Transcript PowerPoint - 埼玉医科大学総合医療センター 内分泌・糖尿病内科

Journal Club
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/dc121128.
2013年1月31日 8:30-8:55
８階 医局
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
Ghrelin / obstatin
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.
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
分子量：3370.9
アミノ酸配列：1 GSSFLSPEHQRVQQRKESKKPPAKLQPR 28
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.
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).
obestatin NMR structure in SDS/DPC micellar solution
http://en.wikipedia.org/wiki/Ghrelin
http://www.japan-acad.go.jp/japanese/news/2008/031201.html
GSK894490A CP-464709-18 認識力増大
Capromorelin
TZP-101
GHRP-2
RM-131 グレリンより100倍強力！
GHRP-6
AEZS-130
Hexarelin
ONO-7643
Ipamorelin
MK-677
SM-130,686
など
Tabimorelin
http://en.wikipedia.org/wiki/Growth_hormone_secretagogue_receptor
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
OBJECTIVE
To investigate the pharmacokinetics (PK),
pharmacodynamics, and safety of singledose RM-131 in type 2 diabetic patients
with gastrointestinal cardinal symptoms
(GCSI) and previously documented delayed
gastric emptying (DGE).
RESEARCH DESIGN AND METHODS
In 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).
PD evaluations included
upper GI motility evaluation
by scintigraphy.
Patients received a subcutaneous
injection of RM-131 or placebo (5%
mannitol), which had identical
appearance.
After a 7-day washout period, patients
crossed over to receive the alternative
therapy
Supplementary Figure 1. Patient disposition using CONSORT approach; all
participants completed all studies, and data were analyzed using intention to treat
principles.
Patients received a subcutaneous injection of RM-131 or
placebo (5% mannitol), which had identical appearance.
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.
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 2
Change 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.
RESULTS
At 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 singledose RM-131. Only light-headedness was reported more
on RM-131.
CONCLUSIONS
RM-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．．．