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 micrograms/kg, 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 micrograms/kg, trough concentrations of IGF-I were increased by 277 +/- 50 micrograms/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 micrograms/kg/day (3.5 mg/day). Patients with GHRD had low baseline IGF-I concentrations (30-50 micrograms/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 micrograms/kg once daily for 7 days. The maximum increase in IGF-I levels was 111 +/- 12 micrograms/l and 150 +/- 3 micrograms/l following daily subcutaneous injections of 40 x 1 and 40 x 2 micrograms/kg for 7 days, respectively.

Pharmacokinetic profile of recombinant human insulin-like growth factor I given subcutaneously in normal subjects.

The pharmacokinetic profile of recombinant human insulin-like growth factor I (IGF-I) was studied in healthy volunteers. Following a single subcutaneous injection of 40 micrograms/kg or 80 micrograms/kg, mean serum IGF-I concentrations increased by 150 ng/ml and 245 ng/ml, respectively. During repeated daily injections of 40 micrograms/kg, a steady-state IGF-I level of 150 ng/ml above baseline was reached. Of the pharmacokinetic indices measured, only Tmax varied between single and multiple dose regimens (6.9 hours versus 3.5 hours). No hypoglycaemic symptoms were observed, and after injection of IGF-I no depression of endogenous IGF-I production was observed. Fasting insulin levels were unaltered, but postprandial insulin was lowered by IGF-I with respect to placebo.

Clinical spectrum of the syndrome of growth hormone insensitivity. Advisory Committee on Growth Hormone Insensitivity.

A survey of 46 patients with suspected growth hormone (GH) insensitivity is presented. Clinical details and plasma samples from these patients were analysed centrally. A diagnostic score based on basal levels of GH and insulin-like growth factor I (IGF-I), IGF-I response to GH (0.1 U/kg daily for 4 days) and height SDS was determined for all patients to identify those with GH insensitivity. A total of 29 such patients was identified (14 males and 15 females; age range, 3.2-22.6 years). Their mean height SDS was -6.0 (range, -8.9 to -2.6), mean weight SDS was -2.9 (range, -5.2 to 1.2). Pubertal development was delayed in three out of three boys and two out of six girls of pubertal age. Their basal GH level was 32.4 mU/l (range, 0.8-158.2 mU/l) and mean basal IGF-I level was 33.6 ng/ml (range, 20-97 ng/ml). None of the 29 patients showed a significant serum IGF-I response to injections of GH.

Recombinant human growth hormone treatment in short children with chronic renal disease, before transplantation or with functioning renal transplants: an interim report on five European studies.

Growth retardation is common in children with chronic renal disease. Final adult height is often reduced, even in children with a functioning renal transplant. The five European studies considered here aim to investigate the efficacy and safety of recombinant human growth hormone therapy (rhGH) in two groups of short children with chronic renal disease. The first group comprises 29 prepubertal children with preterminal chronic renal failure (i.e. before renal transplantation), and the second group comprises 39 prepubertal and pubertal children with functioning renal transplants. The median bone age retardation in the groups at the start of treatment was between 2.2 and 3.7 years; this did not change during the first year of treatment. This interim report concentrates on patients who have been treated for at least 1 year (i.e. 22 children from the first group, and 28 children from the transplant group (15 prepubertal and 13 pubertal children). The median height velocity increased from 4.8 cm/year to 10.0 cm/year in the first group (the chronic renal failure group), from 2.6 cm/year to 6.2 cm/year in prepubertal children with renal transplants and from 3.8 cm/year to 6.7 cm/year in pubertal children with renal transplants. The corresponding changes in height velocity SDS were from -1.3 to 5.1 for the chronic renal failure group and -2.8 to 2.3 for the prepubertal children with renal transplants. Renal function declined in the chronic renal failure group but this decline corresponded to expected progression of the disease. Some of the children with renal transplants showed a decreased renal function, which in most cases was explained by non-compliance or chronic rejection.

An open-labelled study of the safety, acute metabolic activity and pharmacokinetic profile of a short-term course of recombinant human growth hormone in healthy volunteers.

The safety and short-term biological effects of recombinant human GH (Genotropin, KmbiVitrum AB, Stockholm, Sweden), given i.m. (8 IU/d) for 4 consecutive days to 10 healthy male volunteers, have been evaluated. No adverse reactions were detected by clinical investigation. Haematological parameters, clinical chemistry and the acute phase inflammatory profile showed no negative effects of the drug. The well-known metabolic effects of GH were seen as an increase in free fatty acids and in the somatomedin level (IGF-1). No antibodies to GH or periplasmic Escherichia coli peptides developed during the first month after treatment. The peak plasma level of hGH (62 +/- 20 mU/l) occurred between 3.0 and 3.5 h. This study shows that recombinant hGH induces no toxic or other adverse reactions and that the acute metabolic effects and the pharmacokinetic profiles are comparable to those reported after injections of GH extracted from pituitary glands.

Effect of domperidone on apomorphine inhibition of the copulatory response and exploratory behaviour in the female rat.

The effects of domperidone, a peripheral dopamine receptor blocker which poorly crosses the blood-brain barrier, on copulatory and exploratory behaviour were studied in apomorphine (oestrogen + progesterone) treated ovariectomized rats. The dose of domperidone (1.0 mg/kg) which clearly prevented the inhibitory action of apomorphine on the lordotic response did not influence the effect of apomorphine in an exploratory test situation. This finding indicates that peripherally (intraperitoneally) administered domperidone influences dopaminergic mechanisms implicated in the copulatory behaviour of the female rat, but not dopaminergic mechanisms involved in exploratory behaviour. The possibility that domperidone reaches the brain region responsible for the lordotic behaviour, e.g. the hypothalamus, is discussed.

Involvement of 5-HT2 receptors in the LSD- and L-5-HTP-induced suppression of lordotic behavior in the female rat.

Copulatory behavior in the ovariectomized rat, the lordotic response (L.R.), was induced by estrogen followed by progesterone. L.R. is inhibited by lysergic acid diethylamide (LSD) (greater than or equal to 0.05 mg/kg) and by Levo-5-hydroxytryptophan (L-5-HTP) (greater than or equal to 2.5 mg/kg). The effects of the putative 5-HT antagonists lisuride, metergoline, methysergide, mianserin, cinanserin, cyproheptadine, pirenperone and altanserin on the LSD-induced inhibition of L.R. were tested. Lisuride, metergoline, methysergide and mianserin were found to have no LSD-blocking effect. In contrast, cinanserin, cyproheptadine and pirenperone acted antagonistically to LSD, within a critical dose range. The selective 5-hydroxytryptamine2 (5-HT2) receptor antagonist altanserin effectively prevented the LSD-induced inhibition of L.R., and the doses required (0.05-0.20 mg/kg) indicated a comparatively high antagonistic potency. In addition altanserin (0.2 mg/kg) effectively prevented the lordosis inhibitory effect induced by L-5-HTP (2.5 mg/kg), after pretreatment with pargyline and RO4-4602. It is suggested that the suppression of copulatory behavior caused by LSD and L-5-HTP is mediated by 5-HT2 receptors.

Progesterone enhancement of lysergic acid diethylamide and levo-5-hydroxytryptophan stimulation of the copulatory response in the female rat.

Copulatory behavior in the ovariectomized rat, i.e. the lordosis response (LR) on being mounted by a male, can be induced by administration of either estrogen alone or estrogen followed by progesterone. LR has been shown to be inhibited by lysergic acid diethylamide (LSD) in certain doses (greater than or equal to 50 micrograms/kg) and by Levo-5-hydroxytryptophan (L-5-HTP) (greater than or equal to 2.5 mg/kg). This effect was recently found to be enhanced by increasing doses of progesterone. In contrast, small doses of LSD (5-30 micrograms/kg) have been shown to increase LR activated by estrogen alone. The effects of various hormone treatments on the stimulatory action of LSD were tested in the present study. When the lordosis behavior was activated by estradiol benzoate (EB) alone (25 or 7 X 2 micrograms/kg), LR increased 10 min after injection of LSD in a dose of 10 micrograms/kg. There were no detectable effects in animals treated with estrogen alone when the dose of LSD was lowered to 1 microgram/kg. LSD in the latter dose gave an increased response, however, when LR was activated by EB (5 micrograms/kg) in combination with progesterone (4.0 mg/rat). An analogous study was conducted with L-5-HTP, after pretreatment with pargyline and R04-4602. Small doses of L-5-HTP (0.25 and 0.05 mg/kg) stimulated the LR and the influence of progesterone was the same as for small doses of LSD. Possible mechanisms underlying the observed influence of progesterone on serotonergic mechanisms involved in the lordosis behavior are discussed.

Enhancement by progesterone of 5-hydroxytryptophan inhibition of the copulatory response in the female rat.

A study was made of the influence of different hormonal treatments used to induce copulatory behavior in ovariectomized female rats (lordosis behavior), on the effects of an endogenous increase of 5-HT or catecholamines achieved by DL-5-HTP and L-Dopa. The lordosis response (LR) has been shown to be inhibited by increased serotonergic and catecholaminergic neuronal activity. The 5-HT agonist lysergic acid diethylamide (LSD) has been found to inhibit the LR. This effect was recently shown to be enhanced by increasing doses of progesterone. In the present study it was demonstrated that the inhibitory effect of the 5-HT precursor 5-hydroxytryptophan was also potentiated by increased doses of progesterone. However, the effect of DL-5-HTP on spontaneous behaviors in an exploratory situation was not influenced by progesterone treatment. In contrast to the results with DL-5-HTP, progesterone had no modulating effects on the lordosis-inhibiting action of the catecholamine precursor levo-dopa. This elective effect on the influence of a progesterone-dependent response suggests a direct relationship between 5-HT mechanisms and the progesterone action involved in the LR. Possible mechanisms underlying the observed interactive effect of progesterone and serotonin on lordosis behavior, such as a progesterone-induced alteration of serotonergic transmission, are discussed.

Enhancement by progesterone of lysergic acid diethylamide inhibition of the copulatory response in the female rat.

Copulatory behavior in the ovariectomized rat, the lordosis response (L.R.) was induced by either estrogen alone or estrogen followed by progesterone. L.R. has been shown to be inhibited dose-dependently by lysergic acid diethylamide (LSD). The effects of various hormone treatments on the LSD-induced inhibition were tested in the present study. Progesterone but not estrogen was found to significantly enhance the LSD effect in a dose-dependent manner. In contrast, the effect of LSD on spontaneous behaviors in an exploratory situation was not influenced by progesterone treatment. This phenomenon of increased L.R. inhibitor effect by LSD was probably not due to a steroid-induced change in LSD metabolism. The data show instead that progesterone specifically influences monoaminergic mechanisms, which are related to the action of LSD. This has important implications for the possibility that progesterone induces the L.R. by acting on monoaminergic mechanisms.