Brown MJ, McInnes GT, Papst CC, Zhang J, Macdonald TM.
Aliskiren and the calcium channel blocker amlodipine combination as an
initial treatment strategy for hypertension control (ACCELERATE): a
randomised, parallel-group trial.
Lancet. 2011 Jan 12. [Epub ahead of print]
Chahal HS, Stals K, Unterländer M, Balding DJ, Thomas MG, Kumar AV,
Besser GM, Atkinson AB, Morrison PJ, Howlett TA, Levy MJ, Orme SM,
Akker SA, Abel RL, Grossman AB, Burger J, Ellard S, Korbonits M.
AIP mutation in pituitary adenomas in the 18th century and today.
N Engl J Med. 2011 Jan 6;364(1):43-50.
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
Amlodipine (as besylate, mesylate or maleate) is a longacting calcium channel blocker (dihydropyridine class)
used as an anti-hypertensive and in the treatment of
angina. Like other calcium channel blockers, amlodipine
acts by relaxing the smooth muscle in the arterial wall,
decreasing total peripheral resistance and hence
reducing blood pressure; in angina it increases blood
flow to the heart muscle.
Aliskiren (INN) (trade names Tekturna, U.S.; Rasilez,
U.K. and elsewhere) is the first in a class of drugs
called direct renin inhibitor. Its current licensed
indication is primary (previously essential)
Aliskiren was co-developed by the Swiss
pharmaceutical companies Novartis and Speedel. It
was approved by the U.S. Food and Drug
Administration in 2007 for the treatment of primary
Clinical Pharmacology Unit, Department of Medicine, University of Cambridge,
Cambridge, UK (Prof M J Brown FMedSci); British Hypertension Society, London, UK
(Prof M J Brown, Prof G T McInnes FRCP, Prof T M MacDonald FRCP); Institute of
Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK (Prof G T
McInnes); Novartis Pharma AG, Basel, Switzerland (C Cherif Papst PhD, J Zhang MD);
and Division of Medical Sciences, Ninewells Hospital and Medical School, Dundee,
UK (Prof T M MacDonald)
www.thelancet.com Published online January 13, 2011 DOI:10.1016/S0140-6736(10)62003-X 1
Short-term studies have suggested that the use
of initial combination therapy for the control of
blood pressure improves early effectiveness. We
tested whether a combination of aliskiren and
amlodipine is superior to each monotherapy in
early control of blood pressure without excess of
adverse events, and if initial control by
monotherapy impairs subsequent control by
We did a double-blind, randomised, parallel-group, superiority
trial at 146 primary and secondary care sites in ten countries,
with enrolment from Nov 28, 2008, to July 15, 2009. Patients
eligible for enrolment had essential hypertension, were aged 18
years or older, and had systolic blood pressure between 150 and
180 mm Hg. Patients were randomly assigned (1:1:2) to
treatment with 150 mg aliskiren plus placebo, 5 mg amlodipine
plus placebo, or 150 mg aliskiren plus 5 mg amlodipine. Random
assignment was through a central interactive voice response
system and treatment allocation was masked from the patients.
From 16–32 weeks, all patients received combination therapy
with 300 mg aliskiren plus 10 mg amlodipine. Our primary
endpoints, assessed on an intention-to-treat basis (ie, in patients
who received the allocated treatment), were the adjusted mean
reduction in systolic blood pressure from baseline over 8 to 24
weeks, and then the final reduction at 24 weeks. This trial is
registered with ClinicalTrials.gov, number NCT00797862.
Previous studies have suggested that blockers of the renin-angiotensin system reduce
peripheral oedema, an adverse eff ect of dihydropyridine calcium channel blockers,
maybe because postcapillary venular dilatation reduces the eff ect of precapillary
sphincter dilatation upon intracapillary hydrostatic pressure.18–20 The new fi nding in
ACCELERATE is that serious ankle oedema (that led to withdrawal) was almost twice
as common in the patients that received amlodipine before aliskiren, than in those that
received aliskiren before or with amlodipine.
Figure 4: Plasma renin activity
Data are geometric mean (95% CI).
As expected, the combination
therapy and aliskiren reduced initial
activity of plasma renin, but
increased the concentration.
Amlodipine caused a small initial
increase in both activity and
concentration, but there was no
difference in the final values for
either measure between the three
318 patients were randomly assigned to aliskiren, 316 to
amlodipine, and 620 to aliskiren plus amlodipine. 315
patients initially allocated to aliskiren, 315 allocated to
amlodipine, and 617 allocated to aliskiren plus amlodipine
were available for analysis.
Patients given initial combination therapy had a 6・5 mm Hg
(95% CI 5・3 to 7・7) greater reduction in mean systolic
blood pressure than the monotherapy groups (p<0・0001). At
24 weeks, when all patients were on combination treatment,
the difference was 1・4 mm Hg (95% CI –0・05 to 2・9; p=0・
059). Adverse events caused withdrawal of 85 patients
(14%) from the initial aliskiren plus amlodipine group, 45
(14%) from the aliskiren group, and 58 (18%) from the
amlodipine group. Adverse events were peripheral oedema,
hypotension, or orthostatic hypotension.
We believe that routine initial reduction in blood
pressure (>150 mm Hg) with a combination such
as aliskiren plus amlodipine can be
Funding Novartis Pharma AG.
N Engl J Med 2011;364:43-50.
Background and Aim:
Gigantism results when a growth hormone–secreting
pituitary adenoma is present before epiphyseal fusion.
In 1909, when Harvey Cushing examined the skeleton
of an Irish patient who lived from 1761 to 1783, he
noted an enlarged pituitary fossa.
In our cohort of 140 families with familial isolated
pituitary adenoma, we identified four families from
Northern Ireland with the same AIP (the aryl
hydrocarbon–interacting protein) mutation (c.910C→T,
p.R304X), which is known to be a mutational hot spot.
We explored the possibility that an 18th-century giant
from Northern Ireland (the index patient), whose
skeleton is preserved, and the four Northern Irish
families we identified inherited the same mutation from
a common ancestor.
DNA from peripheral-blood leukocytes was extracted
with the use of a commercial kit (Nucleon BACC
Genomic DNA Extraction Kit, GE Healthcare). DNA was
extracted from the dental samples from the index patient
in a separate laboratory (Mainz, Germany) with the use
of previously described methods.
Sequencing and fragment analysis were carried out
according to standard protocols on a DNA analyzer (ABI
3730, Applied Biosystems).
To estimate the time since the common ancestor of the
mutant AIP allele in the four families and in the index
patient, we applied coalescent theory, which is a
retrospective model of gene genealogies for a sample
from a population with a defined demographic history.
Figure 1. Images of the Index Patient and the Structure and Specific
Mutation of AIP. In Panel A, the aryl hydrocarbon–interacting protein (AIP)
sequence change c.910C→T (red arrows) generates a premature stop codon,
resulting in a truncated protein with loss of the final 26 amino acids. The site
appears to be a mutational hot spot, since it is located at a typical CpG site16
and has been identified in five families from three countries (three from Italy,
one from England, and one from Romania), as well as in two patients with
apparently sporadic cases in France and India, in addition to the Irish cases we
describe here. It was not found to be present in any other patients with
sporadic or familial pituitary adenoma, in patients studied for AIP abnormalities
who had other diseases, or in the general population15 (and unpublished data).
Panel B shows schematic representations of AIP and the AIP protein. The red
arrows point to the location of AIP and protein mutations. The AIP protein has
three pairs of conserved antiparallel α helixes (tetratricopeptide repeat
domains [TPR]) and a final extended α helix, α7. These helical structures are
important for the protein–protein binding and antiproliferative action of AIP.
Panel C shows a three-dimensional model of AIP based on the crystal
structure of the structurally related protein FKBP51.13 The red amino acid is
number 304, which is replaced by a termination codon in the families described
in this study. This mutation results in a loss of 26 amino acids at the end of the
α7 helix (gray).
The index patient was born in Northern Ireland in
1761. As a child he grew rapidly, and in his late
teens he was featured in street shows in Ireland. At
the age of 19 years, he traveled to London to exhibit
himself in similar settings. A contemporary etching
shows him in the company of twin brothers, also
giants, who were born in a neighboring village (12
km away) and who were said to be related to him.
His general health slowly deteriorated, and he died
at 22 years of age.
Images of the Index Patient and the Structure and Specific Mutation of AIP.
Panel D shows the index patient beside the twin brothers who also had gigantism, in an
etching by John Kay (1742–1826) (National Portrait Gallery, London). Panel E shows
microtomographic reconstructions of the skull of the index patient (right) alongside a
normal male skull (left). The images have been clipped at the plane indicated to allow
observation of the differences in the size of the pituitary fossa (red circles), the size of
the frontal sinuses, and the thickness of the parietal bone (red arrow).
Figure 3. Microsatellite Data for the Index Patient, Mutation Carriers from the Four Contemporary Irish Families, and a NonIrish Patient with Sporadic Gigantism. For the four Irish families, the microsatellite data shown are for mutation carriers from the
eldest available generation. The green area is the conserved region around the R304X mutation among the five lineages; the red
bands represent the mutant c.910T allele, and the black bands represent the wild-type c.910C allele. Numbers next to the
identification number of the microsatellite represent the length in base pairs of the microsatellite assay products. Data in red denote
findings that differ from those in the other families. For the index patient, we were unable to infer the phase of alleles 95 and 101 at
Chr11-64-AC-110 and of alleles 104 and 106 at D11S1883 because none of the other patients studied carried these alleles. The
minimal common region for the index patient and the four families is 2.68 megabases (Mb), which is equivalent to 1.74 centimorgans
(cM) according to the Rutgers map and 1.15 cM according to the HapMap.
Two teeth were removed from the skull of the index patient. All eight products
contained the heterozygous c.910C→T change.
To investigate whether the four families carry the c.910C→T mutation by
common descent, we typed seven microsatellites distal to and seven proximal
to AIP in subjects from the four living families and from the index patient (Fig. 3,
and Fig. 1 in the Supplementary Appendix). We found a single common
haplotype in a region between microsatellite markers Chr11-64-TG-110 and
D11S987 spanning 2.68 megabases (Mb) shared among all five lineages. The
shared haplotype might extend from Chr11-64-AC-110 to Chr11- 67-TG-107,
covering 3.50 Mb, but to be conservative, we used the minimal shared region
(2.68 Mb) in our calculations.
We also typed these microsatellites in a sporadic case of gigantism in a patient
from India who carried the c.910C→T mutation. This patient did not share the
common haplotype found in the four Irish families.
Since the validated microsatellites are highly polymorphic in the common region
(heterozygosity scores between 0.58 and 0.82, National Center for
Biotechnology Information [http://ncbi.nlm.nih.gov]), the sharing of the five
microsatellite alleles and the c.910C→T mutation in AIP strongly supports the
hypothesis of a single, shared haplotype spanning this genomic region and
carrying the same founder c.910C→T mutation.
According to the Rutgers genetic map, the genetic distance across the minimal
region (2.68 Mb, including the five markers shared by the index patient and the
four families) is 1.74 centimorgans (cM), whereas the population-based
HapMap data results in a map distance of 1.15 cM. Both estimates are subject
to some uncertainty, and the true map distance probably lies between these
estimates. Given the observation of a shared haplotype, the coalescent-theory
estimate of the time since the most recent common ancestor is 57 generations
(95% credible interval, 15 to 132), or between 375 and 3300 years ago,
assuming a mean intergenerational time of 25 years, based on the Rutgers
genetic-map distance, and 66 generations (95% credible interval, 17 to 150), or
between 425 and 3750 years ago, based on the HapMap estimate. With the
condition that the present generation includes at least four carriers, and with the
use of the above distribution of values for the number of generations since the
mutation arose, forward simulations indicate that the expected number of
carriers in one generation would be 68 (95% credible interval, 5 to 350) and 90
(95% credible interval, 5 to 500), according to the two genetic-map estimates,
On the basis of these studies, we believe that
the index patient, and possibly the giant twin
brothers from the neighboring village who lived
contemporaneously, carried the same founder
mutation as four contemporary Northern Irish
families who presented with gigantism,
acromegaly, or prolactinoma.
Using coalescent theory, we infer that these
persons share a common ancestor who lived
about 57 to 66 generations earlier.
Role of the AIP gene in tumorigenesis of growth hormone-producing cells
代表者：吉本 勝彦 2007年度～2008年度
る。 AIP過剰発現による細胞増殖抑制 EK293, GH3, TIG3細胞に野生型AIPを発現させ