Human Growth Hormone Preparations Research Articles

Prospects of biosimilar recombinant human growth hormone manufacture in the Republic of Moldova

In collaboration of SUMPh „N.Testemițanu”, the pharmaceutical company Balkan Pharmaceuticals and ICGEB the technology transfer during scale-up from the laboratory phase to the pilot phase of the processes of creating the working cell bank and growing Pichia pastoris strains in the Erlenmeyer flask were carried out. Pichia pastoris was selected for recombinant growth hormone as an expression system, which has many advantages over other organisms, including protein folding, post-translational changes in protein, and easy handling. The GH1 altered recombinant human somatropin gene was introduced into the genome of Pichia pastoris culture using restriction near the AOX1 gene promoter as a vector serving the pPIC9K plasmid. The GH1 gene was activated by the AOX1 gene promoter which can be easily induced by the presence of methanol in the culture medium. Subsequently, the „Prepro-alpha Factor Leader” sequence from Saccharomyces cerevisiae was added to the modified sequence so that the obtained somatropin could be secreted into the culture medium. In the technological transfer process the influence of the chosen technological processes on some parameters of the obtained product were examined, Technological Regulations were developed for short and long term storage processes of Pichia pastoris cells and for the process of inoculum preparation, inoculation and growth of P. pastoris strains with recombinant human growth hormone in the Erlenmeyer flask. Standard Operating Procedures were developed for the processes of creating the working cell bank, determining the in-vitro biological activity of the recombinant human growth hormone preparation, with subsequent implementation in the process of producing rhGH biosimilar at CS Balkan Pharmaceuticals Ltd.

Effect of Growth Hormone Therapy on Height Velocity in Korean Children with Idiopathic Short Stature: A Phase III Randomised Controlled Trial

Background/Aims: The SYNERGY (Saizen® for Your New Life and Brighter Tomorrow without Growth Deficiency) study is the first randomised multi-centre, open-label study to assess the short-term efficacy and safety of this recombinant human growth hormone (r-hGH) preparation for prepubertal children with idiopathic short stature in South Korea. Methods: The SYNERGY study (ClinicalTrials.gov NCT01746862) was conducted at 9 centres throughout South Korea between December 2012 and March 2015. The primary endpoint was difference in height velocity from baseline to 6 months in the treatment and control arms. Results: 97 children were screened; 90 were randomly assigned: 60 children to 0.067 mg/kg/day r-hGH for 12 months (treatment) and 30 children to 6 months of no treatment followed by 0.067 mg/kg/day r-hGH for 6 months (control). The 6-month mean height velocity in the treatment group increased from 5.63 cm/year (SD 1.62) to 10.08 cm/year (SD 1.92) (p < 0.0001) and from 4.94 cm/year (SD 1.91) to 5.92 cm/year (SD 2.01) (p = 0.0938) in the control group (between-group difference 3.47 cm/year, 95% CI 2.17–4.78; p < 0.0001). Adherence was > 90% throughout the study. The safety profile was consistent with that already known for r-hGH. Conclusion: Treatment with r-hGH in the SYNERGY study demonstrated a statistically significant increase in height velocity at 6 months.

Switching to Omnitrope(®) from Other Recombinant Human Growth Hormone Therapies: A Retrospective Study in an Integrated Healthcare System.

IntroductionThis study was conducted using an integrated retrospective database to evaluate the effectiveness of Omnitrope® (Sandoz) on children with growth hormone deficiency (GHD), idiopathic short stature (ISS), and Turner Syndrome (TS) who switched from a non-Omnitrope recombinant human growth hormone (rhGH) preparation during routine clinical care.MethodsThis was a retrospective study which identified patients with GHD, ISS, and TS during the study time period of January 1, 2006 and July 31, 2011. Patients were included if they switched to Omnitrope from another non-Omnitrope rhGH therapy during the study time period, were <18 years of age at time of switch, and on a prior rhGH therapy for at least 15 months pre-switch and on Omnitrope for 15 months post-switch. Auxological parameters (height, height standard deviation score [HSDS], height velocity [HV], and height velocity standard deviation score [HVSDS]) were evaluated during post-switch.ResultsOne hundred and three patients were identified: GHD (n = 57), ISS (n = 26), and TS (n = 20). There was continuous growth in height for all 103 patients with an average rate of 6.52 cm over the 15-month post-switch period. Patients with GHD grew an average rate of 6.30 cm, patients with ISS grew an average rate of 6.58 cm, and patients with TS grew an average rate of 6.52 cm over the 15-month post-switch period. The average rate of HSDS was increased by 0.04 for all patients. The HV and HVSDS demonstrated the expected decline with advancing age and prolonged duration of treatment.ConclusionsThe growth trajectories of rhGH-treated patients were not negatively impacted by switching to Omnitrope and growth rates remained as expected prior to the switch.Electronic supplementary materialThe online version of this article (doi:10.1007/s13554-014-0017-1) contains supplementary material, which is available to authorized users.

Preparation of human growth hormone in Pichia pastoris under a constitutive promoter

Preparation of human growth hormone in Pichia pastoris under a constitutive promoter

Developments in human growth hormone preparations: sustained-release, prolonged half-life, novel injection devices, and alternative delivery routes.

Since the availability of recombinant human growth hormone (rhGH) enabled the application of human growth hormone both in clinical and research use in the 1980s, millions of patients were prescribed a daily injection of rhGH, but noncompliance rates were high. To address the problem of noncompliance, numerous studies have been carried out, involving: sustained-release preparations, prolonged half-life derivatives, new injectors that cause less pain, and other noninvasive delivery methods such as intranasal, pulmonary and transdermal deliveries. Some accomplishments have been made and launched already, such as the Nutropin Depot® microsphere and injectors (Zomajet®, Serojet®, and NordiFlex®). Here, we provide a review of the different technologies and illustrate the key points of these studies to achieve an improved rhGH product.

Preparation and characterization of recombinant human growth hormone–Zn2+-dextran nanoparticles using aqueous phase–aqueous phase emulsion

An effective and simple method was developed to prepare spherical and uniform-sized recombinant human growth hormone (rhGH)–Zn2+-dextran nanoparticles (NPs) for a variety of delivery applications of the delicate protein. The results showed that the prepared rhGH-Zn2+-dextran particles were spherical, glassy, and uniform in size. rhGH recovered from the NPs maintained its structural integrity and its bioactivity well, as suggested by the Nb2-11 cell proliferation assay. Using polyethylene glycol and polysaccharide to mediate Zn2+-induced precipitation has proved to be a promising method to prepare spherical protein-loaded NPs with desired sizes and preserved protein stability. From the Clinical EditorThis basic science paper discusses a simple yet effective method to prepare spherical and uniform-sized recombinant human growth hormone (rhGH)-Zn2+-dextran nanoparticles for a variety of delivery applications.

Heterogeneity of Commercial Recombinant Human Growth Hormone (r-hGH) Preparations Containing a Thioether Variant

The objective of the present study was to assess (I) the potential presence of a recently discovered thioether variant in commercially available recombinant human growth hormone (r-hGH) preparations, and (II) the impact of the thioether modification on the in-vivo bioactivity and the receptor binding kinetics. Samples were tested employing European (EP) and US Pharmacopeia (USP) Somatropin monograph and mass spectrometry methods. None of the international standards contained this variant. All products conformed to EP specifications but six out of eight lots contained the variant. An artificially enriched thioether sample exhibited a significantly reduced in vivo biopotency and altered receptor-binding properties compared with a control. The absence of the variant in the pituitary hGH standard, and the possibility to generate it artificially suggests that it is not naturally occurring and that it may arise from an uncontrolled manufacturing process. Controlled studies may be required to assess its clinical efficacy and safety. EP and USP methods may need to be adapted to reliably detect the presence of the variant. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4511–4524, 2009

Влияние гормона роста человека на состояние коллагена в области повреждения кожи крыс

Investigation of opportunities to affect the synthesis of collagen is of current importance to surgery as the synthesis of extracellular matrix collagen is the constituent of wound healing, which determines the rate and quality of tissue restoration. Growth hormone is one of the factors influencing the synthesis of the major protein of connective tissue - collagen. We have hypothesized that after making a subcutaneous wound, by impairing the basement membrane integrity, and by causing skin defect resolution, a recombinant human growth hormone (rh GH) preparation may affect the starting synthesis of an extracellular collagen matrix. An electric dermatome was used for partial skin thickness damage. The experimental animals - Wistar rats were randomized into two groups. The experimental group received subcutaneous rhGH injections (2.0 mg/kg) every day. The control group was daily given subcutaneous placebo injections. Wound tissue histomorphometry was used to estimate the area of the dermal fibrillary collagen network, the number of fascicles and the length of their perimeter and to calculate the volume of the fibrillary collagen network. There were both a statistically significant prevalence of collagen synthesis in the matrix of a wound on days 3, 6, 9 (66.55tl2.65, 64.23±7.19, and 65.74±8.I8) versus (51.32+- 14.85; 52.77+-2.41 , and 61.53±9.35), respectively, and signs of early mature connective tissue formation in the region of partial skin thickness damage in the rats receiving rh GH injections, which manifested as fewer collagen fibrils (156.23±5.53 and 166.14±4.24 to 143.34±2.90) as compared with the controlgroup (200.13±4.6S and 193.79+-.5.35 to I54.14±5.42, respectively).

Iatrogenic Creutzfeldt–Jakob disease 22 years after human growth hormone therapy: clinical and radiological features

Creutzfeldt–Jakob disease (CJD) is a human transmissible spongiform encephalopathy or prion disease. Although CJD is most frequently sporadic, numerous acquired or iatrogenic CJD (iCJD) cases have been reported, about half...

Somatropin for the treatment of short bowel syndrome in adults

Somatropin (rDNA origin) injection (Zorbtive™) is a highly purified preparation of human growth hormone (GH) produced from a mammalian cell line by recombinant DNA technology. It is the only human GH approved for the treatment of short bowel syndrome in patients receiving specialised nutritional support. The process of intestinal adaptation begins immediately after surgery and continues for 2 – 3 years. During this period, the bowel begins to increase fluid and nutrient absorption. Under the influence of tropic factors, such as GH, intestinal adaptation is enhanced. Supplying a therapeutic regimen of GH, optimised diet and glutamine supplementation for 4 weeks to patients with short bowel syndrome who are dependent on parenteral nutrition, has been shown to reduce their long-term requirements for parenteral nutrition.

100 years of hormonology: a view from No. 1 Wimpole Street

100 years of hormonology: a view from No. 1 Wimpole Street

A new sustained‐release preparation of human growth hormone and its pharmacokinetic, pharmacodynamic and safety profile

Adult GH replacement is currently given by daily subcutaneous (sc) injections. Recently, sustained-release (SR) preparations of GH have been developed, the preparations being characterized by a dominant early release, resulting in supraphysiological early GH peaks, and a rapid decline thereafter. We present data on a new SR GH preparation. Phase I/II study of hGH-Biosphere(R) (SkyePharma AB, Malmo, Sweden), a new SR preparation of recombinant human GH in amylopectin microspheres coated with polylactide-coglycolide. Eight adults with severe, untreated GH deficiency (stimulated GH peaks between < 1 and 1.7 microg/l), aged 36.1 years (range 22-49 years) in good general health. Pharmacokinetic (PK), pharmacodynamic (PD) and safety data over a period of 28 days. The systemic and local tolerability of the drug was satisfactory, and no serious adverse events occurred. PK analysis showed a smaller early serum hGH peak followed by a broad sustained second peak of hGH (C(max) 1.20 microg/l at 7.2 days), and hGH levels were maintained above baseline for at least 14 days. The mean GH level never exceeded 1.1 microg/l, making the GH fluctuations comparable to continuous sc infusion. Resultant IGF-I concentrations were characterized by sustained elevation at a level near C(max) of 103 microg/l (at t(max) of 9.7 days), equal to an SD score of +0.8. IGF-I generation per administered GH was more efficient compared with reports of other SR preparations. hGH-Biosphere(R) is a well-tolerated SR GH preparation with superior efficacy in achieving target IGF-I levels without causing supraphysiological GH concentrations. Our data suggest the suitability of this preparation for longer-term trials in adults with injection frequencies of no more than once every 2-3 weeks.

Maxime Schwartz, How the cows turned mad, transl. Edward Schneider, Berkeley and London, University of California Press, 2003, pp. viii, 238, £17.95 (hardback 0-520-23531-2).

Billed as a “detective story” that “illuminates the remarkable progression of science”, How the cows turned mad is the English translation of a French text by Maxime Schwartz, molecular biologist and former head of the Institut Pasteur, Paris. Schwartz goes beyond existing histories of Bovine Spongiform Encephalopathy (BSE or “mad cow disease”) to consider the growth of knowledge about related diseases, which since the 1960s have been grouped together under the heading Transmissible Spongiform Encephalopathies (TSEs). These include scrapie in sheep, Creutzfeld Jacob Disease (CJD) in man, and kuru, a disease of cannibalistic Papua New Guinea tribesmen. To Schwartz, TSEs are “the disease”, and BSE, CJD, kuru and scrapie are the different “guises” that it has adopted in a bid to escape scientific detection. Starting in the eighteenth century, he moves effortlessly over time and space, tracing its diverse clinical and pathological manifestations. He describes how late nineteenth- and twentieth-century advances in bacteriology, genetics, biochemistry and molecular biology enabled European and American scientists to make important discoveries that contributed to the understanding of disease aetiology, pathology and epidemiology. He also recounts how, in recent years, the consumption of BSE-infected meat and the use of contaminated human growth hormone preparations has given rise to CJD in young adults, and asks whether, in the light of concurrent scientific knowledge, such tragedies could have been avoided. The English translation of this text is brought up to date with a new chapter, which describes the events and discoveries of the year 2001. In conclusion, the author identifies several impediments to the growth of knowledge about “the disease”: its elusive behaviour; the existence of disciplinary and professional barriers which meant that scientists were often unaware of relevant work undertaken in another field; and the fact that scientists' findings, in suggesting that an infectious protein (prion) caused “the disease”, ran counter to accepted scientific thought. Written for a lay audience in the year 2000, when BSE and CJD were subject to widespread media attention, Schwartz's aims were two-fold: to educate readers, so enabling them “rationally [to] assess the often alarmist information” that came their way, and to celebrate the successes of modern science. It is impossible to assess whether he has managed to dispel fears about BSE and CJD, but in his second goal he has largely succeeded. This is a concise and extremely readable account, which provides a good overview of the growth of knowledge about TSEs and renders accessible some extremely complex scientific information. As such, it is a good starting point for anyone wishing to learn more about the nature of these unusual diseases, although the bibliography is limited, and the reader may find irritating Schwartz's portrayal of “the disease” as a sentient being that has repeatedly tried to evade capture. Historians, however, will find this work rather less useful. The author's retrospective narrative runs counter to mainstream academic history of medicine, as does his celebration of scientific heroes and their discoveries, and his imposition of a present-day disease category upon the past. In confining his attention to the science of “the disease”, Schwartz mentions but does not address the controversies that surrounded it and so neglects its immense political, economic and cultural significance. There is also much scope for deepening his analysis of how scientific dogma and disciplinary boundaries have influenced not only the growth of scientific knowledge but wider perceptions of and responses to the TSEs. That said, Schwartz's book is a good departure point for future studies, and it is to be hoped that historians will succeed as well as he in popularizing this extremely important subject.

Efficacy and Safety of Valtropin™ in the Treatment of Short Stature in Girls with Turner's Syndrome

Valtropin (somatropin, BioPartners and LG Life Sciences [LGLS]) is a recombinant human growth hormone (GH) preparation produced using a yeast expression system. An open single-arm phase III study was conducted to evaluate efficacy and safety at a dose of 0.16 IU/kg/day (0.053 mg/kg/day) s.c. for 12 months in the treatment of short stature in girls (n = 30, aged 2-9 years) with Turner's syndrome. The primary efficacy variable was height velocity (HV) at 12 months. Secondary efficacy variables included serum GH dependent growth factors. HV increased from 3.8 +/- 1.8 cm/yr at baseline to 9.7 +/- 1.6 cm/yr (mean +/- SD) after 12 months of treatment. Marked treatment effects were also observed on other growth parameters, serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). Treatment was well tolerated with no significant adverse events. It is concluded that Valtropin is as safe and effective as other human GH preparations for the treatment of growth failure in girls with Turner's syndrome.

High-yield purification of biosynthetic human growth hormone secreted in Escherichia coli periplasmic space

A six-step, high-yield purification procedure for the preparation of clinical grade recombinant human growth hormone (rhGH) secreted in bacterial periplasmic space is described. Particular emphasis is given to hormone recovery yields and maximum contaminant host cell elimination. The strategy adopted, in addition to using one precipitation and five chromatographic steps in a particularly efficient sequence, was also based on running E. coli proteins – immunoradiometric assay profiles right after each chromatographic elution. Thus, an overall rhGH recovery higher than 40%, with a final concentration of E. coli proteins below 10 ppm is described for the first time. The accuracy of hGH and total protein quantification, especially in the early steps of the process, and the maximum elimination of hGH-related forms were also studied in detail. For these purposes size-exclusion and reversed-phase HPLC were found to be extremely valuable analytical tools.

ANALYSIS OF HUMAN GROWTH HORMONE BY HYDROPHOBIC INTERACTION HPLC. METHOD DEVELOPMENT, VALIDATION, AND COMPARATIVE SELECTIVITY TO REVERSED PHASE HPLC

A hydrophobic interaction HPLC method was developed and validated for the analysis of human growth hormone (hGH) preparations. Separations were carried out on a TSK-Phenyl 5PW column using a descending linear gradient of 100% 1M ammonium phosphate dibasic/n-propanol (99.5:0.5), pH 8.0 to 100% 0.1M sodium phosphate/n-propanol (97.5:2.5), pH 8.0 over 30 minutes. The method proved highly reproducible for retention times, peak areas and peak heights, and the detector response for the main peak was linear between 1 and 1000 μg hGH/mL. Under these conditions, several hGH variants were resolved from the main hGH peak. A number of hGH preparations including the first WHO International Standard for hGH of pituitary origin and the new International Standard for hGH of recombinant origin were analysed. Of particular interest was the detection of a major impurity in the latter preparation. This impurity could not be detected by other conventional chromatographic or electrophoretic techniques. The same preparations were also analysed using a previously reported, neutral pH reversed phase HPLC method. A comparison of the impurity profiles detected by the two methods demonstrated that they have complementary selectivities.

Which route of growth hormone administration serves best? An invited commentary.

In the 1960s pharmacotherapy with pituitary-derived human growth hormone (GH) preparations was introduced into clinics for the treatment of children with severely impaired longitudinal bone growth (1). Initially, the generally accepted route of GH administration was deep intramuscular injections. It was not until the advent of recombinant growth hormone preparations in the 1980s that subcutaneous injection of GH proved to be at least equally effective and was propagated widely (2). The less traumatic subcutaneous injection then facilitated investigation of effectiveness as a function of number of injections per week. With respect to the promotion of longitudinal bone growth in children and adolescents, daily subcutaneous injection was shown to be more effective than administration of the same weekly dose by injection thrice weekly. Extrapolation of these findings promoted further studies in animals and humans that unanimously demonstrated the superior effectivity of continuous GH infusion as compared to administration of the same dose in up to eight pulses (2. 3).

Roferon (rIFN-α2a) Is More Immunogenic Than Intron A (rIFN-α2b) in Patients with Chronic Myelogenous Leukemia

number of genetically engineered cytokines, including recombinant interferons (rIFNs), have become a option for the treatment of various malignant and infectious diseases. As well as natural IFN-a preparations, both rIFN-a2a and rIFN-a2b have proved to induce hematological remissions in most patients with chronic myelogenous leukemia (CML), and also to suppress to a significant extent the Philadelphia chromosome-positive cell clone in a minority of patients,'1'2) a result so far otherwise achieved only by bone marrow transplantation. Recent results from the Italian Co-operative Study Group on CML'3> even suggest that continued administration of an IFN-a preparation prolongs the duration of the chronic phase of CML, and so increases the life span of patients with this disease. It has been found that when cancer patients are treated with rIFN-a2, high-titered IFN neutralizing antibodies against this cytokine develop in a significant minority. Importantly, such high-titered antibodies are associated with reduced biological activity of the rIFN-a2 and loss of clinical response.'4) IFNs are not unique in this respect: recombinant preparations of human insulin, growth hormone, interleukin-2 (IL-2), and granulocytemacrophage colony-stimulating factor (GM-CSF) have also been reported to induce an immune response in a proportion of patients treated with these agents.'56) The reasons why these homologous recombinant proteins are immunogenic in man is not yet known, although there are some clues.'6) To compare the immunogenic potential of the two clinically available recombinant preparations of IFN-a2, 164 newly diagnosed CML patients enrolled in a single large multicenter trial were treated under identical conditions with one or the other, and their sera were screened for the emergence of antibodies against IFN-a2. In this prospective, randomized, three-armed multicenter trial, patients entered into the IFN arm were treated with either Roferon (rIFN-a2a, Hoffman LaRoche, Basel) or Intron A (rIFN-a2b, Essex Pharma, Munich) at a dose of 5 Mu/m2 daily. Before participating in this study, the principal investigator in each center chose which of the two rIFN-a2 preparations would be used to treat all the patients enrolled into the study at his/her institution, and only this one was used. In the whole study, the two groups of IFN-a2-treated patients did not differ statistically in terms of age, sex, initial leukocyte and platelet counts, Karnofsky index, and the proportion of those who were Philadelphia chromosome positive. Five of the original 164 patients were excluded from further analysis, 4 patients because of wrong diagnosis, and 1 due to deficient documentation. The remaining 159 patients were evaluable: 106 of these were treated with rIFN-a2a, and 53 with rlFNa2b. Twenty-three of these received rIFN-a2 treatment for less than 3 months, 7 patients because of intolerance of the side effects, 14 patients gained no clinical benefit, and 2 patients withdrew from the study at their own wish. Serum from 105 patients were screened for the presence of both binding antibodies and neutralizing antibodies against IFNa2. None of the patients had detectable antibodies before treatment was started, but these were found in 25 of the 105 patients (24%) during treatment. Thirty-four patients were treated with rIFN-a2b, and binding antibodies were found in 3 (9%); these were also found in 22 out of 71 patients (31%) treated with IFNa2a, a statistically significant difference (p = 0.024). These antibodies were first detected in the serum between 60 and 750 days from the start of the rIFN-a2 treatment (Fig. 1). Antibodies neutralizing rIFN-a2 were detected in only 1 of the 34 patients treated with rIFN-a2b (3%), but in 17ofthe71 treated with rlFNa2a (24%), again a statistically significant difference (p < 0.02). The association between the development of binding antibodies against a rIFN-a2 preparation and secondary resistance to the treatment was investigated. Within 12 months from the start of therapy, 18 patients (3 treated with rIFN-a2b, 15 with rlFN-a^) developed a secondary resistance after initially responding. Nine of these patients (50%) had high-titered rIFN-a2 antibodies (titer above 900 Interferon Binding Units (IBU)/ml), and relapsed despite continued IFN therapy: all had received rlFN-a^. Thus, there was a stringent association between such high-titered antibodies against rIFN-a2a and secondary resistance. The observed differences in the immunogenic potential of the two recombinant IFN-a2 preparations were surprisingly clearcut. rIFN-a2a induced the formation of anti-IFN-a2 antibodies significantly more often than rIFN-a2b, and the titers of the induced antibodies were higher. Since all the patients were treated with the two recombinant IFN-a2 under identical conditions, the

Subcutaneous Absorption Kinetics of Two Highly Concentrated Preparations of Recombinant Human Growth Hormone

The relative bioavailability of two highly concentrated (12 IU/ml) formulations of biosynthetic human growth hormone (GH) administered subcutaneously was compared. A randomized, crossover study. Conventional GH therapy was withdrawn 72 hours before each study period. There was a washout period of at least four weeks between the study periods. Participants were recruited from an outpatient clinic and were hospitalized during the two study periods. Fourteen GH-deficient patients (mean age 25.2 y, range 14-54). One patient was excluded from data analysis because of signs of endogenous GH secretion. At the start of each study period, GH 3 IU/m2 was injected subcutaneously. The two formulations, PenFill and PenSet, differ in the buffers used and in the relative content of mannitol and glycine. Serum profiles of GH were monitored frequently for 24 hours. Samples were taken every 30 minutes for 6 hours and then hourly. Bioavailability (F) and absorption dynamics of human GH were measured. The relative absorption fractions estimated from the areas under the individual serum concentration curves from 0 to 24 hours, and the observed time (Tmax) to reach the maximum concentration (Cmax) were determined. Short-term metabolic effects of GH on insulin-like growth factor (IGF-I), glucose, and insulin were determined. The geometric mean (SD) of F was 0.910 (1,236). The 90 percent confidence interval was 0.819-1.010. Mean (+/- SD) of Cmax was 12.65 +/- 5.89 and 12.58 +/- 4.40 ng/mL for PenFill and PenSet, respectively. Corresponding values for Tmax were 5.49 +/- 1.55 and 5.89 +/- 1.79 hours for PenFill and PenSet, respectively. There was a considerable interindividual variation, but the relative absorption fraction did not significantly differ from 1 (p = 0.13). Neither Cmax (p = 0.74) nor Tmax (p = 0.58) of the two formulations was significantly different. Injection of the two formulations induced similar increments in serum IFG-I (p = 0.48). Serum insulin and blood glucose concentrations were not significantly different. There is no significant difference between the absorption kinetics and short-term metabolic effects of these two highly concentrated formulations of biosynthetic GH. The two formulations are bioequivalent.

Inhibition of recombinant human growth hormone-induced and prolactin-induced activation of neutrophils by octreotide.

Growth hormone, prolactin and somatostatin are polypeptide hormones of the neuroendocrine and peripheral nervous systems. In vitro, these have opposing effects on cells of the immune system. We compared the effects of these peptides on activation of neutrophils using a recombinant preparation of human growth hormone, human prolactin and octreotide, a long acting analog of somatostatin. In the absence of growth hormone, octreotide did not affect either neutrophil locomotion or respiratory burst. Octreotide, however, significantly antagonized growth hormone-induced activation of neutrophils for enhanced respiratory burst as well as growth hormone-induced inhibition of stimulated migration. As the effect of growth hormone on neutrophils is mediated by the prolactin receptor, its inhibition by octreotide was also tested using prolactin as priming agent. Data indicate comparable effects of octreotide on priming of neutrophils by prolactin. The effect of octreotide was dose-dependent and appeared to be selective, as activation of neutrophil respiration burst by gamma-interferon, and inhibition of stimulated migration by tumor necrosis factor-alpha were unaffected by octreotide. The present study suggests that octreotide may act on neutrophils directly by antagonizing growth hormone or prolactin at the cellular level.