Long-term effects of continuous subcutaneous infusion versus daily subcutaneous injections of growth hormone (GH) on the insulin-like growth factor system, insulin sensitivity, body composition, and bone and lipoprotein metabolism in GH-deficient adults.

It remains uncertain whether close imitation of the physiological pulsatile GH pattern determines the effects of GH treatment in humans. However, human studies have reported comparable metabolic responses to short-term constant and intermittent GH exposure. The aim of the study was to compare the metabolic effects of GH after continuous and intermittent sc delivery. In a parallel design, 14 GH-treated GH-deficient patients (mean age, 37 yr; mean body mass index, 27.4 kg/m(2)) were studied during steady state at the start of the study and after 6 months. Seven patients received daily injections (inj) in the evening as usual, and 7 received a continuous infusion (inf) of GH by means of a portable pump. The GH dose was kept unchanged before and during the study. Serum levels of insulin-like growth factor I (IGF-I) tended to increase in the patients switched to constant infusion (from 175 +/- 36 to 209 +/- 50 microg/L), but the differences obtained during the two regimens [+34.3 (inf) vs. -11.9 (inj)] were not significant (P = 0.34). Serum levels of IGF-II (P = 0.71) and IGF-binding protein (IGFBP)-3 (P = 0.75) were identical during the two modes of treatment. Serum levels of IGFBP-1 (P = 0.72), IGFBP-2 (P = 0.34), and GH-binding protein (P = 0.75) were unaffected by treatment regimen. Serum levels of free fatty acids, reflecting lipolysis, decreased significantly (16%) in the group switched to GH infusion (difference, -99.8 vs. +5 micromol/L; P < 0.03). The GH pattern did not influence insulin sensitivity (P = 0.71) or glucose effectiveness (P = 0.15) derived from Bergman's minimal model. Similarly, the two treatment regimens had no differential impact on lipoprotein levels, bone metabolism, or body composition. In conclusion, continuous and intermittent administrations of GH for 6 months are comparable with respect to the IGF-IGFBP axis, whereas intermittent exposure may be of importance for the lipolytic effect of GH. The data on insulin sensitivity and lipoproteins suggest that constant GH exposure is as safe as intermittent GH administration.

Effect of cyclodextrins on the solubility and stability of a novel soft corticosteroid, loteprednol etabonate.

To increase the aqueous solubility and stability of the soft corticosteroid loteprednol etabonate (LE), drug complexation using various cyclodextrins (CDs), such as gamma-cyclodextrin (gamma-CD), 2-hydroxypropyl-beta-cyclodextrin (HPBCD), maltosyl-beta-cyclodextrin (MBCD), mixture of glucosyl/maltosyl-alpha-, beta-, and gamma-cyclodextrin (GMCD), and heptakis (2,6-di-O-methyl)-beta-cyclodextrin (DMCD), were attempted. The solubilizing and stabilizing effects of CD by itself or combined with various co-solvents were also investigated. Micronized (5 micron) LE was mixed in various aqueous CD or CD with cosolvent solutions. After equilibration and filtration at 23 degrees C, the solubility of LE was determined by HPLC. Subsequently, the stability of LE in the solutions was also determined by following the LE concentration change in the solution for an appropriate period. CD complexation significantly increased the aqueous solubility and stability of LE. The increase in solubility displayed a concentration dependency on CDs (0-50%). Among the five CDs used, DMCD showed the highest effects on the solubility (4.2-18.3 mg/ml in 10-50% DMCD) and stability (t90 > 4 years at 4 degrees C, when LE 0.5 mg/ml was dissolved in 10% DMCD solution) of LE. By adding co-solvents, such as glycerol, propylene glycol (PG), polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP-10), the solubility of LE in DMCD solutions was further increased. Degradation of LE to the corresponding metabolites, delta 1-cortienic acid etabonate (AE) and delta 1-cortienic acid (A), in aqueous CD solutions appeared to be a predicted, two-step kinetics. Differential Scanning Calorimetry (DSC) was used to assist explaining the solubilizing and stabilizing activity differences between CDs. LE/CD mixture or lyophilized LE/CD complex was scanned at a rate of 20 degrees C/min. The exothermic peak found in the DSC diagram with LE/DMCD sample, but not with LE/HPBCD samples, suggests a stronger complex formed between LE and DMCD, resulting in higher solubility and stability of LE in DMCD than in HPBCD.

Plasma concentration of hGH and anti-hGH antibodies after subcutaneous administration of hGH for 3 weeks to immunosuppressed pigs.

OBJECTIVE: The objective of the present study was to evaluate the dosing regimen of immunosuppressants necessary to avoid the formation of anti-hGH antibodies in a pig model. ANIMALS: Sixteen pigs were divided into four groups. PROCEDURE: Three different immunosuppressive treatments were tested (group 1: Control (no treatment); group 2: 10 mg; group 3: 20 mg; and group 4: 40 mg cyclosporine; combined with 2 mg azatioprine and 2 mg prednisolone p.o./kg/day). The treatments were given from days -7 to 22. All groups were dosed subcutaneously (s.c.) with 0.5 mg hGH/kg once daily from days 1 to 22. On the first and the last days of dosing blood samples were collected to describe the hGH concentration versus time profile. Before dosing and on days 5, 10, and 15 blood samples were collected for measuring hGH antibody formation. RESULTS: A dose-dependent decrease in white blood cell counts was observed in all immunosuppressive-treated groups. Groups 1 and 2 produced antibodies against hGH during the 22 days of dosing while the formation of antibodies was suppressed in groups 3 and 4. In the control group and group 2 the pharmacokinetic parameters of hGH were influenced by the formation of anti-hGH antibodies. In groups 3 and 4, the pharmacokinetic parameters were comparable on the first and the last day of dosing. CONCLUSION: The formation of anti-hGH antibodies influenced the pharmacokinetics of hGH in pigs, but it could be prevented by immunosuppressive therapy. From the present experiment, a dose of 20 mg cyclosporine, 2 mg azatioprine, and 2 mg prednisolone p.o./kg/day was able to prevent the pigs from producing antibodies without having severe adverse effects. This model may by useful in future experiments using sustained release formulations of hGH, and possibly for other compounds that may induce antibody production in pigs.