Фармакокинетика и Фармакодинамика ГР (В общем иследование на людях_

MGT - Russia · 15 ноя 2016

Spoiler: Вот вся бригада которая проводила тест

Hospital for Children and Adolescents, University of Leipzig, Oststr. 21-25, D-04317 Leipzig, Germany, 1Division of Clinical Endocrinology, Department of Medicine, Charite´ University-Medicine, 10117 Berlin, Germany, 2Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, 61350 Leipzig, Germany, 3Eli Lilly & Co., Bad Homburg, Germany and Children’s Hospital, University of Giessen, 01731 Giessen, Germany, 4Institute of Doping Analysis and Sports Biochemistry, 04107 Kreischa, Germany, 5Institute of Clinical Pharmacology, University of Leipzig,

Leipzig, Germany and 6Department of Internal Medicine, Ludwig Maximillian University of Munich, 80336 Munich, Germany

Сказ пойдет о получения данных о ГР (в кратце), использовав различные дозы и способы введения.
Мышки-человеческие проекта: 10 Мужчин и 10 женщин, получали
1)0,033мг/кг массы тела подкожно
1)0,083мг/кг массы тела подкожно
1)0,033мг/кг массы тела внутримышечно
А так же проверили ИГФ: до инжектов и в течении 36 часов.
Так же узнаем, как и на что влияют уколы в ЖИР и в МЯСО. Все кто еще думает про ЖИР обязательно прочитать

Вообще желательно перевести переводчиком статью, очень полезная

===========================те кто не сможет скачать, читаем ниже=======================

Spoiler: исходгный текст

CLINICAL STUDY

Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration

Alexandra Keller, Zida Wu1, Juergen Kratzsch2, Eberhard Keller, Werner F Blum3, Astrid Kniess4, Rainer Preiss5, Jens Teichert5, Christian J Strasburger1 and Martin Bidlingmaier6

Hospital for Children and Adolescents, University of Leipzig, Oststr. 21-25, D-04317 Leipzig, Germany, 1Division of Clinical Endocrinology, Department of Medicine, Charite´ University-Medicine, 10117 Berlin, Germany, 2Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, 61350 Leipzig, Germany, 3Eli Lilly & Co., Bad Homburg, Germany and Children’s Hospital, University of Giessen, 01731 Giessen, Germany, 4Institute of Doping Analysis and Sports Biochemistry, 04107 Kreischa, Germany, 5Institute of Clinical Pharmacology, University of Leipzig,

Leipzig, Germany and 6Department of Internal Medicine, Ludwig Maximillian University of Munich, 80336 Munich, Germany

(Correspondence should be addressed to A Keller; Email: alexandra.keller@medizin.uni-leipzig.de)

Abstract
Objective: Pharmacokinetic and pharmacodynamic data after recombinant human GH (rhGH) administration in adults are scarce, but necessary to optimize replacement therapy and to detect doping. We examined pharmacokinetics, pharmacodynamics, and 20 kDa GH after injection of rhGH at different doses and routes of administration.

Design: Open-label crossover study with single boluses of rhGH.

Methods: Healthy trained subjects (10 males, 10 females) received bolus injections of rhGH on three occasions: 0.033 mg/kg s.c., 0.083 mg/kg s.c., and 0.033 mg/kg i.m. Concentrations of 22 and 20 kDa GH, IGF-I, and IGF-binding proteins (IGFBP)-3 were measured repeatedly before and up to 36 h after injection.

Results: Serum GH maximal concentration (Cmax) and area under the time-concentration curve (AUC) were higher after i.m. than s.c. administration of 0.033 mg/kg (Cmax 35.5 and 12.0 mg/l; AUC 196.2 and 123.8). Cmax and AUC were higher in males than in females (P!0.01) and pharmacodynamic changes were more pronounced. IGFBP-3 concentrations showed no dose dependency. In response to rhGH administration, 20 kDa GH decreased in females and remained suppressed for 14–18 h (low dose) and 30 h (high dose). In males, 20 kDa GH was undetectable at baseline and throughout the study.

Conclusions: After rhGH administration, pharmacokinetic parameters are mainly influenced by route of administration, whereas pharmacodynamic variables and 20 kDa GH concentrations are determined mainly by gender. These differences need to be considered for therapeutic use and for detection of rhGH doping.

European Journal of Endocrinology 156 647–653

Introduction
In growth hormone (GH)-deficient adult patients, subcutaneous (s.c.) administration of recombinant human GH (rhGH) at a fixed dose results in less pronounced effects in females than in males (1–3). This is thought to be at least partly due to modulation of hepatic insulin-like growth factor-I (IGF-I) generation by endogenous and exogenous estrogens (4, 5). In addition, male and female patterns of fat distribution differ substantially and could potentially be associated with differences in absorption from the injection depot of rhGH (6, 7). The administration route in early studies of rhGH was by intramuscular (i.m.) injection; sex differences were not noted but these studies were in children who would not have developed adult

differences between the sexes. The route was changed to the current standard of s.c. injection due to patient preference, but there were differences in absorption characteristics noted between the two routes of administration (8, 9). While pharmacokinetic data have been reported from early studies in children (8, 10), literature reports of pharmacokinetics in adults are scarce (11).

Unfortunately, rhGH has been misused, particularly in sport, and the methods to uncover such misuse have limitations (12, 13). Exogenously administered rhGH is structurally identical to endogenous 22 kDa GH, which is the isoform predominantly secreted in humans (14, 15). The most commonly used GH immunoassays recognize equally the 22 kDa isoform and the 20 kDa GH, which results from alternative splicing. It was suggested that development of immunoassays that could differentiate between the isoforms could be used to assess misuse of rhGH (15).

The current study was designed to investigate the pharmacokinetics and pharmacodynamics of rhGH in recreationally trained adults after single dose injections via s.c. and i.m. routes and to assess differences between males and females. Pharmacokinetics of the 22 kDa isoform were determined and pharmacodynamics were assessed from changes in the serum concentrations of the 20 kDa isoform, IGF-I, and IGF-binding proteins (IGFBP)-3.

Subjects and methods
Subjects
Ten males and ten females were selected from a cohort of 50 healthy young adults based on the level of sport activities. Inclusion criteria were: aged 18–35 years, body mass index (BMI) 19–27 kg/m2, regular physical exercise at least three times per week and, in females, continuous use of oral contraceptives. Subjects were excluded if they had any chronic illness, took any medications known to interfere with endocrine func- tion or reported any previous use of rhGH. Before entering the study, a full physical examination was performed and blood was taken for routine biochem- istry, hematology, fasting blood glucose, and liver enzymes. The local ethics committee of the University of Leipzig, Germany, approved the protocol. All subjects gave written informed consent and the study was conducted in accordance with the principles of the Declaration of Helsinki and the guidelines of good clinical practice.

Study design
The study used a randomized crossover design. Subjects were admitted to our clinical research unit for the three study periods, each starting at 0600 h after an overnight fast. Intravenous catheters were inserted in an antecubital vein and blood samples were drawn at 60 and 0 min (baseline) before rhGH administration then at 2-h intervals for the following 36 h. At 0 h, rhGH (Humatrope, Eli Lilly) was administered as a bolus of either 0.033 mg/kg body weight s.c., 0.083 mg/kg s.c. or 0.033 mg/kg i.m., according to a previously defined randomization scheme. Over the three study periods, each patient received each of the three rhGH doses in randomized order; patients were blinded regarding the low and high s.c. doses. Study periods were separated by a washout of 4 weeks to synchronize with the menstrual cycle in females.

Hormone measurements
Serum GH concentration was assayed by two sandwich immunoassays. Assay 1 (mAb 3B4/biotinylated mAb 10A7) utilized a capture antibody, which preferentially recognizes the monomeric 22 kDa isoform of GH, which is identical to rhGH and the lower detection limit was

0.1 mg/l (12). Intraassay coefficients of variation were 6.5 and 4.8% at concentrations of 0.8 and 6.2 mg/l respectively. Interassay coefficients of variation at the same concentrations were 8.2 and 6.1% respectively (12). Assay 2 was used for measuring the 20 kDa GH isoform using two monoclonal antibodies with no cross-reactivity to 22 kDa GH; intra- and interassay coefficients of variation were 5.4 and 7.5% at 1 mg/l and the limit of quantification was 0.05 mg/l (13). Assay 1 is referred to as ‘22 kDa GH’ while assay 2 is referred to as ‘20 kDa GH’. Serum IGF-I was measured by an automated chemiluminescence immunoassay (Nichols Advantage IGF-I, Nichols Institute Diagnostics, San Juan Capis- trano, CA, USA) using acidification and IGF-II excess to eliminate interference from IGFBP. Serum IGFBP-3 was analyzed by a RIA described previously (16). All serum

samples were stored at K20 8C until analysis.

Calculation of pharmacokinetic and pharma- codynamic parameters
Pharmacokinetic parameters were estimated using standard noncompartmental analyses with the Win- Nonlin pharamacokinetic software version 4.01 (Phar- sight Corp., Mountain View, CA, USA).

Area under the time-concentration curve (AUClast) was defined as the area under the curve from the time of dosing to the last measurable concentration, calculated using the linear trapezoidal rule. AUCinf was calculated by extrapolation to infinity using the terminal half-life (t1/2z) estimated with log-linear regression (AUCZ AUClastCAUCinf). Mean residence time (MRT) was estimated as the area under the first moment curve (AUMC) divided by AUC. Apparent plasma clearance (CL/F) was defined as the ratio of dose injected and AUC, and apparent volume of distribution (Vz/F) was calculated as (CL/F)/lz (17).

Instead of total AUC, the increase of IGF-I or IGFBP-3

above baseline levels was used for calculating the parameter DAUC 0–36.

Statistical methods
Data are given as meanGS.D. or as median and interquartile range (Q1, Q3). The GH concentrations below the detection limit of the assays were assigned to 0 mg/l. Comparisons between sexes, dosages, and routes of administration were performed with the Wilcoxon test or the non-paired U-Mann–Whitney test as
indicated. Spearman rank correlation with two-tailed probability values was used to test the association between the variables. Statistical significance was assumed for P!0.05. All statistical calculations were performed with Excel version 8.0 and SPSS version 11.0 for Windows (SPSS Inc., Chicago, IL, USA).

Results
Baseline characteristics
Baseline characteristics of the study subjects are shown in Table 1. Both 22 and 20 kDa GH at baseline were significantly higher in females than in males. In contrast, baseline serum IGF-I levels were significantly lower in females than in males. Differences between females studied in the follicular phase and in the luteal phase were not significant (data not shown).

Pharmacokinetics
Figure 1A depicts serum concentration profiles of 22 kDa GH over time in males and females by rhGH dose and route of administration. The pharmacokinetic parameters (Table 2) were not correlated with age or BMI at any dose or route of administration.

When the same rhGH dose (0.033 mg/kg) was administered, a significantly higher 22 kDa GH peak maximal concentration (Cmax) and AUC were observed with the i.m. compared with s.c. route in males but not females. There was no difference between males and females for Cmax and AUC with

s.c. rhGH, irrespective of the dose. In contrast, after

i.m. administration mean Cmax and AUC were significantly higher in males than females, with a concomitantly lower CL/F in males. MRT was shorter in males than females in the low-dose group, irrespective of route of administration.

Pharmacodynamics: IGF-I and IGFBP-3 responses
Figure 1B and C show the time course of serum IGF-I and IGFBP-3 concentrations in males and females by rhGH dose and route of administration. Subjects with higher baseline IGF-I concentrations showed a greater response to rhGH than those with a lower baseline concentration (P!0.01); this association was observed at all three study periods.

The increase from baseline integrated over time (DAUC 0–36) was higher with the high dose for both IGF-I and IGFBP-3. There were no significant differences for IGF-I or IGFBP-3 parameters between s.c. and i.m. routes with the same rhGH dose. Tmax for serum IGF-I differed between males and females in the high-dose group. IGF-I DAUC 0–36 showed a clear sex difference at the low dose, with higher values in males compared with females; this was independent of the route of administration. At the high dose, the difference between the sexes was not significant. IGFBP-3 DAUC 0–36 was significantly higher in males than females at the low s.c. dose, while at the high s.c. dose similar values were observed (Table 3).

Pharmacodynamics: 20 kDa GH
At baseline, 20 kDa GH was detectable in all women in all three study periods; rapid suppression occurred after injection of rhGH (Fig. 2). In females, mean 20 kDa GH levels decreased from 0.4 at baseline to below 0.2 mg/l within 2 h after injection of rhGH. Duration of 20 kDa GH suppression in females was dose dependent; reoccurrence of 20 kDa GH secretion was observed in the low-dose s.c. group after 26 h, in the low-dose i.m. group after 28 h, and in the high dose s.c. group after 34 h. In contrast, in males 20 kDa GH levels were close to or below the lower limit of quantification (0.05 mg/l) of the assay at baseline and throughout the observation period.

Table 1 Baseline characteristics of the study subjects.

Figure 1 Time course of 22 k GH (A) IGF-I (B) and IGFBP-3 (C) after bolus injection of rhGH (shown by arrow) at different doses and routes of administration in males and females. Individual responses are shown together with group medians (black line).

Discussion
The present data demonstrate that gender, dose and route of administration specifically alter bioavailability of and response to exogenous rhGH in healthy young adults. Pharmacokinetic variables were mainly influ- enced by the route of administration, whereas pharma- codynamic responses were primarily determined by sex. Furthermore, suppression of the 20 kDa GH isoform after injection of rhGH could be demonstrated only in women; 20 kDa GH levels in males were already low at baseline.

We assessed trained, but not elite level, subjects and highly trained individuals may respond differ- ently to rhGH administration. With no exogenous rhGH, reduced serum IGF-I and IGFBP-3 concen- trations have been reported during intense training (18, 19). The dose of rhGH used in this study was supraphysiological, because it can be assumed that illegal use by athletes will be at high doses (20). Physiological rhGH replacement in GH-deficient adults requires approximately one-third to one-fifth of the dose used in this study (21). Despite the high rhGH doses, we observed few of the side effects

Table 2 Pharmacokinetic data of 22 kDa growth hormone (GH) by sex. Values are given as median (range).

previously described in adults with GH deficiency (22, 23). However, a high frequency of diarrhea was seen, particularly after administration of the high rhGH dose. We found no explanation in regard to diet or gastrointestinal infections, and speculate that fluid regulation disturbances induced by the high dose could have caused the diarrhea (24).

Cmax and AUC were higher after i.m. than s.c. injection of the identical dose, in accordance with previous reports (25) indicating that serum GH after

i.m. injection shows a higher amplitude and shorter duration compared with s.c. injection. Significant differences between males and females were found for GH Cmax and AUC after i.m., but not s.c. injection.

Table 3 Pharmacodynamics of insulin-like growth factor-I (IGF-I) and IGF-binding protein (IGFBP)-3 stratified by sex. Values are given as median (range)

http://chat.anabolicshops.at/file:///C:/Users/AWESOM~1/AppData/Local/Temp/msohtmlclip1/01/clip_image001.gifFigure 2 Serum concentration of 20 kDa GH after administration of rhGH at three different dosages; (A) males, (B) females. Values are median with the interquartile range (Q1–Q3).

Although one could have expected a higher t1/2z after

s.c. administration in women, due to the higher s.c. fat (26), t1/2z was not affected by gender, perhaps because the women in the study were trained and lean.

The increase in IGF-I was positively correlated to baseline concentration, and was not affected by route of administration. Compared to IGFBP-3, the increase in serum IGF-I was faster and more pronounced, consist- ent with previous publications indicating that the ratio of IGF-I/IGFBP-3 increases immediately after rhGH injection (27). The increase in IGFBP-3 was delayed, not clearly dose dependent and did not return to baseline during the observation period, confirming that IGF-I is a more sensitive marker of GH action in trained adults than IGFBP-3.

The increase in IGF-I, but not the increase in IGFBP- 3, shows a marked sexual dimorphism. Integrated IGF-I release after rhGH injection was significantly higher in males than females, whereas Tmax and Cmax did not differ between sexes. IGF-I and IGFBP3 response is higher in males at low dose. However, it might be the case that the high dose of rhGH being a stronger stimulus also evokes a higher response in females. The difference between sexes is of course most likely due to the influence of estrogens, as all females were on oral contraceptives. No clear difference was seen in IGF-I response but the study was not specifically designed to investigate the impact of estrogens. It has been proposed that use of oral estrogens interferes with hepatic IGF-I

production, but women not using estrogen supple- mentation also exhibit a lower IGF-I response than males (1). Studies in animals indicate that complex mechanisms, including modification of hepatic GH receptor expression, lead to the sexual dimorphism in the somatotropic axis (28). In contrast to serum GH concentrations, IGF-I and IGFBP-3 concentrations did not return to pre-treatment levels within the obser- vation period, supporting the idea of use of these markers to detect doping with rhGH (13, 27, 29).

http://chat.anabolicshops.at/file:///C:/Users/AWESOM~1/AppData/Local/Temp/msohtmlclip1/01/clip_image007.gifThe existing studies on the relationship between 22 kDa and 20 kDa isoforms suggest that the secretion is a part of constant percentage of total GH. Therefore, the lower 20 kDa level and the long-term suppression in males seem to be a consequence of the lower total GH concentration. The 20 kDa GH isoform was also suppressed in females after administration of rhGH, consistent with a negative feedback of exogenous rhGH on pituitary GH secretion; the duration of suppression was dose dependent and re-occurrence of 20 kDa in the circulation was seen 26–28 h after low-dose rhGH and 34 h after high dose rhGH. The prolonged changes provide further evidence that the GH isoform pattern can be used to detect the administration of rhGH in females. With the assay method used in this study, 20 kDa GH levels in males were almost undetectable, making it impossible to demonstrate further suppres- sion. Thus, more sensitive assays to quantify the amount of 20 kDa GH are necessary.

In summary, our data show that in healthy trained adults, responsiveness to rhGH administration is regulated by a variety of factors. Pharmacokinetic parameters are mainly influenced by the route of administration, with higher GH Cmax and AUC after

i.m. injection, while pharmacodynamic parameters

are mainly determined by gender. These differences need to be considered when decisions are made regarding therapeutic dosing with rhGH. Changes in the molecular isoforms in circulation after injection of rhGH show that in females, measurement of 20 kDa GH could be a useful parameter to detect rhGH doping in athletes.

Acknowledgements
We thank all subjects for their full co-operation. Furthermore, we are grateful to the nurses and accompanying persons of the Endocrine Research Unit of the Hospital for Children and Adolescents, University of Leipzig, Germany. Additionally, we thank Dr Go¨tz Gelbrich (Center of Coordination of Clinical Studies, University of Leipzig, Germany) for his support in data management. This study was supported by the National Institute of Sports Research (BISp), Bonn, Germany and by Eli Lilly Company, Bad Homburg, Germany.

Перевод статьи , спасибо latspb

kastorkaru · 11 ноя 2016

А по-русски?

iCool · 11 ноя 2016

По картинке понятно что в мясо круче. Там больше всяких штук нарисовано и живее, значит круче.
На самом деле напряжение в поезде с просонья читать. Но не нужно быть ванной что бы понять что мясо збс выбор.

TED · 11 ноя 2016

iApply сказал(а): ↑

не нужно быть ванной
Нажмите, чтобы раскрыть...

или раковиной, да?)))

iCool · 11 ноя 2016

TED сказал(а): ↑

или раковиной, да?)))
Нажмите, чтобы раскрыть...

Нужен пиздатый Т9 и не читать что пишешь)

Lastik · 11 ноя 2016

iApply сказал(а): ↑

Но не нужно быть ванной что бы понять что мясо збс выбор.
Нажмите, чтобы раскрыть...

Смесь Т9 и гугл-переводчика - божественно)))))

Put in · 11 ноя 2016

MGT - Russia сказал(а): ↑

Spoiler: Вот вся бригада которая проводила тест

Hospital for Children and Adolescents, University of Leipzig, Oststr. 21-25, D-04317 Leipzig, Germany, 1Division of Clinical Endocrinology, Department of Medicine, Charite´ University-Medicine, 10117 Berlin, Germany, 2Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, 61350 Leipzig, Germany, 3Eli Lilly & Co., Bad Homburg, Germany and Children’s Hospital, University of Giessen, 01731 Giessen, Germany, 4Institute of Doping Analysis and Sports Biochemistry, 04107 Kreischa, Germany, 5Institute of Clinical Pharmacology, University of Leipzig,

Leipzig, Germany and 6Department of Internal Medicine, Ludwig Maximillian University of Munich, 80336 Munich, Germany

Сказ пойдет о получения данных о ГР (в кратце), использовав различные дозы и способы введения.
Мышки-человеческие проекта: 10 Мужчин и 10 женщин, получали
1)0,033мг/кг массы тела подкожно
1)0,083мг/кг массы тела подкожно
1)0,033мг/кг массы тела внутримышечно
А так же проверили ИГФ: до инжектов и в течении 36 часов.
Так же узнаем, как и на что влияют уколы в ЖИР и в МЯСО. Все кто еще думает про ЖИР обязательно прочитать

Вообще желательно перевести переводчиком статью, очень полезная

===========================те кто не сможет скачать, читаем ниже=======================
CLINICAL STUDY

Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration

Alexandra Keller, Zida Wu1, Juergen Kratzsch2, Eberhard Keller, Werner F Blum3, Astrid Kniess4, Rainer Preiss5, Jens Teichert5, Christian J Strasburger1 and Martin Bidlingmaier6

Hospital for Children and Adolescents, University of Leipzig, Oststr. 21-25, D-04317 Leipzig, Germany, 1Division of Clinical Endocrinology, Department of Medicine, Charite´ University-Medicine, 10117 Berlin, Germany, 2Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, 61350 Leipzig, Germany, 3Eli Lilly & Co., Bad Homburg, Germany and Children’s Hospital, University of Giessen, 01731 Giessen, Germany, 4Institute of Doping Analysis and Sports Biochemistry, 04107 Kreischa, Germany, 5Institute of Clinical Pharmacology, University of Leipzig,

Leipzig, Germany and 6Department of Internal Medicine, Ludwig Maximillian University of Munich, 80336 Munich, Germany

(Correspondence should be addressed to A Keller; Email: alexandra.keller@medizin.uni-leipzig.de)

Abstract
Objective: Pharmacokinetic and pharmacodynamic data after recombinant human GH (rhGH) administration in adults are scarce, but necessary to optimize replacement therapy and to detect doping. We examined pharmacokinetics, pharmacodynamics, and 20 kDa GH after injection of rhGH at different doses and routes of administration.

Design: Open-label crossover study with single boluses of rhGH.

Methods: Healthy trained subjects (10 males, 10 females) received bolus injections of rhGH on three occasions: 0.033 mg/kg s.c., 0.083 mg/kg s.c., and 0.033 mg/kg i.m. Concentrations of 22 and 20 kDa GH, IGF-I, and IGF-binding proteins (IGFBP)-3 were measured repeatedly before and up to 36 h after injection.

Results: Serum GH maximal concentration (Cmax) and area under the time-concentration curve (AUC) were higher after i.m. than s.c. administration of 0.033 mg/kg (Cmax 35.5 and 12.0 mg/l; AUC 196.2 and 123.8). Cmax and AUC were higher in males than in females (P!0.01) and pharmacodynamic changes were more pronounced. IGFBP-3 concentrations showed no dose dependency. In response to rhGH administration, 20 kDa GH decreased in females and remained suppressed for 14–18 h (low dose) and 30 h (high dose). In males, 20 kDa GH was undetectable at baseline and throughout the study.

Conclusions: After rhGH administration, pharmacokinetic parameters are mainly influenced by route of administration, whereas pharmacodynamic variables and 20 kDa GH concentrations are determined mainly by gender. These differences need to be considered for therapeutic use and for detection of rhGH doping.

European Journal of Endocrinology 156 647–653

Introduction
In growth hormone (GH)-deficient adult patients, subcutaneous (s.c.) administration of recombinant human GH (rhGH) at a fixed dose results in less pronounced effects in females than in males (1–3). This is thought to be at least partly due to modulation of hepatic insulin-like growth factor-I (IGF-I) generation by endogenous and exogenous estrogens (4, 5). In addition, male and female patterns of fat distribution differ substantially and could potentially be associated with differences in absorption from the injection depot of rhGH (6, 7). The administration route in early studies of rhGH was by intramuscular (i.m.) injection; sex differences were not noted but these studies were in children who would not have developed adult

differences between the sexes. The route was changed to the current standard of s.c. injection due to patient preference, but there were differences in absorption characteristics noted between the two routes of administration (8, 9). While pharmacokinetic data have been reported from early studies in children (8, 10), literature reports of pharmacokinetics in adults are scarce (11).

Unfortunately, rhGH has been misused, particularly in sport, and the methods to uncover such misuse have limitations (12, 13). Exogenously administered rhGH is structurally identical to endogenous 22 kDa GH, which is the isoform predominantly secreted in humans (14, 15). The most commonly used GH immunoassays recognize equally the 22 kDa isoform and the 20 kDa GH, which results from alternative splicing. It was suggested that development of immunoassays that could differentiate between the isoforms could be used to assess misuse of rhGH (15).

The current study was designed to investigate the pharmacokinetics and pharmacodynamics of rhGH in recreationally trained adults after single dose injections via s.c. and i.m. routes and to assess differences between males and females. Pharmacokinetics of the 22 kDa isoform were determined and pharmacodynamics were assessed from changes in the serum concentrations of the 20 kDa isoform, IGF-I, and IGF-binding proteins (IGFBP)-3.

Subjects and methods
Subjects
Ten males and ten females were selected from a cohort of 50 healthy young adults based on the level of sport activities. Inclusion criteria were: aged 18–35 years, body mass index (BMI) 19–27 kg/m2, regular physical exercise at least three times per week and, in females, continuous use of oral contraceptives. Subjects were excluded if they had any chronic illness, took any medications known to interfere with endocrine func- tion or reported any previous use of rhGH. Before entering the study, a full physical examination was performed and blood was taken for routine biochem- istry, hematology, fasting blood glucose, and liver enzymes. The local ethics committee of the University of Leipzig, Germany, approved the protocol. All subjects gave written informed consent and the study was conducted in accordance with the principles of the Declaration of Helsinki and the guidelines of good clinical practice.

Study design
The study used a randomized crossover design. Subjects were admitted to our clinical research unit for the three study periods, each starting at 0600 h after an overnight fast. Intravenous catheters were inserted in an antecubital vein and blood samples were drawn at 60 and 0 min (baseline) before rhGH administration then at 2-h intervals for the following 36 h. At 0 h, rhGH (Humatrope, Eli Lilly) was administered as a bolus of either 0.033 mg/kg body weight s.c., 0.083 mg/kg s.c. or 0.033 mg/kg i.m., according to a previously defined randomization scheme. Over the three study periods, each patient received each of the three rhGH doses in randomized order; patients were blinded regarding the low and high s.c. doses. Study periods were separated by a washout of 4 weeks to synchronize with the menstrual cycle in females.

Hormone measurements
Serum GH concentration was assayed by two sandwich immunoassays. Assay 1 (mAb 3B4/biotinylated mAb 10A7) utilized a capture antibody, which preferentially recognizes the monomeric 22 kDa isoform of GH, which is identical to rhGH and the lower detection limit was

0.1 mg/l (12). Intraassay coefficients of variation were 6.5 and 4.8% at concentrations of 0.8 and 6.2 mg/l respectively. Interassay coefficients of variation at the same concentrations were 8.2 and 6.1% respectively (12). Assay 2 was used for measuring the 20 kDa GH isoform using two monoclonal antibodies with no cross-reactivity to 22 kDa GH; intra- and interassay coefficients of variation were 5.4 and 7.5% at 1 mg/l and the limit of quantification was 0.05 mg/l (13). Assay 1 is referred to as ‘22 kDa GH’ while assay 2 is referred to as ‘20 kDa GH’. Serum IGF-I was measured by an automated chemiluminescence immunoassay (Nichols Advantage IGF-I, Nichols Institute Diagnostics, San Juan Capis- trano, CA, USA) using acidification and IGF-II excess to eliminate interference from IGFBP. Serum IGFBP-3 was analyzed by a RIA described previously (16). All serum

samples were stored at K20 8C until analysis.

Calculation of pharmacokinetic and pharma- codynamic parameters
Pharmacokinetic parameters were estimated using standard noncompartmental analyses with the Win- Nonlin pharamacokinetic software version 4.01 (Phar- sight Corp., Mountain View, CA, USA).

Area under the time-concentration curve (AUClast) was defined as the area under the curve from the time of dosing to the last measurable concentration, calculated using the linear trapezoidal rule. AUCinf was calculated by extrapolation to infinity using the terminal half-life (t1/2z) estimated with log-linear regression (AUCZ AUClastCAUCinf). Mean residence time (MRT) was estimated as the area under the first moment curve (AUMC) divided by AUC. Apparent plasma clearance (CL/F) was defined as the ratio of dose injected and AUC, and apparent volume of distribution (Vz/F) was calculated as (CL/F)/lz (17).

Instead of total AUC, the increase of IGF-I or IGFBP-3

above baseline levels was used for calculating the parameter DAUC 0–36.

Statistical methods
Data are given as meanGS.D. or as median and interquartile range (Q1, Q3). The GH concentrations below the detection limit of the assays were assigned to 0 mg/l. Comparisons between sexes, dosages, and routes of administration were performed with the Wilcoxon test or the non-paired U-Mann–Whitney test as
indicated. Spearman rank correlation with two-tailed probability values was used to test the association between the variables. Statistical significance was assumed for P!0.05. All statistical calculations were performed with Excel version 8.0 and SPSS version 11.0 for Windows (SPSS Inc., Chicago, IL, USA).

Results
Baseline characteristics
Baseline characteristics of the study subjects are shown in Table 1. Both 22 and 20 kDa GH at baseline were significantly higher in females than in males. In contrast, baseline serum IGF-I levels were significantly lower in females than in males. Differences between females studied in the follicular phase and in the luteal phase were not significant (data not shown).

Pharmacokinetics
Figure 1A depicts serum concentration profiles of 22 kDa GH over time in males and females by rhGH dose and route of administration. The pharmacokinetic parameters (Table 2) were not correlated with age or BMI at any dose or route of administration.

When the same rhGH dose (0.033 mg/kg) was administered, a significantly higher 22 kDa GH peak maximal concentration (Cmax) and AUC were observed with the i.m. compared with s.c. route in males but not females. There was no difference between males and females for Cmax and AUC with

s.c. rhGH, irrespective of the dose. In contrast, after

i.m. administration mean Cmax and AUC were significantly higher in males than females, with a concomitantly lower CL/F in males. MRT was shorter in males than females in the low-dose group, irrespective of route of administration.

Pharmacodynamics: IGF-I and IGFBP-3 responses
Figure 1B and C show the time course of serum IGF-I and IGFBP-3 concentrations in males and females by rhGH dose and route of administration. Subjects with higher baseline IGF-I concentrations showed a greater response to rhGH than those with a lower baseline concentration (P!0.01); this association was observed at all three study periods.

The increase from baseline integrated over time (DAUC 0–36) was higher with the high dose for both IGF-I and IGFBP-3. There were no significant differences for IGF-I or IGFBP-3 parameters between s.c. and i.m. routes with the same rhGH dose. Tmax for serum IGF-I differed between males and females in the high-dose group. IGF-I DAUC 0–36 showed a clear sex difference at the low dose, with higher values in males compared with females; this was independent of the route of administration. At the high dose, the difference between the sexes was not significant. IGFBP-3 DAUC 0–36 was significantly higher in males than females at the low s.c. dose, while at the high s.c. dose similar values were observed (Table 3).

Pharmacodynamics: 20 kDa GH
At baseline, 20 kDa GH was detectable in all women in all three study periods; rapid suppression occurred after injection of rhGH (Fig. 2). In females, mean 20 kDa GH levels decreased from 0.4 at baseline to below 0.2 mg/l within 2 h after injection of rhGH. Duration of 20 kDa GH suppression in females was dose dependent; reoccurrence of 20 kDa GH secretion was observed in the low-dose s.c. group after 26 h, in the low-dose i.m. group after 28 h, and in the high dose s.c. group after 34 h. In contrast, in males 20 kDa GH levels were close to or below the lower limit of quantification (0.05 mg/l) of the assay at baseline and throughout the observation period.

Table 1 Baseline characteristics of the study subjects.
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Figure 1 Time course of 22 k GH (A) IGF-I (B) and IGFBP-3 (C) after bolus injection of rhGH (shown by arrow) at different doses and routes of administration in males and females. Individual responses are shown together with group medians (black line).

Discussion
The present data demonstrate that gender, dose and route of administration specifically alter bioavailability of and response to exogenous rhGH in healthy young adults. Pharmacokinetic variables were mainly influ- enced by the route of administration, whereas pharma- codynamic responses were primarily determined by sex. Furthermore, suppression of the 20 kDa GH isoform after injection of rhGH could be demonstrated only in women; 20 kDa GH levels in males were already low at baseline.

We assessed trained, but not elite level, subjects and highly trained individuals may respond differ- ently to rhGH administration. With no exogenous rhGH, reduced serum IGF-I and IGFBP-3 concen- trations have been reported during intense training (18, 19). The dose of rhGH used in this study was supraphysiological, because it can be assumed that illegal use by athletes will be at high doses (20). Physiological rhGH replacement in GH-deficient adults requires approximately one-third to one-fifth of the dose used in this study (21). Despite the high rhGH doses, we observed few of the side effects

Table 2 Pharmacokinetic data of 22 kDa growth hormone (GH) by sex. Values are given as median (range).
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previously described in adults with GH deficiency (22, 23). However, a high frequency of diarrhea was seen, particularly after administration of the high rhGH dose. We found no explanation in regard to diet or gastrointestinal infections, and speculate that fluid regulation disturbances induced by the high dose could have caused the diarrhea (24).

Cmax and AUC were higher after i.m. than s.c. injection of the identical dose, in accordance with previous reports (25) indicating that serum GH after

i.m. injection shows a higher amplitude and shorter duration compared with s.c. injection. Significant differences between males and females were found for GH Cmax and AUC after i.m., but not s.c. injection.

Table 3 Pharmacodynamics of insulin-like growth factor-I (IGF-I) and IGF-binding protein (IGFBP)-3 stratified by sex. Values are given as median (range)

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http://chat.anabolicshops.at/file:///C:/Users/AWESOM~1/AppData/Local/Temp/msohtmlclip1/01/clip_image001.gifFigure 2 Serum concentration of 20 kDa GH after administration of rhGH at three different dosages; (A) males, (B) females. Values are median with the interquartile range (Q1–Q3).

Although one could have expected a higher t1/2z after

s.c. administration in women, due to the higher s.c. fat (26), t1/2z was not affected by gender, perhaps because the women in the study were trained and lean.

The increase in IGF-I was positively correlated to baseline concentration, and was not affected by route of administration. Compared to IGFBP-3, the increase in serum IGF-I was faster and more pronounced, consist- ent with previous publications indicating that the ratio of IGF-I/IGFBP-3 increases immediately after rhGH injection (27). The increase in IGFBP-3 was delayed, not clearly dose dependent and did not return to baseline during the observation period, confirming that IGF-I is a more sensitive marker of GH action in trained adults than IGFBP-3.

The increase in IGF-I, but not the increase in IGFBP- 3, shows a marked sexual dimorphism. Integrated IGF-I release after rhGH injection was significantly higher in males than females, whereas Tmax and Cmax did not differ between sexes. IGF-I and IGFBP3 response is higher in males at low dose. However, it might be the case that the high dose of rhGH being a stronger stimulus also evokes a higher response in females. The difference between sexes is of course most likely due to the influence of estrogens, as all females were on oral contraceptives. No clear difference was seen in IGF-I response but the study was not specifically designed to investigate the impact of estrogens. It has been proposed that use of oral estrogens interferes with hepatic IGF-I

production, but women not using estrogen supple- mentation also exhibit a lower IGF-I response than males (1). Studies in animals indicate that complex mechanisms, including modification of hepatic GH receptor expression, lead to the sexual dimorphism in the somatotropic axis (28). In contrast to serum GH concentrations, IGF-I and IGFBP-3 concentrations did not return to pre-treatment levels within the obser- vation period, supporting the idea of use of these markers to detect doping with rhGH (13, 27, 29).

http://chat.anabolicshops.at/file:///C:/Users/AWESOM~1/AppData/Local/Temp/msohtmlclip1/01/clip_image007.gifThe existing studies on the relationship between 22 kDa and 20 kDa isoforms suggest that the secretion is a part of constant percentage of total GH. Therefore, the lower 20 kDa level and the long-term suppression in males seem to be a consequence of the lower total GH concentration. The 20 kDa GH isoform was also suppressed in females after administration of rhGH, consistent with a negative feedback of exogenous rhGH on pituitary GH secretion; the duration of suppression was dose dependent and re-occurrence of 20 kDa in the circulation was seen 26–28 h after low-dose rhGH and 34 h after high dose rhGH. The prolonged changes provide further evidence that the GH isoform pattern can be used to detect the administration of rhGH in females. With the assay method used in this study, 20 kDa GH levels in males were almost undetectable, making it impossible to demonstrate further suppres- sion. Thus, more sensitive assays to quantify the amount of 20 kDa GH are necessary.

In summary, our data show that in healthy trained adults, responsiveness to rhGH administration is regulated by a variety of factors. Pharmacokinetic parameters are mainly influenced by the route of administration, with higher GH Cmax and AUC after

i.m. injection, while pharmacodynamic parameters

are mainly determined by gender. These differences need to be considered when decisions are made regarding therapeutic dosing with rhGH. Changes in the molecular isoforms in circulation after injection of rhGH show that in females, measurement of 20 kDa GH could be a useful parameter to detect rhGH doping in athletes.

Acknowledgements
We thank all subjects for their full co-operation. Furthermore, we are grateful to the nurses and accompanying persons of the Endocrine Research Unit of the Hospital for Children and Adolescents, University of Leipzig, Germany. Additionally, we thank Dr Go¨tz Gelbrich (Center of Coordination of Clinical Studies, University of Leipzig, Germany) for his support in data management. This study was supported by the National Institute of Sports Research (BISp), Bonn, Germany and by Eli Lilly Company, Bad Homburg, Germany.
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Супер!!! Спасибо. будет что на ночь почитать!!!

Put in · 11 ноя 2016

По шкале А это что за значение?
Мю.грамм/мл Мю это вроде как микрограммы. В лабораториях РФ мерят нг/мл либо мме/мл.
Плохо что по другой шкале, время (часы) не проставлены (увидел).
Это заказная статья. Тебе заплатил TED, !

Put in · 11 ноя 2016

Кстати помимо 22 и 20 КДА существует еще около 20 изоформ соматотропина, и они все активны. Но ифа метод в лабораториях настроен лишь на 22 КДА. Поэтому остальные изоформы как и 20 КДА в РФ лабораториях не отследить, как и IGFBP3 (о чем я писал раннее)

morinos · 11 ноя 2016

Читал с переводчиком, тяжко статья дается. Вот бы кто-нибудь вкратце резюме написал))
Я только понял, что лучше колоть внутримышечно.

И еще такой вопрос раз тут зашла речь про дозу на КГ тела.. Если ставлю по 5ед, стоит ли делить дозу на 2 приема как все советовали? Или инъекции 2 раза по 2.5ед поднимут СТГ только ближе к макс реф значениям, и такой СТГ не сыграет нужного стимула для роста мышц?

MGT - Russia · 11 ноя 2016

Put in сказал(а): ↑

По шкале А это что за значение?
Мю.грамм/мл Мю это вроде как микрограммы. В лабораториях РФ мерят нг/мл либо мме/мл.
Плохо что по другой шкале, время (часы) не проставлены (увидел).
Это заказная статья. Тебе заплатил TED, !
Нажмите, чтобы раскрыть...

нанограм\мл это тоже что микрограм \литр

MGT - Russia · 11 ноя 2016

morinos сказал(а): ↑

Читал с переводчиком, тяжко статья дается. Вот бы кто-нибудь вкратце резюме написал))
Я только понял, что лучше колоть внутримышечно.

И еще такой вопрос раз тут зашла речь про дозу на КГ тела.. Если ставлю по 5ед, стоит ли делить дозу на 2 приема как все советовали? Или инъекции 2 раза по 2.5ед поднимут СТГ только ближе к макс реф значениям, и такой СТГ не сыграет нужного стимула для роста мышц?
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Да лучше найти переводчика толкового, я бы оплатил

Put in · 12 ноя 2016

MGT - Russia сказал(а): ↑

Да лучше найти переводчика толкового, я бы оплатил
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Да можно впринципе запрячь контору, которая занимается проф переводами текстов по конкретному направлению фармацевтика.

MGT - Russia · 12 ноя 2016

Put in сказал(а): ↑

Да можно впринципе запрячь контору, которая занимается проф переводами текстов по конкретному направлению фармацевтика.
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Займешься? я оплачу

Put in · 12 ноя 2016

MGT - Russia сказал(а): ↑

Займешься? я оплачу
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Я могу попробовать. Но, не могу обещать, что быстро сделаю. Может в парралель, еще кого из ребят попросим. Кто первее сдаст на перевод, тот и не Алеша!!

TED · 12 ноя 2016

Put in сказал(а): ↑

Я могу попробовать. Но, не могу обещать, что быстро сделаю. Может в парралель, еще кого из ребят попросим. Кто первее сдаст на перевод, тот и не Алеша!!
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Профессиональный медицинский перевод по приятным расценкам - Бюро переводов «Альянс-Альфа»

Медицинский перевод | Перевод медицинских текстов, документов, литературы от ТрансЛинк

Стоимость примерно одинакова, около 1000 руб.

morinos · 12 ноя 2016

на доче цацулин вроде статьи переводил)) хотя тогда он был никому не известный, а сейчас блоггер, денег может много захочет)

TED · 12 ноя 2016

morinos сказал(а): ↑

на доче цацулин вроде статьи переводил)) хотя тогда он был никому не известный, а сейчас блоггер, денег может много захочет)
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Нахуй он нужен? Есть спец организации, ссылки выше.

MGT - Russia · 13 ноя 2016

TED сказал(а): ↑

Нахуй он нужен? Есть спец организации, ссылки выше.
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Действиетльно на*уй

Отправил запрос уже им

MGT - Russia · 14 ноя 2016

TED сказал(а): ↑

Профессиональный медицинский перевод по приятным расценкам - Бюро переводов «Альянс-Альфа»

Медицинский перевод | Перевод медицинских текстов, документов, литературы от ТрансЛинк

Стоимость примерно одинакова, около 1000 руб.
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Стоимость перевода (медицинский перевод, сложность выше базовой) составит 4 920 руб. Если качество перевода стоит не на первом месте, то можем перевести дешевле (студенческий перевод и тд.).

При работе в стандартном (несрочном) режиме выполним в течение 2 - 3 дней. Можем выполнить быстрее, с возможной наценкой за срочность (в какой срок требуется перевод?). В несрочном режиме работа в выходные дни возможна, но не гарантирована.
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Вот так вот, плюс за срочность еще денег. с ума сошли
Жду что второй ответит

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Вложения:

pharmacokinetics.pdf

kastorkaru Главный Самоварщик

iCool вечный статус Выступающий спортсмен Public Enemies

TED Плюшевый Тестер нашей площадки South park clan

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