biosynthetic human growth hormone in man A double-blind cross-over study
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1 Serum profiles and short-term metabolic effect of pituitary and authentic biosynthetic human growth hormone in man A double-blind cross-over study J. O. L. J\l=o/\rgensen, A. Flyvbjerg, J. Dinesen H. Lund, K. G. M. M. Alberti, H. \l=o/\rskov and J. S. Christiansen Institute ofxperimental Clinical Research1, Second University Clinic ofinternal Medicine, Department ofpaediatrics2, Aarhus Kommunehospital, Aarhus, Department ofpaediatrics3, Randers Central Hospital, Randers, Denmark, and Department of Clinical Biochemistry4, Royal Victoria Infirmary, Newcastle upon Tyne, ngland Abstract. In a double-blind cross-over study we compared pituitary and methionine-free biosynthetic human growth hormone (P-hGH and B-hGH) with respect to pharmacokinetics and short-term metabolic effects in 9 hypopituitary children. They treated themselves for 4 weeks with 2 IU sc daily at h. After admittance to hospital 2 IU was given: im the first day, and sc the second. They then switched over to the alternative preparation. The serum profiles of B- and P-hGH were identical. Comparing im and sc adsorption, the latter was slower and resulted in smaller areas under the curves, indicating greater local degradation. Both preparations caused identical increases in somatomedin-c, but slightly more sustained after sc injection. Plasma glucose, plasma glucagon, and serum insulin fluctuated within normal ranges. The glucose pro- at a modest anti-insulin effect of hgh when file pointed given in the morning. The concentration in the blood of lactate, alanine, glycerol and B-OH-butyrate, and in serum of triglyceride, cholesterol and carbamide revealed no abnormalities with either hgh preparation. Finally, no development of anti-gh or. coli polypeptide antibodies was seen. In conclusion, the pharmacokinetics and short-term metabolic effects of B\x=req-\ hgh and P-hGH were identical. Until recently the only source of human growth hormone (hgh) has been extracts from human pituitary glands (P-hGH). This implied that the indications for the clinical use of hgh have been restrictive. In addition, it has lately been sus pected that some hgh preparations included in fectious contamination (Beardsley 1985). Human growth hormone is now produced biosynthetically using recombinant DNA technology (Goeddel et al. 1979). The first preparations of biosynthetic hgh (B-hGH) contained an extra amino acid methionine at the N-terminal end, so-called methionyl-hgh, but recently B- hgh with the native 191 amino acid sequence of hgh has become the 22 fraction of pituitary available for clinical purposes. The only previous study comparing B-hGH with P-hGH deals with methionyl-b-hgh and involved normal adult male volunteers (Hintz et al. 1982). The aim of the present work is to compare 'methionine-free' B-hGH and P-hGH with respect to pharmacokinetics and short-term metabolic effects in hypopituitary patients.
2 TabU 1. Clinical data in GH-deficient participants at the onset of the study. Subjects Sex (M/F) Age (years) Height (cm) Weight (kg) Disease Surgery/ radiotherapy (yes/no) Pituitary state Duration of GH treatment (years) Other medications F Idiopathic No F Cranio- Yes pharyngeoma M Cystis Yes epidermoides M Basal tumour Yes 5 F Idiopathic No 6 M Idiopathic No 7 M Idiopathic No 8 F Idiopathic No 9 M Cranio- Yes pharyngeoma Panhypopituirarism Panhypopituitarism Panhypopituitarism Panhypopituitarism 13 Vasopressin Testoviron Vasopressin Mean : SM Patients Patients and Methods Nine patients were investigated (Table 1). All patients were treated with P-hGH (Nanormon, Nordisk Gentofte A/S, Denmark) 2 IU sc daily at h, and the mean duration of treatment was 4.2 years (± 1.3 years) (Table 1). In addition to hgh, 4 of the patients received other pituitary replacement therapy (Table 1). The was study protocol approved by the Danish health authorities and the local thical Committee. After thorough information, the experimental conditions were accepted by as well the patients as their parents. Design The study was performed in a randomized doubleblind cross-over design. The patients were allocated to treatment with P-hGH (Nanormon, Nordisk Gentofte A/S, Denmark) or B-hGH (Norditropin, Nordisk Cen tofte A/S) for a four-week period receiving 2 IU sc daily at h. They were then admitted to the hospital. On the day of admission no hgh was given. The following 2 days, 2 IU of hgh was given at h: im the first day, and sc the second day. At h, an indwelling catheter was placed in an antecubital vein for blood sampling during the following 48 h. Thereafter the patients were discharged from hospital continuing daily hgh injections for the next 4 weeks with the alternative preparation according to the randomization procedure, and re-admitted for another two days of blood sampling. Blood samples were drawn every hour from to and subsequently at 18.00, 20.00, 22.00, 24.00, and h. During the sampling period food was served and 'daily life' activity other than sport allowed.
3 Parameters and analyses Serum hgh, serum insulin and plasma glucagon were measured in all samples by radioimmunoassay as pre viously described (0rskov et al. 1968). P-glucose was measured according to the same schedule by means of a glucose oxidase method. Serum somatomedin-c (Sm-C) was measured using Sm-C antibody CH549/805 (raised by Underwood and Wyk) donated by the US National Hormone and Pitui tary Program. For standards ( µg/l) and iodina tion a full amino acid sequence analogue (AMGN Biologicals, CA) was purchased from Amersham (Buckinghamshire, ngland). The assay was performed using unextracted serum in dilutions 1:40 and 1:80 and all constituents were made up in 0.04 mol/1 phosphate buffer, ph 8.0, with 0.2% bovine serum albumin and 0.6 mmol/1 sodium merthiolate. Almost identical values were obtained using unextracted serum and acetic acid/ methanol extracts. Separation was achieved using PG 6000 with 0.5% Tween 20 (Merck, Darmstadt, FRG). Free and antibody-bound activities were counted. Sm-C was measured in samples from every second hour from to h, and h. The concentration in blood of alanine, lactate, ß-hydroxybutyrate and gly cerol was measured at 08.00, 12.00, and h by an enzymatic fluorimetrie technique (Lloyd et al. 1978). The serum concentration of triglycéride, cholesterol and carbamide was determined at and h using conventional laboratory techniques. Statistics Statistical calculations were based on Student's «-test. The results are expressed as mean ± SM. Results After im injections of both preparations a serum GH peak level of µg/l was reached in 2 h ( > 0.05). A return to baseline values was seen 8 9 h following injections. There was no signifi cant difference between the area under the two absorption curves (Fig. 1). Following sc injections of the same amount of hgh, the absorption was somewhat delayed as compared with im injection with the peak values obtained after 4 h showing significantly lower values (P 0.01) (Fig. 1). In addition, the disappearance rate was slower, reaching baseline values after h. No dif ference between the absorption curves of P-hGH and B-hGH after sc injection was seen. With either preparation the area under the curves (AUC) was significantly smaller following sc as compared with im injection (P 0.01). A significant increase in Sm-C regardless of preparation and route of administration was seen with maximum values between µg/l (Fig. 1), with a tendency to more sustained elevations after sc administration (Fig. 1). The fluctuations in glucose, insulin and glucagon concentrations were all within the normal range (Fig. 2). How ever, the plasma glucose is abnormal, in that it does not return to baseline levels between meals (served at 08.00, and h), in spite of a significant increase in serum insulin. There were only minimal fluctuations in serum triglycéride, cholesterol and carbamide concentrations, all within normal range and with no difference be tween values obtained during P-hGH and B-hGH administration. Likewise, no differences between the concen trations of lactate, alanine, glycerol and ß-hydroxybutyrate monitored during P-hGH and B-hGH treatment were seen. of the patients had anti-gh antibodies either at the onset, or during or after the 8-week study period, and no titre rise antibodies was observed. in. coli polypeptide Discussion The introduction of recombinant DNA techno logy in the production of hgh (Goeddel et al. 1979) may prove to be a major leap forward in the treatment of, since unlimited supply of the native peptide free of suspicion of slow virus contamination will become available. The clinical experience gained since the introduc tion of hgh treatment of is based on the use of P-hGH preparations. Obviously it is of clinical importance to compare the pharmacokinetics and metabolic characteristics of B-hGH with those of P-hGH. This paper is the first dealing with a comparison of P-hGH and so-called methionine-free B-hGH in man. From the present results we conclude that B- hgh possesses the same pharmacokinetic and short-term metabolic characteristics as the P-hGH preparations. Im injections of hgh resulted in a high (supraphysiological), but short-lived peak of serum GH when compared with sc injection (Figs. 1 and 2). This is in accordance with earlier find ings (Albertson-Wikland et al. 1986; Christiansen et al. 1983), but at variance with those of Russo & Moore (1982). The reasons for this discrepancy
4 î 2 u s.c. Fig.l. Serum concentrations of somatomedin-c and growth hormone (mean ± sem) after im and sc injection of 2 IU of P-hGH ( - ) and B-hGH (0-0). The arrows indicate time of injection (09.00 h). are not quite clear, but may relate to the fact that the latter report deals with a comparison between small groups of patients, whereas the present and former studies compare results within patients. It is also likely that there were differences in the im and sc injection techniques in the different studies. When comparing the serum profiles of hgh after im and sc injections, a significantly smaller area under the curve (AUC) was found using the latter regimen. In an earlier report where the same observation was made, it was shown that the molecular structure of hgh absorbed into plasma after sc injection did not differ from a standard sample (Christiansen et al. 1983). Hence, a sible pos explanation for the reduction in AUC may be that hgh is destroyed subcutaneously. Further studies are necessary to elucidate this problem. We have previously recommended (Christian sen et al. 1983) that hgh administration is best performed subcutaneously, every day and at bed time. The fact that Sm-C concentrations return to basal levels after 24 h supports the concept of daily injections. In the present study, where GH was injected in the morning, it is obvious that this induces de finitely abnormal glucose and insulin patterns in the period from h to h. Albeit the serum concentrations are within the normal range, they do not return to baseline levels between meals. This abnormal pattern is not seen after GH given in the evening, where the slight insulin resistance appears to disappear shortly after dawn (Christensen et al. 1985), thus further supporting the advantage of GH injections in the evening.
5 o u in O o => _ 250 ö o a. 10 O O 3 S V) 8 î 2 IU l.m. 1ß t 2 IU s.c. 1ß 8 hours Fig. 2. Plasma glucose and glucagon ( 1 pmol 3.49 ng) and = = serum insulin ( 1 pmol mu) concentrations (mean ± SM) after im and sc injections of 2 IU of P-hGH ( - ) and B-hGH (o-0). The arrows indicate time of injection (09.00 h on both days). If or when the safety and efficacy of methionine-free B-hGH become generally confirmed, an extension of the use of hgh therapy may take place. A possible field would be short statured children without classic, many of whom have previously been shown to benefit from GH therapy (Frazer et al. 1982; Rudman et al. 1981; Van Vliet et al. 1983). Other potential
6 candidates could be hypopituitary adults, patients with Turner's syndrome (Takano et al. 1983), and a variety of 'catabolic' patients (i.e. suffering from burns, fractures or severe infections). But of course controlled clinical trials are needed first. Finally, it is important to stress that at present we know very little of the optimum treatment regimen for classic. Studies investigating the total dose to be used as well as the proper frequency of administration are a prerequisite, and should be conducted in these patients in the future. References Albertson-Wikland K, Westphal O & Westgren U (1986): Daily subcutaneous administration of human growth hormone in growth hormone deficient child ren. Acta Paediatr Scand 75: Beardsley (1985): FDA ban on pituitary product. Nature 315: Christensen S, Christiansen J S, Hansen Aa P, Schmitz O & 0rskov H (1985): Three lines of evi dence that nocturnal GH is involved in the dawn phenomenon. Acta ndocrinol (Copenh). Suppl 273: 19. Abstr. Christiansen J S, 0rskov H, Binder C & Kastrup W (1983): Imitation of normal plasma growth hormone profile by subcutaneous administration of human growth hormone to growth hormone deficient child ren. Acta ndocrinol (Copenh) 102: Frazer T, Gavin J R, Daughaday W H, Hillman R & Weldon V V (1982): Growth hormone-dependent growth failure. J Pediatr 101: Goeddel D V, Heyreker H L, Hozumi et al. (1979): Direct expression in scherichia coli of a DNA se quence coding for human growth hormone. Nature 281: Hintz R L, Rosenfeld R G, Wilson D M et al. (1982): Biosynthetic methionyl human growth hormone is biologically active in adult man. Lancet 1: Lloyd P, Burrin J, Smythe & Alberti K G M M (1978): nzymic fluorimetrie continuous flow assay for blood glucose, lactate, pyruvate, alanine, glycerol and 3- hydroxybutyrate. Clin Chem 24: rskov H, Thomsen H G & Yde H (1968): Wickchromatography for rapid and reliable immunoassay of insulin, glucagon and growth hormone. Nature 219: Rudman D, Kutner M H, Blackston R D, Cushman R A, Bain R P & Patterson J H (1981): Children with normal-variant short stature: treatment with human growth hormone for six months. nglj Med 305: Russo L & Moore W (1982): A comparison of subcu taneous and intramuscular administration of human growht hormone in the therapy of growth hormone deficiency. J Clin ndocrinol Metab 55: Takano K, Shizume K, Hizuka et al. (1983): Treat ment of idiopathic pituitary dwarfism with methionyl human growth hormone. ndocrinol Jpn 30: Van Vliet G, Styne D M, Kaplan S L & Grumbach M M (1983): hgh therapy can increase height velocity in short children with normal serum somatomedin C and GH by RIA. Pediatr Res 17: 174A. Received February 26th, Accepted July 15th, Dr J. O. L. J0rgensen, Institute of xperimental Clinical Research, Second University Clinic of Internal Medicine, DK-8000 Aarhus C, Denmark.
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