Pharmacokinetic and pharmacodynamic characteristics of a long-acting growth hormone (GH) preparation (nutropin depot) in GH-deficient children.

Long-term GH replacement therapy is indicated for children with growth failure due to GH deficiency (GHD). We evaluated the feasibility of administering a long-acting GH preparation [Nutropin Depot (somatropin, rDNA origin) for injectable suspension] to prepubertal children with GHD by examining pharmacokinetic and pharmacodynamic response parameters after single or multiple doses. Data were collected from three studies involving 138 children treated with Nutropin Depot 0.75 mg/kg once per month, 0.75 mg/kg twice per month, or 1.5 mg/kg once per month. Twenty-two patients underwent intensive sampling to estimate mean peak serum GH concentrations (C(max)) and time to achieve C(max) for GH and IGF-I. Thereafter, weekly serum concentrations were measured and compared with baseline. C(max) and area under the curve were approximately proportional to the dose administered. Fractional area under the curve data indicate that at least 50% of GH exposure occurs during the first 2 d after administration. Serum GH levels remained above 1 microg/liter for 11-14 d. IGF-I levels remained above baseline for 16-20 d, but increases were not proportional to dose. After multiple doses over a 6-month period, peak and trough concentrations showed no progressive accumulation of GH, IGF-I, or IGF binding protein-3. Nutropin Depot administration once or twice per month provides serum levels of GH and IGF-I expected to promote growth, without accumulation of GH, IGF-I, or IGF binding protein-3, in children with GHD.

Innovations in mission architectures for exploration beyond low Earth orbit.

Through the application of advanced technologies and mission concepts, architectures for missions beyond Earth orbit have been dramatically simplified. These concepts enable a stepping stone approach to science driven; technology enabled human and robotic exploration. Numbers and masses of vehicles required are greatly reduced, yet the pursuit of a broader range of science objectives is enabled. The scope of human missions considered range from the assembly and maintenance of large aperture telescopes for emplacement at the Sun-Earth libration point L2, to human missions to asteroids, the moon and Mars. The vehicle designs are developed for proof of concept, to validate mission approaches and understand the value of new technologies. The stepping stone approach employs an incremental buildup of capabilities, which allows for future decision points on exploration objectives. It enables testing of technologies to achieve greater reliability and understanding of costs for the next steps in exploration.

The pharmacokinetic and pharmacodynamic characteristics of a long-acting growth hormone (GH) preparation (nutropin depot) in GH-deficient adults.

A pharmacokinetic-pharmacodynamic study of a long-acting GH [Nutropin Depot; somatropin (rDNA origin) for injectable suspension] was performed in 25 patients with adult GH deficiency. Single doses of 0.25 mg/kg and 0.5 mg/kg, based on ideal body weight, were administered sc. After either dose, serum GH concentrations rose rapidly in both sexes. In men, the lower dose maintained serum IGF-I levels within 1 SD of the mean for age and sex for 14-17 d; the higher dose raised IGF-I levels 2 SD above the mean. In most women, all of whom were receiving oral estrogen, the lower dose did not normalize IGF-I levels; the higher dose maintained IGF-I near the mean for approximately 14 d. Increases in IGF binding protein-3 and acid-labile subunit levels were observed in both sexes; however, a sex-related difference was not obvious. Fasting glucose and insulin concentrations were transiently elevated in men receiving the higher dose. Patients tolerated the injections well. We concluded that a single injection of Nutropin Depot at these doses in patients with adult GH deficiency increased serum IGF-I to within normal limits for 14-17 d. Estrogen-treated women required approximately twice the dose needed in men to produce comparable IGF-I concentrations.

A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency.

Treatment of naive children with GH deficiency has relied upon long-term replacement therapy with daily injections of GH. The daily schedule may be inconvenient for patients and their caregivers, possibly promoting nonadherence with the treatment regimen or premature termination of treatment. We studied a new sustained release GH formulation, administered once or twice monthly, to determine its efficacy and safety in this population. Seventy-four prepubertal patients with documented GH deficiency were randomized to receive sustained release recombinant human GH at either 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by sc injection in a 6-month open-label study. Efficacy was determined by growth data from 69 patients completing 6 months and 56 patients completing 12 months in an extension study. Growth rates were significantly increased over baseline and were similar for the two dosage groups. The mean (+/-SD) annualized growth rate (pooled data) was 8.4 +/- 2.1 cm/yr at 6 months, and the growth rate was 7.8 +/- 1.8 at 12 months compared with 4.5 +/- 2.3 at baseline. Standardized height, bone age, and predicted adult height assessments demonstrated catch-up growth without excessive skeletal maturation. Injection site-related events (including pain, erythema, and nodules) were the most commonly reported adverse events; no serious adverse events related to treatment were reported. Laboratory studies documented no accumulation of trough GH or IGF-I levels during treatment, nor did glucose intolerance or persistent hyperinsulinism develop. Sustained release recombinant human GH is safe and effective for long-term GH replacement in children with GH deficiency. Patients achieved similar growth velocities when sustained release GH was given once or twice monthly. The enhanced convenience of this dosage form may result in greater long-term adherence to the treatment regimen.

In vitro studies on the methylation of histones in rat brain nuclei.

When isolated nuclei from 12-day-old rat brains were incubated with S-adenosyl-L-[methyl-3H]methionine, significant amounts of 3H-methyl were incorporated into lysyl residues in histones H3 and H4. About 0.024% of the total methylation sites on histone H3 and 0.013% of the sites on histone H4 were unmethylated at the time the nuclei were isolated. Methylation of these sites proceeded stepwise, progressing to a stable ratio of 0.93:1.0:0.17 for N epsilon-mono-, N epsilon-di-, and N epsilon-trimethyllysine in histone H3 and 0.19:1.0 for N epsilon-mono- and N epsilon-dimethyllysine in histone H4. The Km values of the enzyme for S-adenosyl-L-methionine were 11.5 +/- 1.1 micron and 12.5 +/- 1.3 micron with histones H3 and H4 as methyl acceptors, respectively. The Vmax values were 11.1 and 5.3 pmol of 3H-methyl incorporated/min/mg of histone H3 and H4, respectively. Since histone H3 contains 2 mol of N epsilon-methyllysine/mol and histone H4 contains 1 mol/mol, no difference in the overall rates of methylation can be deduced from the data. S-Adenosyl-L-homocysteine, one of the products of the reaction, was a competitive inhibitor with respect to S-adenosyl-L-methionine. The Ki values for S-adenosyl-L-homocysteine were 5.5 +/- 0.4 micron and 5.9 +/- 0.5 micron with histones H3 and H4 as methyl acceptors, respectively.