Conceived and designed the experiments: NN KK MN HK RM MY KM SM SO NM K. Yamahara. Performed the experiments: RM KM HK MN NN TH MM SK K. Yoshimura YT MY SM YA NM SO. Analyzed the data: KM RM HK MN NN TH MM SK K. Yoshimura YT MY SM YA NM SO K. Yamahara KK. Wrote the paper: KM.
The authors have declared that no competing interests exist.
Pulmonary cachexia is common in advanced chronic obstructive pulmonary disease (COPD), culminating in exercise intolerance and a poor prognosis. Ghrelin is a novel growth hormone (GH)-releasing peptide with GH-independent effects. The efficacy and safety of adding ghrelin to pulmonary rehabilitation (PR) in cachectic COPD patients were investigated.
In a multicenter, randomized, double-blind, placebo-controlled trial, 33 cachectic COPD patients were randomly assigned PR with intravenous ghrelin (2 µg/kg) or placebo twice daily for 3 weeks in hospital. The primary outcomes were changes in 6-min walk distance (6-MWD) and the St. George Respiratory Questionnaire (SGRQ) score. Secondary outcomes included changes in the Medical Research Council (MRC) scale, and respiratory muscle strength. At pre-treatment, serum GH levels were increased from baseline levels by a single dose of ghrelin (mean change, +46.5 ng/ml; between-group p<0.0001), the effect of which continued during the 3-week treatment. In the ghrelin group, the mean change from pre-treatment in 6-MWD was improved at Week 3 (+40 m, within-group p = 0.033) and was maintained at Week 7 (+47 m, within-group p = 0.017), although the difference between ghrelin and placebo was not significant. At Week 7, the mean changes in SGRQ symptoms (between-group p = 0.026), in MRC (between-group p = 0.030), and in maximal expiratory pressure (MEP; between-group p = 0.015) were better in the ghrelin group than in the placebo group. Additionally, repeated-measures analysis of variance (ANOVA) indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (p = 0.049) and MEP (p = 0.021). Ghrelin treatment was well tolerated.
In cachectic COPD patients, with the safety profile, ghrelin administration provided improvements in symptoms and respiratory strength, despite the lack of a significant between-group difference in 6-MWD.
UMIN Clinical Trial Registry
Pulmonary cachexia is common in the advanced stage of chronic obstructive pulmonary disease (COPD), and it is an independent risk factor for death in such patients
Pulmonary rehabilitation (PR) including exercise training is well accepted to improve exercise performance and quality of life in COPD patients
During the 1970s and 1980s, many gut peptides were identified
The protocol for this trial, supporting CONSORT checklist, and Supplementary Methods are available as supporting information; see
The study was a 3-week, multicenter, randomized, double-blind, placebo-controlled trial of ghrelin administration during PR. The study was finally conducted at four clinical centers (National Cerebral and Cardiovascular Center, Miyazaki University School of Medicine, Nara Medical University, and National Hospital Organization Toneyama National Hospital) in Japan from September 2005 through May 2009, because Graduate School of Medicine, Osaka City University did not participate just before the start of the clinical trial. The study was conducted according to the Declaration of Helsinki and Good Clinical Practice guidelines and approved by the ethics committees of all participating study centers: The ethics committee of the National Cerebral and Cardiovascular Center (approval number, M17–13); The ethics committee of Miyazaki University School of Medicine (approval number, 218): The ethics committee of Nara Medical University (approval number, 05–012); and The ethics committee of the National Hospital Organization Toneyama National Hospital (approval number, 0311). All patients gave written informed consent (in Japanese). The inclusion criteria were as follows: 1) severe to very severe COPD (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) of less than 70% and FEV1 percent predicted of less than 50%); 2) underweight (body mass index (BMI)<21 kg/m2); 3) clinically stable and able to participate in PR; 4) between 20 and 85 years old; and 5) signed the agreement for participation in this study. Participants were excluded for any of the following: 1) malignant tumors; 2) active infection; 3) severe heart disease; 4) hepatic dysfunction (serum aspartate aminotransferase and alanine aminotransferase levels at least twice the upper limit of normal); 5) renal dysfunction (serum creatinine levels ≥2.0 mg/dl); 6) asthma; 7) definitely or possibly pregnant; 8) change in drug regimen within 4 weeks before participation in this study; or 9) judged to be unable to participate in this study by their physician. This study was registered with UMIN (University Hospital Medical Information Network in Japan:
Ghrelin, n = 14 | Placebo, n = 15 | p value | |
Age, years |
70.5 (6.2), 63–80 | 73.9 (6.0), 63–82 | 0.15 |
Sex, male/female |
13/1 | 13/2 | 1.00 |
BMI, kg/m2 |
18.6 (2.1), 14.4–20.9 | 18.0 (2.1), 14.7–20.9 | 0.38 |
Cigarette smoking, pack years |
62.0 (30.9), 3.8–125 | 52.5 (28.8), 0.0–97.5 | 0.38 |
Pulmonary function |
|||
FEV1, L | 0.78 (0.20), 0.54–1.21 | 0.77 (0.21), 0.47–1.21 | 0.90 |
%FEV1, % predicted | 31.6 (8.1), 21.2–49.5 | 34.5 (9.1), 17.7–45.9 | 0.32 |
FEV1/FVC, % | 38.0 (8.9), 24.6–50.5 | 38.8 (8.7), 25.4–52.9 | 0.74 |
VC, L | 2.48 (0.37), 1.90–3.45 | 2.52 (0.50), 1.62–3.69 | 0.98 |
%VC, % | 78.8 (9.3), 64.0–94.3 | 84.5 (12.6), 71.4–113.4 | 0.38 |
Exercise capacity on ICPET |
|||
Peak |
11.5 (3.3), 5.2–17.5 | 11.3 (3.5), 6.2–18.7 | 0.74 |
6-MWD, m |
328 (110), 148–619 | 315 (118), 85–498 | 0.84 |
SGRQ |
|||
Total score | 58.2 (16.5), 36.3–84.4 | 50.2 (15.5), 21.3–77.3 | 0.23 |
Symptoms score | 61.5 (22.5), 29.4–97.5 | 51.6 (19.8), 19.7–78.5 | 0.34 |
Activity score | 72.5 (14.9), 41.7–92.5 | 65.9 (16.3), 35.3–92.5 | 0.34 |
Impacts score | 46.7 (19.5), 20.0–84.4 | 39.2 (17.7), 9.4–69.7 | 0.53 |
Medications |
|||
LAMA | 9 | 6 | 0.27 |
SAMA | 3 | 2 | 0.65 |
LABA | 9 | 7 | 0.46 |
SABA | 2 | 0 | 0.22 |
ICS | 5 | 2 | 0.21 |
Methylxanthines | 7 | 7 | 1.00 |
Data are presented as means (SD), and the minimum and maximum values unless otherwise stated. BMI = body mass index; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; ICPET = incremental cardiopulmonary exercise testing; ICS = inhaled corticosteroids; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting β2-agonist; SAMA = short-acting muscarinic antagonist; VC = vital capacity.
The groups shown represent only patients analyzed for efficacy. Medications are not mutually exclusive, and data are presented separately.
Analyzed using a Wilcoxon rank sum test.
Analyzed using a Fisher’s exact test.
Randomization was done in each center considered as a block. The randomization list was generated by a statistician from Hamamatsu University School of Medicine and maintained there until the study was finished and unblinded. Neither the physicians nor the patients were aware of the treatment assignments. Patients who met the eligibility criteria were enrolled and randomly assigned in a 1∶1 ratio to receive PR with either ghrelin (2 µg/kg) or placebo twice a day for 3 weeks in hospital. The administration of ghrelin (2 µg/kg, ghrelin solution with 10 ml saline) or placebo was done intravenously over 30 minutes at a constant rate and repeated twice a day for 3 weeks. Patients were tested at pre-treatment, Week 3 after start of ghrelin or placebo administration with PR, and Week 7 after start of ghrelin or placebo administration with PR, i.e., 4 weeks after the completion of the combination treatment (
Human ghrelin obtained from the Peptide Institute Inc. was dissolved in distilled water with 3.75% D-mannitol and sterilized as described previously
Exercise training, which was included in the PR program, was conducted in three sets daily, every weekday for 3 weeks (i.e. 15 days) at high-intensity targets. Additional details are described online in Supplementary
Efficacy: The primary outcomes were changes in 6-min walk distance (6-MWD) and the score evaluated using the St. George Respiratory Questionnaire (SGRQ)
Safety: All randomized patients who received at least one dose of the study treatments (ghrelin group, n = 18; placebo group, n = 15) were included in the safety analyses using intention-to-treat analysis. Blood tests were done up to Week 7. All serious adverse events were monitored throughout the study period.
Open circles, ghrelin; closed circles, placebo. Data are presented as mean differences±SE. * p<0.05: change between pre- and post-treatment (within-group difference). † p<0.05: change between pre-treatment and post-treatment (between ghrelin and placebo group difference). ‡ p<0.05: time course effect of ghrelin versus placebo by repeated-measures ANOVA. A) In both groups, 6-MWD increases significantly to a similar level from pre-treatment at Week 3. Prolonged effects can be seen in the ghrelin group at Week 7, though the improvement in 6-MWD declined in the placebo group. B) Though the MRC score became progressively worse in the placebo group, the maintained effects in the MRC score can be seen in the ghrelin group at Week 7. C) Repeated-measures ANOVA indicated significant time course effects of ghrelin versus placebo in MEP (F (2, 51) = 4.17, p = 0.021).
The 6-MWD was measured as described previously
While breathing room air with a mask, symptom-limited CPET was conducted on an electrically braked cycle ergometer using an incremental protocol (continuous ramp rate of 5 W/min). Expired gas data were measured breath-by-breath and collected as 30-s averages at rest and during exercise. The CPET was done until subject exhaustion.
At Week 3 | At Week 7 | |||||
Ghrelin,n = 14 | Placebo,n = 15 | Treatment effect(95% CI; p value) | Ghrelin,n = 14 | Placebo,n = 13 | Treatment effect(95% CI; p value) | |
Exercise capacity | ||||||
6-MWD, m | 40 (17) |
35 (12) |
5 (−37 to 48; 0.81) | 47 (17) |
18 (11) | 29 (−15 to 73; 0.19) |
Peak |
1.2 (0.4) |
0.5 (0.3) | 0.7 (−0.4 to 1.8; 0.21) | ND | ND | ND |
Peak |
0.5 (0.2) |
−0.4 (0.5) | 0.9 (−0.2 to 2.0; 0.11) | ND | ND | ND |
PFT | ||||||
FEV1/FVC, % | −1.1 (1.0) | −2.7 (0.9) |
1.6 (−1.2 to 4.3; 0.26) | −1.7 (1.2) | −1.2 (1.1) | −0.5 (−3.8 to 2.8; 0.77) |
VC, L | 0.14 (0.07) | 0.11 (0.07) | 0.03 (−0.16 to 0.23; 0.74) | 0.09 (0.11) | −0.10 (0.07) | 0.19 (−0.09 to 0.47; 0.17) |
Others | ||||||
MIP, cmH20 | −8.2 (4.9) | −9.8 (3.2) |
1.6 (−10.1 to 13.4; 0.78) | −8.4 (5.6) | −4.3 (2.6) | −4.1 (−17.7 to 9.5; 0.52) |
MEP, cmH20 | 6.8 (4.4) | −3.8 (4.5) | 10.7 (−2.2 to 23.5; 0.099) | 15.6 (5.7) |
−4.3 (4.8) | 19.9 (4.1 to 35.6; 0.015) |
Food intake,kcal/day | 122 (93) | −17 (86) | 139 (−122 to 399; 0.28) | ND | ND | ND |
MRC, score | −0.2 (0.2) | 0.3 (0.3) | −0.4 (−1.2 to 0.3; 0.22) | −0.2 (0.2) | 0.6 (0.3) | −0.7 (−1.4 to −0.1; 0.030) |
Plasma NE, ng/ml | −0.063 (0.061) | −0.066 (0.067) | 0.004 (−0.183 to 0.190; 0.97) | ND | ND | ND |
IL-6 NE, pg/ml | 1.52 (1.33) | 0.08 (0.21) | 1.44 (−1.35 to 4.22; 0.31) | ND | ND | ND |
TNF-α, pg/ml | 0.29 (0.15) | 0.08 (0.06) | 0.21 (−0.12 to 0.54; 0.21) | ND | ND | ND |
Mean BP, mmHg | −13 (3) |
−3 (4) | −10 (−20 to 1; 0.061) | −2 (3) | 4 (4) | −6 (−17 to 4; 0.20) |
Body weight, kg | 0.1 (0.3) | 0.4 (0.3) | −0.3 (−1.2 to 0.7; 0.58) | 0.8 (0.4) | 0.4 (0.4) | 0.4 (−0.7 to 1.4; 0.49) |
Total lean mass, kg | 0.2 (0.5) | 0.5 (0.3) | −0.2 (−1.5 to 1.1; 0.73) | ND | ND | ND |
Grip strength, kg | 0.3 (0.9) | −0.0 (0.5) | 0.3 (−1.7 to 2.3; 0.76) | 1.1 (0.9) | 2.5 (1.1) |
−1.5 (−4.4 to 1.4; 0.31) |
Data are means (SE), or mean effect (95% CI; p value) unless otherwise indicated. BP = blood pressure; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; IL = interleukin; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MRC = medical research council; ND = not done; NE = norepinephrine; PFT = pulmonary function test; VC = vital capacity.
p<0.05,
p<0.01: change between pre-treatment and post-treatment within-group difference.
Food intake was assessed as described previously
The maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were measured as described previously
All participating centers measured dual energy x-ray absorptiometry (DEXA) to assess the total body composition, including lean body mass. The measurements were performed with the subject lying in a supine position. As a general rule, a single expert from each center analyzed the scans from the corresponding center.
Serum GH, serum insulin-like growth factor (IGF)-1, serum tumor necrosis factor α (TNF-α), serum interleukin-6 (IL-6), and plasma norepinephrine were measured as described previously
The study’s target accrual was 60 in the original protocol at the time of study design (see supporting information;
Open circles, ghrelin; closed circles, placebo. Data are presented as mean differences±SE. * p<0.05: change between pre- and post-treatment (within-group difference). † p<0.05: change between pre-treatment and post-treatment (between ghrelin and placebo group difference). ‡ p<0.05: time course effect of ghrelin versus placebo by repeated-measures ANOVA. At Week 3, marked improvements in SGRQ scores are not seen in both groups. However, SGRQ scores, especially SGRQ symptom scores, are significantly improved in the ghrelin group at Week 7. B) Repeated-measures ANOVA indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (F (2, 51) = 3.19, p = 0.049).
At Week 3 | At Week 7 | |||||
Ghrelin,n = 14 | Placebo,n = 15 | Treatment effect(95% CI; p value) | Ghrelin,n = 14 | Placebo,n = 13 | Treatment effect(95% CI; p value) | |
SGRQ | ||||||
Total | −5.0 (3.2) | −3.9 (3.5) | −1.1 (−10.9 to 8.7; 0.83) | −6.0 (2.7) |
0.8 (2.4) | −6.8 (−14.4 to 0.7; 0.072) |
Symptoms | −1.7 (3.0) | 0.3 (5.9) | −1.9 (−16.2 to 12.3; 0.77) | −9.4 (4.0) |
6.4 (5.4) | −15.8 (−29.5 to −2.1; 0.026) |
Activity | −4.5 (3.5) | −5.0 (3.9) | 0.4 (−10.5 to 11.4; 0.94) | 0.1 (2.2) | 1.3 (2.7) | −1.2 (−8.3 to 5.9; 0.73) |
Impacts | −6.3 (4.1) | −4.1 (3.1) | −2.2 (−12.6 to 8.2; 0.67) | −8.9 (3.7) |
−1.9 (3.0) | −7.0 (−16.9 to 2.9; 0.16) |
SF-36 | ||||||
Physicalfunctioning | 4.6 (6.1) | 0.3 (3.9) | 4.3 (−10.0 to 18.5; 0.55) | 3.1 (4.7) | −6.9 (4.9) | 10.0 (−3.9 to 23.9; 0.15) |
Role physical | −8.3 (6.9) | −4.6 (5.4) | −3.7 (−21.6 to 14.1; 0.67) | −12.0 (4.1) |
−22.6 (7.3) |
10.6 (−6.8 to 27.9; 0.22) |
Bodily pain | −6.8 (5.3) | 8.4 (6.4) | −15.2 (−33.0 to 2.6; 0.090) | −7.6 (6.5) | −3.8 (6.8) | −3.8 (−23.2 to 15.7; 0.69) |
General health | −0.6 (4.5) | 2.9 (5.2) | −3.5 (−17.9 to 11.0; 0.63) | 0.5 (3.4) | 5.8 (5.4) | −5.3 (−18.5 to 7.9; 0.41) |
Vitality | 5.7 (5.5) | 7.8 (4.4) | −2.0 (−16.3 to 12.3; 0.77) | 3.4 (4.8) | −2.9 (3.4) | 6.2 (−5.9 to 18.4; 0.30) |
Social functioning | −3.1 (9.5) | 3.3 (7.2) | −6.5 (−30.5 to 17.6; 0.59) | −12.5 (8.1) | −2.9 (6.0) | −9.6 (−30.5 to 11.3; 0.35) |
Role emotional | −13.9 (5.2) |
−9.5 (9.2) | −4.4 (−27.7 to 18.8; 0.68) | −19.9 (6.6) |
−16.0 (10.4) | −3.9 (−29.3 to 21.5; 0.76) |
Mental health | 0.4 (6.0) | 3.7 (4.2) | −3.3 (−18.0 to 11.5; 0.65) | 3.5 (3.3) | −8.2 (4.6) | 11.7 (0.0 to 23.4; 0.050) |
Data are means (SE), or mean effect (95% CI; p value) unless otherwise indicated. SGRQ = St. George Respiratory Questionnaire; SF 36 = short-Form 36.
p<0.05,
p<0.01: change between pre-treatment and post-treatment within-group difference.
All data are expressed as means±SD or SE unless otherwise indicated. Comparisons of baseline characteristics between the two groups were made by Fisher’s exact tests and Wilcoxon rank sum tests. Effects were examined once or twice; that is i) at Week 3 soon after 3-week treatment or ii) at Week 3 and Week 7 (i.e., 4 weeks after the completion of 3-week treatment). The results at Week 3 and Week 7, respectively, were compared with the pre-treatment within each group, and between the two groups using paired
Event | Ghrelin, n = 18 | Placebo, n = 15 |
Patients with at least 1 adverse event | 12 (67) | 5 (33) |
Adverse events not considered study therapy-related | ||
Pneumonia | 1 (6) | 0 (0) |
Depression | 1 (6) | 0 (0) |
Infective enteritis | 1 (6) | 0 (0) |
Lung cancer* | 1 (6) | 0 (0) |
Hypercalcemia | 0 (0) | 1 (7) |
Adverse events considered study therapy-related | ||
Stomach rumbling | 3 (17) | 2 (13) |
Feeling of being warm | 4 (22) | 0 (0) |
Feeling of hunger | 2 (11) | 2 (13) |
Thirst | 2 (11) | 0 (0) |
Slight liver dysfunction | 1 (6) | 0 (0) |
Hypercholesterolemia | 1 (6) | 0 (0) |
Hypoproteinemia | 1 (6) | 2 (13) |
Values are presented as n (% of group). * One patient developed lung cancer 2 years and 9 months after study treatment.
Of the 33 randomized patients, 31completed the 3-week study; 2 patients in the ghrelin group discontinued study medications due to pneumonia and depression, respectively. Of the 31 patients who completed the randomized 3-week study, in the ghrelin group, one patient had infective enteritis after 3 weeks of medications, and one had low back pain due to lumbar spondylosis before and throughout the 3 weeks of medications. Two patients in the placebo group were lost to follow-up after the Week 3 measurements. Therefore, 29 patients (ghrelin, n = 14; placebo, n = 15) were included in the study analyses to ensure adequate efficacy evaluation using pre-protocol analysis. The mean BMI in the enrolled patients (n = 29) was very low (mean±SD, 18.3±2.1 kg/m2). The treatment groups were generally well-matched with regard to demographics and baseline characteristics (
At pre-treatment, compared with placebo, a single administration of ghrelin markedly increased serum GH levels from baseline (mean change±SE: ghrelin group 46.4±6.2 ng/ml at the mean peak time (35 min) versus the placebo group 1.1±0.5 ng/ml at the mean peak time (55 min); between group p<0.0001), the effect of which was maintained at Week 3 (mean change±SE: ghrelin group 15.8±2.1 ng/ml at the mean peak time (30 min) versus the placebo group 0.4±0.2 ng/ml at the mean peak time (65 min); between group p<0.0001). Three-week ghrelin-PR combination treatment tended to increase serum IGF-1 levels (mean change±SE: 12±6 ng/ml, within-group p = 0.093).
At both Week 3 and Week 7, there were no significant differences between the ghrelin and placebo groups in 6-MWD. In each group, at Week 3, a similar significant increase from pre-treatment in 6-MWD was observed (mean difference: ghrelin group +40 m, within group p = 0.033 versus placebo group +35 m, within group p = 0.013). The effect remained at Week 7 in the ghrelin group, whereas in the placebo group, the improvement in 6-MWD was reduced at Week 7 (mean difference: ghrelin group within group +47 m, p = 0.017 versus placebo group +18 m, within group p = 0.14) (
In the ghrelin group, the peak
In both groups, there was no significant difference in each SGRQ score and MRC score between pre-treatment and at Week 3. At Week 7, there was a significant treatment effect between the two groups in SGRQ symptoms (between-group: p = 0.026,
In the ghrelin group, at Week 1, the relative increase in body weight was+0.42 kg (within group p = 0.092), which was reduced by Week 3 and followed by a re-increase at Week 7 (+0.8 kg, within group: p = 0.054). However there was no significant difference in body weight between the groups at each Week (
In the ghrelin group, at Week 3, the post-treatment increase in respiratory muscle strength, as indicated by MEP and MIP, was not significantly different from that in the placebo group, but at Week 7, the mean increase from pre-treatment in MEP (+15.6 cmH2O) was significantly different from that in the placebo group (between group p = 0.015) (
At Week 3 and Week 7, there was no significant treatment effect between the two groups in grip strength (
Ghrelin treatment did not significantly change any parameters of the pulmonary function tests, serum TNF-α, serum IL-6, or plasma norepinephrine at rest (
Throughout this trial, 67% of patients in the ghrelin group and 33% of patients in the placebo group reported 12 and 5 adverse events, respectively, but there was no significant difference between the groups (
The present study is the first multicenter, randomized, double-blind, placebo-controlled study to assess the effect and safety of repeated ghrelin administration to very severe cachectic patients with COPD. The main results of this study can be summarized as follows. In the ghrelin group, single administration of ghrelin was accompanied by a significant increase in serum GH levels during 3-week treatment, and there was no significant difference in 6-MWD between ghrelin and placebo at Week 3 and at Week 7. With ghrelin, symptomatic improvements in SGRQ symptoms and MRC score were not obtained at Week 3, but significant differences between ghrelin and placebo were seen at Week 7. In the ghrelin group, no significant within-group improvement from pre-treatment was seen in respiratory muscle strength, as indicated by MEP and MIP, at Week 3, but there was a significant difference in MEP between ghrelin and placebo at Week 7. Repeated-measures ANOVA showed significant time course effects of ghrelin versus placebo in SGRQ symptoms and MEP. Finally, ghrelin treatment was well tolerated.
Ghrelin treatment may have beneficial, continuing effects after treatment on HRQoL and MRC measures in this population. Though this study was conducted to determine the effectiveness of ghrelin in cachectic COPD patients, considering a synergistic interaction between ghrelin and PR, the data of this study need to be interpreted with caution, because, especially in advanced stage patients, excessive exercise training may partially worsen the anabolic and catabolic balance
Cachectic elderly patients with COPD who were given intravenous ghrelin showed a continuous increase of pulsatile GH secretion in the present study. There is evidence that insufficiency of sarcopenia-related hormones, such as GH and IGF-1, may contribute to cachexia
The participants in the present study tolerated daily administration of ghrelin for 3 weeks (
This study had some limitations. First, the number of participants was small, and few females were included in this trial. Second, the duration of the study was short. A more effective exercise training program, considering its intensity and frequencies, should have been conducted. Additional studies are needed to evaluate a more suitable regimen of ghrelin-PR.
In conclusion, ghrelin administration provided sustained improvements in symptoms and respiratory strength in cachectic COPD patients. Development of ghrelin administration methods may offer potential advantages over the currently approved treatment options for COPD. The lack of a significant between-group difference in exercise tolerance may result from the exercise training program conducted as the combination therapy. Careful examination is needed to develop more effective administration methods of ghrelin and combination therapy with ghrelin.
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The authors are particularly grateful to the patients who agreed to participate. The authors would also like to thank Dr.