiotics were increasing as serum concentrations were diminishing, especially with cephalothin and cephapirin whose serum concentrations are rapidly declining. The significance of bactericidal concentrations in breast milk remains to be evaluated.     

Multicentre Clinical Trial of Authentic Recombinant Somatropin in Growth Hormone Deficiency

Bierich, J. R. (Department of Paediatrics, University of Tübingen, Tübingen, West Germany). Multicentre clinical trial of authentic recombinant somatropin in growth hormone deficiency. Acta Paediatr Scand [Suppl] 337:135, 1987.
A German multicentre trial of recombinant somatropin was cdmmenced in March 1986. A total of 77 patients with hGH deficiency were recruited, with heights at least 2.5 SD below the normal mean. Of these, 49 were previously untreated (naïve) and 28 had previously received pituitary hGH. Recombinant somatropin, 12 IU/m²/week was administered subcutaneously, divided into six doses. In the naive group, the height velocity reached 14.9 cm/year in the first 3 months, and thereafter stabilized at 12 cm/year. In the previously treated patients, the growth rate was 10.7 cm/year in the first 3 months, and 8.5 cm/year at 9 and 12 months. There were no abnormal findings in tests of laboratory parameters. No anti-hGH antibodies were detected in any of the patients; seven patients had anti-ECP antibodies, but in six of these the antibodies were already present before treatment.     

Clinical Experience with Somatrem in Japan

ABSTRACT. A total of 62 patients with pituitary dwarfism were treated with three different preparations of human growth hormone (hGH) produced by recombinant DNA technology (somatrem). They were given somatrem, 0.5 IU/kg body weight/week for 3–14 months. Their height velocity increased from 3.5 ± 0.9 to 8.2 ± 1.7 cm/year (mean ± SEM) during treatment. There were no significant changes in physical, blood and urine examinations. Anti-hGH antibody was observed in 39 of 62 patients (62.9%) at the end of 3 months of treatment with three different preparations of somatrem and in 16 of 21 patients (76.2%) at the end of 12 months of treatment with highly purified Somatonorm. The presence of antibody to hGH did not affect the growth rate in 48 of 49 hGH deficient children who had measurable antibody.     

Pharmacokinetics of recombinant human insulin-like growth factor I given subcutaneously to healthy volunteers and to patients with growth hormone receptor deficiency

The pharmacokinetics of recombinant human insulin-like growth factor I (rhIGF-I) were studied in healthy volunteers and in patients with growth hormone receptor deficiency (GHRD; Laron syndrome). Following single subcutaneous injections of rhIGF-I, 40 and 80 μgkg, to healthy volunteers, the peptide was absorbed slowly, with a maximum concentration reached after about 7 hours. Following daily multiple subcutaneous injections of rhIGF-I, 40 μg/kg, trough concentrations of IGF-I were increased by 277 ± 50 μg/l (mean ± SD) from baseline. IGF-I was thus characterized as a low-clearance peptide, with a clearance and half-life estimated at about 0.20 ml/minute/kg and 20 hours, respectively, in healthy volunteers. The volume of distribution was low, about 0.20–0.36 litres/kg, the bioavailability of subcutaneously administered rhIGF-I was 100%, and the rate of production of IGF-I was estimated to be about 50 μg/kg/day (3.5 mg/day). Patients with GHRD had low baseline IGF-I concentrations (30–50 μ g/ l) and a much more rapid turnover of IGF-I compared with that in healthy volunteers. The clearance and half-life of IGF-I were estimated to be about 0.60 ml/minute/kg and 6 hours, respectively. The volume of distribution was about the same as in healthy subjects. Due to the rapid turnover of IGF-I, trough IGF-I concentrations were increased to just above baseline during subcutaneous injections of 40 μg/kg once daily for 7 days. The maximum increase in IGF-I levels was 111 ± 12 μg/l and 150 ± 3 μg/l following daily subcutaneous injections of 40 × 1 and 40 × 2 μg/kg for 7 days, respectively.     

Impaired Response of Growth Hormone-Releasing Hormone (GHRH) Measured in Plasma after L-Dopa Stimulation in Patients with Idiopathic Delayed Puberty

ABSTRACT. In order to investigate the regulation of GH secretion in patients with idiopathic delayed puberty (IDP), either prepubertal (stage P1) or early pubertal (P2), GHRH levels in plasma were measured after stimulation with L-Dopa in a group of 16 patients with IDP. The results were compared to those obtained in 12 patients with constitutional short stature (CSS) at the same stages of puberty, who underwent L-Dopa test for insufficient height. Plasma GHRH levels were measured, after extraction and concentration on C18 Sep Pack columns, by radioimmunoassay using an antibody against 1–40 GHRH, which cross-reacts 100% with 1–44 GHRH. The sensitivity of the assay is 6–8 pg/ml. After L-Dopa intake, the peak of GH was mean ± SEM 8.6±1.4 ng/ml in IDP and 12.0±0.8 ng/ml in CSS (NS). The peak of GHRH after L-Dopa was 41±10 pg/ml in IDP and 96±25 pg/ml in CSS ( p <0.02). A significant ( p <0.02) decrease of plasma GHRH peak values (mean ±SEM 17.3±4.4 pg/ml) was noted in the five patients with IDP whose growth velocity was below -2 SD for their bone age compared to the patients with normal growth velocity (mean ± SEM 75.0±14.5 pg/ml). These results suggest a hypothalamic dysfunction in patients with IDP, and a relationship between the well-known partial and transitory somatotropic deficiency found in some adolescents having a pubertal delay and their secretion of the releasing hormone GHRH.     

EFFECT OF SEASON AND VITAMIN D SUPPLEMENTATION ON PLASMA CONCENTRATIONS OF 25-HYDROXYVITAMIN D IN NORWEGIAN INFANTS

ABSTRACT. Plasma concentrations of 25-hydroxyvitamin D (250HD) were determined in 81 vitamin D supplemented or unsupplemented infants at the end of winter. The values were compared with maternal levels and with concentrations found in 22 unsupplemented infants at the end of summer. The 250HD levels of the neonates were lower, but closely related to maternal values ( r =0.95, p <0.0005). Unsupplemented breast-fed infants had lower 250HD levels at 6 weeks than at 4 days (16±7 vs. 32±15 nmol/l, mean ±1 SD, p <0.0005). The mean 250HD level of vitamin D supplemented 6-12 months old infants was intermediate between those of the unsupplemented nursed groups and the unsupplemented children studied during summer (53±28 vs. 85±28 nmol/l, p <0.0005). Six weeks old infants who had received a milk formula containing 400 IU vitamin D₃ per liter had levels similar to the latter group (92±21 nmol/l). The data suggest that the vitamin D stores acquired during fetal life, or from ultraviolet light exposure during the summer, may be inadequate to maintain safe levels of 250HD throughout the winter, but that a daily supplement of 400 IU is adequate to establish concentrations in the summer range.     

Biosynthetic growth hormone therapy in children with growth hormone deficiency: Experience at AIIMS,New Delhi

A total of 20 previously untreated children with growth hormone deficiency (GHD) were treated for one year with biosynthetic human growth hormone (hGH). The mean chronologic age was 9.43±3.52 years with a height age of 5.02 years, and bone age 9.43±3.52 (TW2-RUS) 6.42 years. The mean pretreatment growth velocity was 2.43±0.90 cm/year. Of these 14 children had complete GHD (peak GH levels less than 5 ng/ml) and 6 had partial GHD. They were treated with recombinant GH in a dose of 0.5 IU/kg/week divided into 6–7 injections per week subcutaneously at night. The mean growth velocity increased to 8.88±2.10 cm/yr at the end of 6 months and 8.00±2.21 cm/yr at 12 months. The actual gain ranged from 6–11 cm in a year. There were no local adverse reactions. One child developed vitiligo of the face and another transient hyperglycemia.     

Effects of Short-Term Growth Hormone Therapy in Short Children without Growth Hormone Deficiency

ABSTRACT. Evaluation of 24-hour endogenous growth hormone (GH) secretion was carried out in 62 children, aged 7-16 years, who did not have classic GH deficiency (GHD). The mean 24-hour GH concentration, determined at 20-minute intervals over 24 hours, was variable, ranging from 1.28 to 11.39 μg/l with a mean of 4.95 ± 2.55 μl (± SD). There was a positive correlation between mean 24-hour GH concentration and plasma insulin-like growth factor I (IGF-I) values ( r = 0.54; p < 0.01). Recombinant human GH, 0.1 IU/kg/day was administered to 30 of the 62 children for 6 months followed by 6 months'observation without treatment. Thereafter, GH was administered at the same dose for a further 6 months to 16 children. The mean height velocities before, during, and after the first treatment period were 4.3 ± 0.9, 7.3 ± 1.9 and 4.9 ± 2.0 cm/year (mean ± SD), respectively. The height velocity during treatment was greater than pre- and post-treatment values ( p < 0.001). The height velocity Increased again during the second treatment period to a mean of 8.5 ± 2.0 cm/year ( p < 0.001). Nine other children were treated continuously in a similar manner for 1 year and their height velocity increased significantly from 4.1 ± 1.4 to 6.0 ± 1.9 cm/year ( p < 0.001). According to our criteria, 29 of the 39 children (74.4%) who were treated for 6-12 months showed a GH-dependent height increase during therapy. There were no differences between the children who responded to GH treatment and those who did not in terms of Chronological age, bone age, plasma IGF-I level, maximal GH level to insulin-induced hypoglycaemia, or mean 24-hour plasma GH concentration. These data indicate that some short children without GHD respond to GH treatment with an increased height velocity. Further investigations are required to determine the effect of GH on final height.     

Clinical Experience with Genotropin Worldwide: An Update March 1987

Gunnarsson, R., and Wilton, P. (Medical Department, KabiVitrum Peptide Hormones, Stockholm, Sweden). Clinical experience with Genotropin worldwide: an update March 1987. Acta Paediatr Scand [Suppl] 337:147, 1987.
The efficacy and safety of Genotropin (recombinant somatropin, KabiVitrum AB, Sweden) was analysed in 199 children with hGH deficiency, comprising a combined series of four current multicentre trials. Stimulation of linear growth from pretreatment height velocities of 3–4 cm/year to about 10 cm/year was observed after 6 and 9 months of treatment. Statistical analysis revealed significantly greater height velocities (by 2–3 cm/year) when the weekly dose of the hormone was given in 6–7 injections rather than in 3 injections. Immunogenicity seems to be very low, with only about 2% of the children having detectable antibodies during treatment.