Journal Club
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Transcript of Journal Club
Journal Club
埼玉医科大学 総合医療センター 内分泌・糖尿病内科Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文Matsuda, Masafumi
2013 年 1 月 31 日 8:30-8:558階 医局
Shin A, Camilleri M, Busciglio I, Burton D, Stoner E, Noonan P, Gottesdiener K, Smith SA, Vella A, Zinsmeister AR.Randomized Controlled Phase Ib Study of Ghrelin Agonist, RM-131, in Type 2 Diabetic Women With Delayed Gastric Emptying: Pharmacokinetics and pharmacodynamics.Diabetes Care. 2013 Jan;36(1):41-8. doi: 10.2337/dc12-1128.
Ghrelin / obstatin
http://en.wikipedia.org/wiki/Ghrelin
Ghrelin is a 28 amino acid hunger-stimulating peptide and hormone that is produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas. Ghrelin together with obestatin is produced from cleavage of the ghrelin/obestatin prepropeptide (also known as the appetite-regulating hormone or growth hormone secretagogue or motilin-related peptide) which in turn is encoded by the GHRL gene.
Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels. In some bariatric procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur.
obestatin NMR structure in SDS/DPC micellar solution
The mRNA from the GHRL gene codes for a 117 amino acid peptide called preproghrelin, containing 4 exons. The signalling peptide molecule of this larger precursor is cleaved to produce proghrelin. Proghrelin is cleaved in two to produce the 28 amino acid peptide ghrelin (unacylated) and C-ghrelin (of which obestatin is presumed to be a cleaved form).
分子量: 3370.9アミノ酸配列: 1 GSSFLSPEHQRVQQRKESKKPPAKLQPR 28
1999 年、国立循環器病センターの児島将康・寒川賢治らにより発見された
http://www.japan-acad.go.jp/japanese/news/2008/031201.html
GSK894490A CP-464709-18 認識力増大CapromorelinGHRP-2GHRP-6HexarelinIpamorelinMK-677SM-130,686Tabimorelin
http://en.wikipedia.org/wiki/Growth_hormone_secretagogue_receptor
TZP-101
RM-131 グレリンより 100 倍強力!AEZS-130
など
ONO-7643
http://www.rhythmtx.com/PROGRAMS/RM131.html
the 1Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), College of Medicine, Mayo Clinic, Rochester, Minnesota; 2Rhythm Pharmaceuticals, Boston, Massachusetts; the 3Division of Endocrinology, Nutrition, and Metabolism, College of Medicine, Mayo Clinic, Rochester, Minnesota; and the 4Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, College of Medicine, Mayo Clinic, Rochester, Minnesota.
Diabetes Care 36:41–48, 2013
OBJECTIVETo investigate the pharmacokinetics (PK), pharmacodynamics, and safety of single-dose RM-131 in type 2 diabetic patients with gastrointestinal cardinal symptoms (GCSI) and previously documented delayed gastric emptying (DGE).
RESEARCH DESIGN AND METHODSIn a randomized crossover study, 10 female patients received RM-131 (100 mg s.c.) or placebo and underwent scintigraphic gastric emptying (GE) and colonic filling at 6 h (CF6) of a solid-liquid meal administered 30 min postdosing. Adverse events, plasma glucose, and hormonal levels were assessed. GCSI daily diary (GCSI-DD) was completed during treatments. PK was assessed in this cohort and healthy volunteers (HVs).
Supplementary Figure 1. Patient disposition using CONSORT approach; all participants completed all studies, and data were analyzed using intention to treat principles.
After a 7-day washout period, patients crossed over to receive the alternative therapy
Patients received a subcutaneous injection of RM-131 or placebo (5% mannitol), which had identical appearance.
PD evaluations included upper GI motility evaluation by scintigraphy.
Thirty minutes after subcutaneous administration of the study drug, a standardized radiolabeled study meal was administered, which patients were asked to consume within 10 min. The study meal consisted of the following: 4 oz. of scrambled Egg Beaters that had been radiolabeled with 0.5–1.0 mCi of 99mTc sulfur colloid; 120 mL of water that had been radiolabeled with 100 mCi of 111In diethylene triamine pentaacetic acid; and two slices of white bread with strawberry jam.
Patients received a subcutaneous injection of RM-131 or placebo (5% mannitol), which had identical appearance.
Gamma scans were obtained immediately after completion of the study meal through 6 h postmeal.
Postinjection blood sampling for postdose GH, insulin, prolactin, and cortisol levels were collected. PK(pharmacokinetics) was also collected through 6 h postdose.
Supplementary Figure 2Change in GE t1/2 solid by treatment period for each individual patient [gastric emptying (GE), minutes for solids for all 10 patients by treatment period (placebo and RM-131)]. Data are individual observations for each patient. Patient numbers correspond to the listing in Table 1 in the paper. Median and IQR for healthy volunteers reported in the literature (ref. 27 in paper) are indicated in the figure.
Figure 1 Effect of RM-131 on main transit measurements (GE, minutes for solids and liquids, and CF6, percent). Top: Data in all 10 patients. White bars, placebo; black bars, RM-131, 100 mg, treatment. Data are mean ±SEM. P values by the Student paired t test comparing RM-131 vs. placebo above each comparison (top) and by the Student unpaired t test comparing RM-131 vs. placebo (bottom). Published normal data (28) with this meal show t1/2 solid of median 83 min (IQR 64–103 min).
Figure 1 Effect of RM-131 on main transit measurements (GE, minutes for solids and liquids, and CF6, percent). Bottom: Analysis of data in period 1 only (n = 5 per group; see text for details). White bars, placebo; black bars, RM-131, 100 mg, treatment. Data are mean ± SEM. P values by the Student paired t test comparing RM-131 vs. placebo above each comparison (top) and by the Student unpaired t test comparing RM-131 vs. placebo (bottom). Published normal data (28) with this meal show t1/2 solid of median 83 min (IQR 64–103 min).
Supplementary Figure 3. Effect of RM-131 on plasma hormonal measurements [growth hormone (GH), prolactin, and cortisol] summarized as the 30-90 minute area under the plasma concentration curve. white bars = placebo; black bars = RM-131, 100μg, treatment. Data are mean+SEM; p values by the paired t test comparing RM-131 versus placebo above each comparison.
RM-131 was generally well tolerated. Although the total number of adverse events (P = 0.016 using McNemar test) recorded was higher with RM-131 (Supplementary Table 1), there were no serious adverse effects and no obvious pattern to the adverse effects, and only light-headedness was reported more often on RM-131. All adverse effects resolved spontaneously. No clinically significant effects on physical examination, ECG parameters, vital signs, or routine hematology and chemistry laboratory tests were observed.
RESULTSAt screening, HbA1c was 7.2 ± 0.4% (SEM) and total GCSI-DD score was 1.32 ± 0.21. RM-131 accelerated GE t1/2 of solids (P = 0.011); mean difference (D) in solid GE t1/2 was 68.3 min (95% CI 20–117) or 66.1%. There were numerical differences in GE lag time, CF6 solids, and GE t1/2 liquids (all P < 0.14). With a significant (P < 0.014) order effect, further analysis of the first treatment period (n = 5 per group) confirmed significant RM-131 effects on GE t1/2 (solids, P = 0.016; liquids, P = 0.024;CF6, P = 0.013). PK was similar in DGE patients and HVs. There were increases in 120-min blood glucose (P = 0.07) as well as 30–90-min area under the curve (AUC) levels of growth hormone, cortisol, and prolactin (all P < 0.02) with single-dose RM-131. Only light-headedness was reported more on RM-131.
CONCLUSIONSRM-131 greatly accelerates the GE of solids in patients with type 2 diabetes and documented DGE. PK is similar in diabetic patients and HVs.
Messageグレリンは食欲を増すので神経性食思不振症に効くかもしれない。とりあえずグレリン作動薬は胃の動きをよくしてくれるだろう。実際にこの研究ではそのような結論である。ちょっと Adverse events が多いようにも感じる。 で、六君子湯でも効くのか?ともかくグレリン受容体作動薬はたくさんある!
しかし、グレリンは食欲を増すので逆に阻害薬があれば食欲を減らしてきっと糖尿病の治療に役に立つと思われるけれど...