Effects of recombinant human growth hormone on enterocutaneous fistula patients

AIM： To explore the effects of recombinant human growth hormone （rhGH） on intestinal mucosal epithelial cell proliferation and nutritional status in patients with enterocutaneous fistula. METHODS： Eight patients with enterocutaneous fistulas received recombinant human growth hormone （10 ug/d） for 7 d. Image analysis and immunohistochemical techniques were used to analyse the expression of proliferating cell nuclear antigen （PCNA） in intestinal mucosal epithelial cells in biopsy samples from the patients who had undergone an endoscopic biopsy through the fistula at day 0, 4 and 7. Body weights, nitrogen excretion, serum levels of total proteins, albumin, prealbumin, transferrin and fibronectin were measured at day 0, 4 and 7. RESULTS： Significant improvements occurred in the expression of PCNA in the intestinal mucosal epithelial cells at day 4 and 7 compared to day 0 （24.93 ± 3.41%, 30.46 ± 5.24% vs 12.92 ± 4.20%, p 〈 0.01）. These changes were accompanied by the significant improvement of villus height （500.54 ± 53.79 um, 459.03 ± 88.98um vs 210.94 ± 49.16 um, P 〈 0.01）, serum levels of total proteins （70.52 ± 5.13 g/L, 74.89 ± 5.16 g/L vs 63.51 ± 2.47 g/L, P 〈 0.01）, albumin （39.44 ± 1.18 g/L, 42.39 ± 1.68 g/L vs 35.74 ± 1.75 g/L, P 〈 0.01） and fibronectin （236.3 4- 16.5 mg/L, 275.8± 16.9 mg/L vs 172.5 ± 21.4 mg/L, P 〈 0.01） at day 4 and 7, and prealbumin （286.38 ± 65.61 mg/L vs 180.88 ± 48.28 mg/L, P 〈 0.05）, transferrin （2.61 ± 0.12 g/L vs 2.41 ±0.14 g/L, P 〈 0.05） at day 7. Nitrogen excretion was significantly decreased at day 7 （3.40 ± 1.65 g/d vs 7.25 ± 3.92 g/d, P 〈 0.05）. No change was observed in the body weight. CONCLUSION： Recombinant human growth hormone could promote intestinal mucosal epithelial cell proliferation and protein synthesis in patients with enterocutaneous fistula.

Altered Nutrition State in the Severe Multiple Trauma Patients Undergoing Adjuvant Recombinant Human Growth Hormone Nutritional Support Therapy

In order to observe the nutrition state in the severe multiple trauma patients undergoing adjuvant recombinant human growth hormone (rhGH) nutritional support therapy, 45 patients with severe multiple traumas (ISS>25) were randomly divided into 3 groups. All the 3 groups had been supplied with nitrogen and caloricity according to the need of patients for 16 days. The rhGH therapy started 48 h after surgery and lasted for 14 days in two rhGH-treated groups in which rhGH was 0.2 and 0.4 U/(kg·d) respectively, and the resting group served as control one. The levels of nitrogen balance, prealbumin and safety variables (blood sugar, Na+, TT3 and TT4) were observed and com- pared among the three groups. The levels of nitrogen balance on the postoperative day (POD) 3 and 5 in the rhGH-treated groups were -1.28±3.19, 5.45±2.00 and -0.18±2.55, 6.11±1.60, respectively, which were significantly higher than those in the control group (-5.17±1.68 and -1.08±3.31, P<0.01). The values of prealbumin on the POD 3 and 5 in the rhGH-treated groups were 180.19±27.15, 194.44±50.82 and 194.94±29.65, 194.11±16.17, respectively, which were significantly higher than those in the control group (117.42±19.10 and 135.63±28.31, P<0.01). There was no sig- nificant difference between the rhGH 0.2 U/(kg·d) group and rhGH 0.4 U/(kg·d) group in both of the levels of nitrogen balance and prealbumin. It is concluded that the nutritional support therapy with adjuvant rhGH which starts 48 h after surgery improves the nutrition state of the patients with severe multiple trauma. It is safe for severe multiple trauma patients who accept rhGH at the dose of 0.2 and 0.4 U/(kg·d).

Experimental study on effect of recombinant human growth hormone combined with chemotherapy on stomach neoplasms implanted in nude mice

Objective: To investigate the effect of different doses of recombined growth hormone (rhGH) on stomach neo- plasms implanted in nude mice, and its efficacy in combining with chemotherapy (flurouracil, 5-FU). Methods: Human stom- ach neoplasms model was established in nude mice. The nude mice were divided into control group, moderate-dose of rhGH group, low-dose rhGH group, 5-FU group, moderate-dose rhGH/5-FU group, and low-dose rhGH/5-FU group. The results of each group were observed after ten days. Results: After therapy, the body mass of rhGH groups was significantly increased compared with control group (P<0.05), the body mass of rhGH/5-FU groups was significantly increased compared with 5-FU group (P<0.05), but it was no significant difference between rhGH/5-FU groups and control group (P>0.05). The average tumor mass and volume of rhGH groups were not significantly increased compared with control group (P>0.05), but they were significantly reduced in 5-FU group and rhGH/5-FU groups (P<0.05). They were no significant difference between rhGH/5- FU groups and 5-FU group (P>0.05). After treatment, the percentages of S, G0/G1 and G2/M phases and proliferation index (PI) were not significantly changed in rhGH groups compared with control group (P>0.05), and the same with rhGH/5-FU groups compared with 5-FU group (P>0.05). The difference caused by dose of rhGH was not significant. Conclusion: rhGH enhances body mass, does not stimulate tumor growth, and has no adverse effects on tumor bearing nude mice. Combined with flurouracil, rhGH does not influence the efficacy of chemotherapy, and has no effect on tumor cell cycle kinetics.

Improved Cardiac Contractility of Human Recombinant Growth Hormone on the Congestive Heart Failure of Pig

The enhanced cardiac contractility effect of human recombinant growth hormone (hr-GH) on the congestive heart failure (CHF) was studied on the pig. To build a pig model of congestive heart failure, a temporary artificial cardiac pacemaker was implanted in the pig’s body and paced at 220 beats to 240 beats per minute for 1 week. After the model of congestive heart failure was successfully set up, the frequency of the pacemaker was changed to 150 beats to 180 beats per minute to maintain the CHF model stable. Pigs were divided into three groups: The hr-GH group in which 0.5 mg/kg per day of hr-GH was administrated intramuscularly for 15 days, the injection control group in which an equal amount of physiological saline was injected intramuscularly, and a normal control group. The left ventricular diastolic end pressure was (10.60±2.41) mmHg in the hr-GH group, but (19.00±3.81) mmHg in the saline control group (P<0.01); Cardiac output was (1.86±0.13) L/min in the hr-GH group, but (1.56±0.18) L/min in the saline control group (P<0.05); Peripheral vascular resistance was (56.88±7.51) mmHg·(L/min) -1 in the hr-GH group, whereas (70.30±11.59) mmHg·(L/min) -1 in the saline control group (P<0.05); +dp/dt max was (2900±316.23) and (2280±286.36) in the hr-HG group and the saline control group respectively (P<0.05). The results show that hr-GH enhances myocardial contractility of CHF, and the CHF model built by a temporary artificial cardiac pacemaker at a high rate of stimulation is reasonable and applicable.

Growth-Promoting Effect of Recombinant Human Growth Hormone and Stanozolol in Girls with Turner Syndrome

Summary: Ten girls with Turner syndrome were treated with a combination therapy of recombinant human growth hormone (R hGH) and low dose stanozolol for a period of 8 to 36 months. The results showed that when compared with the growth rate before the treatment, the growth rates after treatment with R hGH and stanozolol showed a sustained increase, reaching 9.0±1.9 cm/year during the first year of treatment; the height age increase by 2.5±0.8 years while the bone age increase were 1.0±0.7 years; and the predicted final adult height at the end of the first year of the treatment increased to 149.4±6.1 cm compared to their original mean of 142.8±4.2 cm. We are led to conclude that therapy with R hGH in combination with stanozolol can increase the growth velocity and significantly increase the predicted adult height of children with Turner syndrome.

Effects of different doses of long-acting growth hormone in treating children with growth hormone deficiency

BACKGROUND With the improvement of economy and living standards,the attention paid to short stature in children has been increasingly highlighted.Numerous causes can lead to short stature in children,among which growth hormone deficiency(GHD)is a significant factor.AIM To investigate the long-term efficacy and safety of different doses of long-acting polyethylene glycol recombinant human growth hormone(PEG-rhGH)in the treatment of GHD in children.METHODS We selected 44 pediatric patients diagnosed with GHD who were treated at Wuhu First People's Hospital from 2014 to 2018.Total 23 patients were administered a high dose of long-acting PEG-rhGH at 0.2 mg/kg subcutaneously each week,forming the high-dose group.Meanwhile,21 patients were given a lower dose of long-acting PEG-rhGH at 0.14 mg/kg subcutaneously each week,establishing the low-dose Group.The total treatment period was 2 years,during which we monitored the patients’height,annual growth velocity(GV),height standard deviation score(HtSDS),chronological age(CA),bone age(BA),and serum levels of insulin-like growth factor-1(IGF-1)and insulin-like growth factor-binding protein-3(IGFBP-3)before treatment and at 6 mo,1 year,and 2 years after treatment initiation.We also monitored thyroid function,fasting plasma glucose,fasting insulin,and other side effects.Furthermore,we calculated the homeostatic model assessment for insulin resistance.RESULTS After 1 year of treatment,the GV,HtSDS,IGF-1,BA,and IGFBP-3 in both groups significantly improved compared to the pre-treatment levels(P<0.05).Moreover,when comparing GV,HtSDS,IGF-1,BA,and IGFBP-3 between the two groups,there were no statistically significant differences either before or after the treatment(P>0.05).During the treatment intervals of 0-1.0 years and 1.0-2.0 years,both patient groups experienced a slowdown in GV and a decline in HtSDS improvement(P<0.05).CONCLUSION The use of PEG-rhGH in treating GHD patients was confirmed to be effective,with similar outcomes observed in both the high-dose group and low-dose groups,and no significant differences in the main side effects.

Optimizing growth in pediatric renal transplant recipients: An update

Growth retardation is a significant complication observed in pediatric renal transplant recipients,originating from a multifactorial etiology.Factors contributing to growth impairment encompass pre-transplant conditions such as primary kidney disease,malnutrition,quality of care,growth deficits at the time of transplantation,dialysis adequacy,and the use of recombinant human growth hormone.Additionally,elements related to the renal transplant itself,such as living donors,corticosteroid usage,and graft functioning,further compound the challenge.Although renal transplantation is the preferred renal replacement therapy,its impact on achieving final height and normal growth in children remains uncertain.The consequences of growth delay extend beyond the physi-ological realm,negatively influencing the quality of life and social conditions of pediatric renal transplant recipients,and ultimately affecting their educational and employment outcomes.Despite advancements in graft survival rates,growth retardation remains a formidable clinical concern among children undergoing renal transplantation.Major risk factors for delayed final adult height include young age at transplantation,pre-existing short stature,and the use of specific immunosuppressive drugs,particularly steroids.Effective management of growth retardation necessitates early intervention,commencing even before transplantation.Strategies involving the administration of recombinant growth hormone both pre-and post-transplant,along with protocols aimed at minimizing steroid usage,are important for achieving catch-up growth.This review provides a comprehensive outline of the multifaceted nature of growth retardation in pediatric renal transplant recipients,emphasizing the importance of early and targeted interventions to mitigate its impact on the long-term well-being of these children from birth to adolescence.INTRODUCTION Children with chronic kidney disease(CKD)endure frequent hospitalizations and ongoing treatment,which significantly affect their quality of life.One of the most noticeable effects of CKD in children is poor growth,with stunted height being a common sign of chronic malnutrition.Growth assessment involves regularly measuring weight and height/length and comparing these against z-score charts,along with other anthropometric indicators like head circumference and mid-upper arm circumference.Data from the North American Pediatric Renal Trials and Collaborative Studies(NAPRTCS)registry shows that over 35%of children enrolled had stunted growth at the time of admission,with growth impairment being more severe in younger children(58%in those aged under 1 year,compared to 22%in those aged over 12 years).Additionally,the same data revealed that growth impairment worsens as the severity of the disease increases.Although recent advances in science have enabled better outcomes for children with CKD,in resource-limited settings,numerous children are still deprived of achieving optimal growth owing to the disease and its related factors.Stunting is a key indicator of chronic growth impairment in children.A study by Wong et al[1]in the United States Renal Data System found that each SD decrease in height among children with stage V CKD is linked to a 14%increase in the risk of death[1].Similarly,research by Furth et al[2]using data from the NAPRTCS indicated that children with a height standard deviation score(SDS)of-2.5 face a relative hazard of death of 2.07.Stunting also correlates with increased hospitalizations.A study in the United States followed 1112 pediatric patients with end-stage renal disease from 1990 to 1995.It showed that children with severe or moderate growth failure had higher hospitalization rates compared to those with normal growth.Specifically,the relative risk for hospitalization was 1.14(95%CI:1.1-1.2)for those with moderate growth failure and 1.24(95%CI:1.2-1.3)for those with severe growth failure,even after adjusting for age,sex,race,cause,and duration of end-stage renal disease,and treatment type[2](dialysis or transplant).The growth of a child significantly affects his/her psychological and overall well-being as an adult.Short children are often embarrassed by peers,and it has been observed that height influences employment status,with unemployment being more prevalent among stunted individuals.Further,marital opportunities can be fewer among stunted individuals[3].Hence,all measures to achieve adequate growth should be attempted in children with CKD,regardless of whether they undergo transplantation.

Changes in Serum Leptin Levels during r-hGH Treatment in Growth Hormone-Deficient Children

To observe the effect of growth hormone on serum leptin levels, serum leptin concentrations were measured by enzyme immunoassay in 12 prebutal children with growth hormone deficiency 1, 3 and 6 months before and after the treatment with recombinant human growth hormone (r hGH). For comparison, 34 normal prepubertal children were also investigated. Relationship between leptin levels and body mass index (BMI) was observed at the same time. Our results showed that serum leptin level in normal prepubertal children was 1.22±0.34 ng/ml; the pretreatment serun leptin levels in GHD children was 3.08±2.41 ng/ml, which was significantly different from those 1, 3 and 6 months after GH treatment (i.e. 1.64±1.37 ng/ml,1.57±1.40 ng/ml and 1.35±0.89 ng/ml respectively) (all P <0.001). Our results suggested that r hGH has a suppressive effect on leptin expression.

Effects of Recombinant Human Growth Hormone on Corneal Healing, Epithelial Nerve Regeneration and Tear Inflammatory Factors in Rabbits

Objective:The goal of this study is to investigate the effects of recombinant human growth hormone(rh GH)on corneal healing,epithelial nerve regeneration and tear inflammatory factor levels in rabbits.Methods:After corneal epithelial injury models were established,fifty adult clean New Zealand white rabbits were randomly divided into two groups,normal saline was administered to the control group,while recombinant human growth hormone was administered to the observation group.The healing rate of corneal epithelial injury,the regeneration ability of corneal epithelial nerve and the level of inflammatory factors in tears were observed and compared between the two groups of rabbits before and 24,48,72 and 96 h after modeling.Results:There were significant differences in corneal epithelial healing rate,time and interaction between the two groups(P<0.05).The experimental group exhibited a superior healing rate of corneal epithelium at 24,48,72,and 96 h compared to the control group(P<0.05).There were significant differences in central cornea sensitivity between the two groups,along with variations in time and interaction(P<0.05).There was no significant difference in the central corneal sensitivity between the two groups before modeling and at 24,72 and 96 h after modeling(P>0.05),whereas the experimental group exhibited a higher central corneal sensitivity compared to the control group at 48 h after modeling(P<0.05).There were significant differences in IL-1α,TNF-α,IL-17a and IL-21 between the two groups(P<0.05).There were significant differences in IL-17a and IL-21 between the two groups(P<0.05).The experimental group exhibited a significant decrease in IL-1αlevels compared to the control group between 24 and 72 h after modeling(P<0.05),the experimental group exhibited a substantial increase in IL-17a levels compared to the control group at 72 h after modeling(P<0.05),and the level of TNF-αin the experimental group was significantly lower than that of the control group between 24 and 96 h after modeling.Conclusion:Recombinant human growth hormone aids in expediting the healing process of the healing of rabbit corneal epithelial injury,facilitating the restoration of epithelial nerve,and mitigating the inflammatory response.

Effects of recombinant human growth hormone (r-hGH) on experimental osteoporotic fracture healing

Objective:: To observe the effect of recombinant human growth hormone (r-hGH) on osteoporotic fracture healing in rats, and to provide an effective therapy for osteoporotic fracture. Methods: Thirty-six female 8-month-old SD rats were randomized into two groups: therapy group and control group. After the experimental model of osteoporotic fracture was established, the therapy group was treated with r-hGH of 2.7 mg/kg body weigh/day (1 mg=3 IU) for 10 days continuously by daily subcutaneous injection; whereas the control group was treated with equivalent saline. Plasma insulin-like growth factor I concentration was detected and bone mineral density (BMD) as well as biomechanical strength of callus were measured at 2, 4, 8 weeks. Results: Plasma insulin-like growth factor I concentration in the therapy group was higher than that in the control group (P< 0.005 ) at 2nd week and began to decline at 4th week. At 8th week, there was no significant difference between the two groups. At 4th week, callus area and BMD in therapy group were higher than those in the control group, but at 8th week, they were lower and BMD had a significant difference between the two groups (P< 0.001 ). Biomechanical testing of callus showed that torsional strength of the therapy group was higher than that of the control group at 4th or 8th week, meanwhile maximum torsional angle had a significant difference between the two groups (P< 0.005 ).Conclusions: The results show that exogenous r-hGH can stimulate osteoporotic fracture healing in rats.

Acromicric dysplasia caused by a mutation of fibrillin 1 in a family:A case report

BACKGROUND Acromicric dysplasia(AD)is a rare skeletal dysplasia.Its incidence is<1/1000000,and only approximately 60 cases are reported worldwide.It is a disease characterized by severe short stature,short hands and feet,facial abnormalities,normal intelligence,and bone abnormalities.Unlike other skeletal dysplasia,AD has a mild clinical phenotype,mainly characterized by short stature.Extensive endocrine examination has not revealed a potential cause.The clinical effect of growth hormone therapy is still uncertain.CASE SUMMARY We report a clinical phenotype of AD associated with mutations in the fibrillin 1(FBN1)(OMIM 102370)gene c.5183C>T(p.Ala1728Val)in three people from a Chinese family.A 4-year-old member of the family first visited the hospital because of slow growth and short stature for 2 years,but no abnormalities were found after a series of laboratory tests,echocardiography,pituitary magnetic resonance imaging,and ophthalmological examination.Recombinant human growth hormone(rhGH)was used to treat the patient for>5 years.The efficacy of rhGH was apparent in the first year of treatment;the height increased from-3.64 standard deviation score(SDS)to-2.88 SDS,while the efficacy weakened from the second year.However,long-term follow-up is required to clarify the efficacy of rhGH.CONCLUSION FBN1-related AD has genetic heterogeneity and/or clinical variability,which brings challenges to the evaluation of clinical treatment.rhGH is effective for treatment of AD,but long-term follow-up is needed to clarify the effect.

BIOEQUIVALENCE BETWEEN rhGH FOR RECONSTITUTION AND READY-TO-USE rhGH IN TWO LIQUID FORMULATIONS

Objective To evaluate the bioequivalence between recombinant human growth hormone （rhGH） for reconstitution, and two dosages of liquid formulation of rhGH [ （151U） 5mg or （301U） lOmg per 3ml ]. Methods The study drugs were tested in a randomized, single-blind and three-period crossover studies in 24 healthy male subjects. The three drugs were administered by subcutaneous injection at a dose of O. 21U/kg body weight. A continuous somatostatin infusion was given in order to suppress the secretion of endogenous GH. The ve- nous blood samples were drawn at different time points to test the serum concentration of GH. The pharmacokinetic parameters were analyzed by statistical methods. Results 90% confidence intervals （CI） of AUC0-24h among three products were all within 80% - 125% interval （ 103. 4% - 116. 5%, 105. 7% - 119. 6% and 91.9% - 103. 7%, respectively）, and the Cls of C,~ among three products were all within 70% - 143% interval （91.9% - 114. 0%, 103. 7% -127. 2% and 81.6% -97. 4%, respectively）. There was no statisitical difference of tmax among all the three products. Conclusion These data demonstrate that there is bioequivalence between rhGH for reconstitution and two liquid formulations of rhGH.

Amomum villosum induces longitudinal bone growth in adolescent female rats

OBJECTIVE:This study was conducted to evaluate the effect of Amomum villosum on longitudinal bone growth.METHODS:Adolescent female Sprague-Dawley rats were divided into 3 groups and treated for 4 days:control(distilled water,p.o.),recombinant human growth hormone(rhGH;100 μg/kg,s.c.),and A.villosum(500 mg/kg,p.o.) groups.On day 3,tetracycline(20 g/kg,i.p.) was injected for growth plate identification.On days 2,3 and 4,5-bromo-2'-deoxyuridine(BrdU)(50 mg/kg,i.p.) was injected to label proliferating cells.On day 5,tibias were dissected and fixed in 4% paraformaldehyde,dehydrated,and sectioned for immunohistochemistry and histomorphometry.RESULTS:The rate of bone growth in the A.villosum and rhGH groups increased to(410 ± 44) and(389 ± 46) μm/day(P<0.01),respectively,as compared with the control(330.7 ± 34.7) μm/day.The thickness of the growth plates also increased to(591 ± 37) and(598 ± 32) μm,respectively,as compared with the control(524± 89) μm(P<0.001).The number of BrdU-positive cells in the chondrocytes of the A.villosum and rhGH groups was also significantly higher(126±24) and(143±18) cells/mm 2,respectively) than in the control(109 ± 25) mm 2(P<0.05).Insulin-like growth factor-1 and bone morphogenetic protein-2 in the A.villosum and rhGH groups were highly expressed in the growth plate as compared with the control samples,indicating increased bone formation.CONCLUSIONS:A.villosum could be used to treat growth retardation during adolescence.