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

Journal Club
Tzoulaki I, Molokhia M, Curcin V, Little MP, Millett CJ, Ng A, Hughes RI,
Khunti K, Wilkins MR, Majeed A, Elliott P.
Risk of cardiovascular disease and all cause mortality among patients with type
2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using
UK general practice research database.
BMJ. 2009 Dec 3;339:b4731. doi: 10.1136/bmj.b4731.
Yamada Y, Kato T, Ogino H, Ashina S, Kato K.
Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight
gain and improves lipid profiles in rats.
Horm Metab Res. 2008 Aug;40(8):539-43. Epub 2008 May 21.
2010年2月4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
HR:0.86, CI:0.75 to 0.98
Setting Ontario, Canada. Participants
Outpatients aged 66 years and older
who were started on rosiglitazone or
pioglitazone between 1 April 2002
and 31 March 2008.
BMJ 2009;339:b2942
1Department of Epidemiology and Public Health, Faculty of Medicine, Imperial College London,
London W2 1PG 2Department of Epidemiology and Population Health, London School of
Hygiene and Tropical Medicine, London 3Department of Computing, Imperial College London,
London, 4Department of Primary Care and Social Medicine, Imperial College London, London
5Department of Experimental Medicine and Toxicology, Imperial College London, London
6Department of Health Sciences, University of Leicester, Leicester 7MRC-HPA Centre for
Environment and Health, London
BMJ 2009;339:b4731
Objective
To investigate the risk of incident
myocardial infarction, congestive
heart failure, and all cause mortality
associated with prescription of oral
antidiabetes drugs.
Method
Design： Retrospective cohort study.
Setting： UK general practice research database,
1990-2005.
Participants： 91 521 people with diabetes.
Main outcome measures： Incident myocardial
infarction, congestive heart failure, and all cause
mortality. Person time intervals for drug treatment
were categorised by drug class, excluding non-drug
intervals and intervals for insulin.
Risk of myocardial infarction, congestive heart failure, and all cause mortality for different comparisons of drug groups.
Analysis is stratified by year of prescription and quartiles of age at treatment, and adjusted for sex, duration of diabetes,
previous peripheral arterial disease, previous cardiovascular disease, aspirin, statin or fibrate, diuretics, calcium channel
blockers, spironolactone, β adrenergic antagonists, angiotensin converting enzyme inhibitors or angiotensin II receptor
blockers, nitrates, steroids, non-steroidal antiinflammatory drugs, digoxin, and any previous complications from diabetes
(model 2). *Any therapy (monotherapy and combinations). †Other drugs and combinations of any oral antidiabetes drugs
excluding rosiglitazone and pioglitazone
Risk of myocardial infarction, congestive heart failure, and all cause mortality for different comparisons of drug groups.
Analysis is stratified by year of prescription and quartiles of age at treatment, and adjusted for sex, duration of diabetes,
previous peripheral arterial disease, previous cardiovascular disease, aspirin, statin or fibrate, diuretics, calcium channel
blockers, spironolactone, β adrenergic antagonists, angiotensin converting enzyme inhibitors or angiotensin II receptor
blockers, nitrates, steroids, non-steroidal antiinflammatory drugs, digoxin, and any previous complications from diabetes
(model 2). *Any therapy (monotherapy and combinations). †Other drugs and combinations of any oral antidiabetes drugs
excluding rosiglitazone and pioglitazone
Risk of myocardial infarction, congestive heart failure, and all cause mortality for different comparisons of drug groups.
Analysis is stratified by year of prescription and quartiles of age at treatment, and adjusted for sex, duration of diabetes,
previous peripheral arterial disease, previous cardiovascular disease, aspirin, statin or fibrate, diuretics, calcium channel
blockers, spironolactone, β adrenergic antagonists, angiotensin converting enzyme inhibitors or angiotensin II receptor
blockers, nitrates, steroids, non-steroidal antiinflammatory drugs, digoxin, and any previous complications from diabetes
(model 2). *Any therapy (monotherapy and combinations). †Other drugs and combinations of any oral antidiabetes drugs
excluding rosiglitazone and pioglitazone
Results
3588 incident cases of myocardial infarction, 6900 of
congestive heart failure, and 18 548 deaths occurred.
Compared with metformin, monotherapy with first or second
generation sulphonylureas was associated with a significant
24% to 61% excess risk for all cause mortality (P<0.001) and
second generation sulphonylureas with an 18% to 30%
excess risk for congestive heart failure (P=0.01 and P<0.001).
The thiazolidinediones were not associated with risk of
myocardial infarction; pioglitazone was associated with a
significant 31% to 39% lower risk of all cause mortality
(P=0.02 to P<0.001) compared with metformin. Among the
thiazolidinediones, rosiglitazone was associated with a 34%
to 41% higher risk of all cause mortality (P=0.14 to P=0.01)
compared with pioglitazone. A large number of potential
confounders were accounted for in the study; however, the
possibility of residual confounding or confounding by
indication (differences in prognostic factors between drug
groups) cannot be excluded.
Conclusion
Our findings suggest a relatively unfavourable
risk profile of sulphonylureas compared with
metformin for all outcomes examined.
Pioglitazone was associated with reduced all
cause mortality compared with metformin.
Pioglitazone also had a favourable risk profile
compared with rosiglitazone; although this
requires replication in other studies, it may
have implications for prescribing within this
class of drugs.
Message
第１世代SU薬
第２世代SU薬
メトホルミン
ロジグリタゾン
ピオグリタゾン
の順で
実際に使ってる患者はイベントが少ない
ピオグリタゾン
をなるべく使う！？
Orlistat works by inhibiting gastric and
pancreatic lipases, the enzymes that
break down triglycerides in the intestine.
中外製薬の開発中止で、日本での発売の目処すら立っていなかった抗肥満薬オル
リスタット（Orlistat）ですが、大正製薬が開発に名乗りを上げた。
抗肥満薬「orlistat」製剤の日本における開発及び販売に関する契約締結について
（大正製薬プレスリリース 2009年1月13日）
http://www.taisho.co.jp/company/release/2009/2009011301.pdf
今回大正製薬が開発・販売権を取得したのは、中外製薬が開発を中止したロシュ
社の医療用医薬品の『ゼニカル』（オルリスタット120mg）ではなく、米国で発売され
ているGSK社のOTC版の『alli』（オルリスタット60ｍｇ）で、薬事日報などではリアッ
プのようにダイレクトスイッチとして開発されるのではないかと伝えている。（発売に
は最低でも4～5年かかるでしょうが）
Horm Metab Res. 2008 Aug;40(8):539-43
Objective
Cetilistat is a novel inhibitor of
pancreatic lipase.
The aim of this report is to evaluate the
anti-obesity action of cetilistat in dietinduced obesity (DIO) rats.
Method
Cetilistat was orally administered
simultaneously with fat emulsion to SpragueDawley rats. Plasma triglyceride (TG)
concentrations were measured before and
after oral fat loading.
Cetilistat was administered to DIO F344 rats
as food admixture in a high-fat diet at 4.9,14.9,
or 50.7mg/kg/day for three weeks.
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Strain Name:
C57BL/6-Apctm1Tyj/J
Capabilities
Inventoried DIO mice
•C57BL/6J (000664, B6) males fed a high fat (60 kcal%) diet (Research Diets Inc. D12492i) starting at six weeks
of age
•Control B6 males (starting at six weeks old) fed a 10 kcal% control diet (D12450Bi), containing the same protein
content as the high fat diet
•Ages available: six to 26 weeks
•Weekly email notices on availability
•Mice are shipped from rooms MP23 and RB04
•Pricing tables: U.S.A., Canada and Mexico or International
•Information on diets and phenotypes
•Order by email to [email protected], or call 1-800-422-6423 and ask for a DIO representative
Custom DIO mice
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frequencies of weighing and of collecting bio-samples, etc.
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http://jaxmice.jax.org/diomice/index.html
Results
Cetilistat inhibited rat and human pancreatic lipase activity
with an IC50 of 54.8nmol/l, and 5.95nmol/l, respectively,
meaning that it is 9.2 times more potent for human pancreatic
lipase than for that of rat. The elevation in plasma triglyceride
concentration by oral fat loading was reduced by cetilistat in
a dose-dependent manner at 3,10, 30, and 100mg/kg,
indicating that cetilistat reduces intestinal fat absorption in
rats.
Both triglyceride and nonesterified fatty acid content in the
feces were dose-dependently and drastically increased,
suggesting the intestinal breakdown of fat and excretion.
Body weight (BW) gain and white adipose tissue (WAT)
weight were reduced in a dose-dependent manner. In addition,
leptin, TG, and total cholesterol (TC) in plasma were reduced
and there were no reports of oily stools.
Conclusion
These results suggest that
cetilistat ameliorates obesity and
hyperlipidemia in DIO rats, a
plausible animal model of the
most common type of human
obesity.
Message
肥満に対する治療薬として色々な薬物が開
発されつつある。
Cetilistatは2010年度申請で，2012年度に承認，発売の予定
今年の５月の日本糖尿病学会年次学術集会
のシンポジウムを聞きに行きましょう！
Journal Club
Okamoto K, Iwasaki N, Nishimura C, Doi K, Noiri E, Nakamura S, Takizawa M, Ogata M,
Fujimaki R, Grarup N, Pisinger C, Borch-Johnsen K, Lauritzen T, Sandbaek A, Hansen T, Yasuda
K, Osawa H, Nanjo K, Kadowaki T, Kasuga M, Pedersen O, Fujita T, Kamatani N, Iwamoto Y,
Tokunaga K.
Identification of KCNJ15 as a susceptibility gene in Asian patients with type 2 diabetes mellitus.
Am J Hum Genet. 2010 Jan;86(1):54-64.
Miyake K, Yang W, Hara K, Yasuda K, Horikawa Y, Osawa H, Furuta H, Ng MC, Hirota Y, Mori H,
Ido K, Yamagata K, Hinokio Y, Oka Y, Iwasaki N, Iwamoto Y, Yamada Y, Seino Y, Maegawa H,
Kashiwagi A, Wang HY, Tanahashi T, Nakamura N, Takeda J, Maeda E, Yamamoto K, Tokunaga
K, Ma RC, So WY, Chan JC, Kamatani N, Makino H, Nanjo K, Kadowaki T, Kasuga M.
Construction of a prediction model for type 2 diabetes mellitus in the Japanese population based
on 11 genes with strong evidence of the association.
J Hum Genet. 2009 Apr;54(4):236-41.
2010年2月18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