Clinical Science (1981) 61,653-656
653
SHORT COMMUNICATION
Effect of a long-acting octapeptide analogue of somatostatin on
growth hormone and pancreatic and gastrointestinal hormones
in man
A . J . B A R N E S , R . G. L O N G , T . E . A D R I A N , W. V A L E * , M. R . B R O W N * , J . E.
R I V I E R * , J . H A N L E Y , M . A . G H A T E I , D . L. S A R S O N A N D S . R . B L O O M
Department of Medicine, Hammersmith Hospital and Royal Postgraduate Medical School, London, and *Salk Institute,
San Diego, U.S.A.
(Received 17 December 1980127 March 1981; accepted 22 April 1981)
Summary
1. The biochemical specificity and duration of
action of a single 5 mg subcutaneous dose of
d e ~ - A A l . ~ * ~13-D-Trps-somatostatin
*
were
evaluated in eight patients with symptomatic
pancreatic endocrine tumours.
2. There was a reduction by more than 50%
for at least 10 h in plasma concentrations of
growth hormone, glucagon, gastrin and motilin
and for 4-5 h in plasma insulin, pancreatic
polypeptide, gastric inhibitory polypeptide and
enteroglucagon.
3. This study shows that this octapeptide
analogue of somatostatin, like somatostatin itself,
lacks specificity in the hormones it suppresses.
However, its prolonged duration of action against
several hormones when given subcutaneously
suggests that it may be of therapeutic use in a
number of disease states where excessive plasma
concentrations of one or more of these hormones
occur.
53
'I
Key words: gastrointestinal hormones, growth
hormone, pancreatic hormones, somatostatin.
Introduction
Somatostatin is a tetradecapeptide which has
been demonstrated both in neural tissue, particularly the hypothalamus, and endocrine cells,
for example the pancreatic D cell. Its action in
reducing the secretion of numerous hormones
Correspondence: Dr S. R. Bloom, Department of
Medicine, Royal Postgraduate Medical School, Du
Cane Road, London W 12 OHS.
0143-5221/81/110653-04%01.50/1/1
including growth hormone [ 11, insulin 121, pancreatic glucagon [31 and gastrin [41 suggested its
use as a treatment in endocrine disease characterized by excess production of one or more of
these hormones. Favourable therapeutic responses have been reported in patients with diabetes
mellitus, nesidioblastosis due to hyperinsulinism
[6] and carcinoid flushing. [71.
However, the clinical use of somatostatin is
limited by its very short duration of action
(plasma half-life about 2-3 min) and by its lack
of hormone specificity. In an attempt to overcome these problems a large number of somatostatin analogues has been synthesized recently,
several of which have been reported with either
prolonged activity or hormone specificity in
experimental animals [8-101. Excision of six of
the constituent 14 amino acids has led to the
development of a hydrophobic molecule which
maintains the effects of the parent compound.
This
analogue
(~~S-AA'~~~~~~*''~'~
somatostatin) was administered by subcutaneous
injection to patients with symptomatic pancreatic endocrine tumours and was found to have
a prolonged duration of action of up to 24 h on
tumour-produced plasma hormones [ I 11. The
aim of the present study was to assess the
selectivity and duration of action of this peptide
against a spectrum of non-tumour-derived
hormones.
Patients and methods
des-AA1~z~4~5~12~'3-~-Trp8-Somatostatin
(hereafter
referred to as the octapeptide analogue) was
0 1 9 8 1 The Biochemical Society and the Medical Research Society
A . J. Barnes et al.
654
krein inactivating units/l ml of blood). Samples
for hormone measurement were centrifuged
immediately and the plasma separated and stored
at -20°C until radioimmunoassay. In view of the
variation in plasma concentrations of some of the
hormones, results are expressed as means & SEM
of the percentage of the basal hormone concentrations (the mean of the -1 and 0 h samples).
Ethical permission was obtained for the study
from the Research Ethics Committee of the
Royal Postgraduate Medical School. The nature
of the study was carefully explained to each
patient and written consent obtained.
synthesized by total solid-phase synthesis and
was administered as a single dose of 5 mg
[dissolved in 1 ml of 10% (w/v) human albumin1
by subcutaneous injection to eight overnight
fasted patients with symptomatic pancreatic
endocrine tumours. There were three patients
with insulinomas, three with gastrinomas and one
each with a vasoactive intestinal polypeptidesecreting tumour (vipoma) and a glucagonoma.
The patients fasted for the 3 h after the
injection, ate lunch at 12.00 hours and dinner at
18.00 hours, and were ambulant during the
investigation. The analogue was injected
at 09.00 hours and venous blood was taken at - 1,
0, 1, 2, 3,4, 5, 8, 12 and 24 h for measurement of
plasma glucose by the glucose oxidase technique
[121 and growth hormone [131, glucagon [141,
insulin [ 151, pancreatic polypeptide [ 161, gastrin
[ 171, motilin [ 181, gastric inhibitory polypeptide
[ 191 and enteroglucagon 1201 by radioimmunoassay.
Blood for glucose analysis was collected into
fluoride oxalate and for hormone analysis into
heparinized tubes containing Trasylol (400 kalli-
Results
Percentage changes in the eight hormones over
the 24 h period after subcutaneous octapeptide
somatostatin are shown in Fig. 1. Mean plasma
concentrations were respectively suppressed by
more than 50% for 11 h for growth hormone, 10
h for glucagon, gastrin and motilin, 5 h for insulin
and pancreatic polypeptide and for 4 h for gastric
inhibitory polypeptide and enteroglucagon. The
I
OJ
I
I
OJ
I
I
rnn-
50
0
I
I
'W'
J
I
I
I
I
1
0
6
12
18
24
,J
I
I
Enteroglucagon
I
I
I
1
I
0
6
12
18
24
Time (hours)
FIG. 1. Effect of subcutaneous ~ ~ s - A A ' ~ * ~ ~ ~ ~somatostatin
~ ' * ~ ' ~ -on
D -plasma
T~~*
concentrations
of (a) growth hormone (HGH), glucagon, insulin and pancreatic polypeptide (PP) and (b)gastrin,
motilin, gastric inhibitory polypeptide (GIP) and enteroglucagon. Results are expressed as means
SEM.
I
Long-acting octapeptide somatostatin analogue
percentage fall in plasma insulin and gastrin was
similar whether the hormone originated from
tumour or non-tumour cells. Plasma glucose
showed no consistent changes over this period of
time, but rose in all cases after meals.
No subject noted any adverse clinical effects
from this somatostatin analogue and haemoglobin, leucocyte count, platelet count, plasma
urea, electrolytes and serum creatinine and liver
function tests were similar before and 24 h after
the peptide was administered. On three occasions
in two patients 10 mg doses of the analogue have
also been given subcutaneously without any
adverse effects.
Discussion
Natural tetradecapeptide somatostatin when
given subcutaneously has a very short duration of
action and coupling to protamine zinc only
prolongs the duration of action for about 30 min
[ 2 11. By contrast, the octapeptide analogue
reduced plasma levels of several hormones by
more than 50% for up to 11 h in the present
study. Previous studies have shown that plasma
concentrations of hormones return to normal in
under 60 min when an intravenous infusion of
this somatostatin analogue is discontinued suggesting its functional half-life to be as rapid as
that of the parent peptide [22]. Thus its prolonged action would appear to be due to slower
release from the site of injection (perhaps the
result of its very hydrophobic nature) rather than
reduced clearance from either plasma or receptor
sites.
The two main limitations of somatostatin as a
therapeutic agent are its short duration of action
and its lack of hormonal specificity. Octapeptide
somatostatin would appear to have overcome the
first of these problems, but retained the capacity
of tetradecapeptide somatostatin to inhibit the
release of a broad spectrum of hormones.
Although the suppression of several hormones for
prolonged periods in patients is theoretically
undesirable the consequences of such a
manoeuvre are far from clear. None of our
patients experienced any untoward symptoms at
the dose of octapeptide somatostatin used in the
present study and intravenous infusion of linear
somatostatin for 3 days in previous reports
similarly had no apparent adverse effects [51. In
patients with pancreatic tumours secreting
somatostatin plasma levels of somatostatin may
be raised to over 500 pmol/l for long periods and
although hyperglycaemia and steatorrhoea are
usual features, symptoms are not incapacitating
and may be fully reversible after treatment [231.
655
Thus, although hormone specificity would be a
desirable property of long-acting somatostatin
analogues, it may not be essential when only
relatively short-term therapy is envisaged.
No subjective, haematological or biochemical
side-effects were seen with these 5 mg injections
of the octapeptide analogue. In short-term infusions of tetradecapeptide somatostatin the
plasma glucose concentration may fall during
fasting but, even though the patients in this study
fasted for the first 3 h of the experiment, no
consistent change in blood glucose concentrations was observed. Thus this dose was free of
complications and in preliminary studies we have
also found no side-effects with 10 mg subcutaneous injections.
The ability of the octapeptide analogue to
effect prolonged suppression of both growth
hormone and glucagon suggests that it might be
useful in patients with acromegaly and hyperglucagonaemia. Other groups of patients who
might benefit from treatment with this analogue
include those with nesidioblastosis, pancreatic
endocrine tumours, the carcinoid syndrome,
diarrhoea of various types and bleeding peptic
ulcers. Clearly further studies of the therapeutic
potential of this peptide are indicated.
Acknowledgments
We are grateful to the Lister Institute, Elstree,
Herts., U.K., for the kind gift of the human
albumin. Dr Barnes and Dr Long were in receipt
of Medical Research Council Training Fellowships.
References
I I I BRAZEAU,
P., VALE,
W., BURGUS,R., LING, N., BUTCHER,M.,
RIVIER,J. & GUILLEMM,R. (1973) Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary
growth hormone. Science, 119,.77-79.
121 ALBERTI,K.G.M.M., CHRISTENSEN,
N.J., CHRISTENSEN,
S.E.,
HANSEN, A.A.P., IVERSEN, J., LUNDBACK, K., SEVER
HANSEN,K. & ORSKOV, H. (1973) Inhibition of insulin
secretion by somatostatin. Lancer, ii, 1299-1302.
131 MORTIMER,C.H., TUNBRIDGE,
W.M.G., CARR, D., YEOMANS,
L., LIND, T., COY, D.H., BLOOM, S.R., KASTM, A.,
A.V. & HALL, R.
MALLINSON,
C.N., BESSER,G.M., SCHALLY,
(1974) Effects of growth-hormone release-inhibiting hormone
in normal, diabetic, acromegalic and hypopituitary patients.
Lancet, ii, 697-701.
141 BARROSD’SA, A.A.J., BLOOM,S.R. & BARON,J.H. (1975)
Direct inhibition of gastric acid by growth hormone releaseinhibiting hormone in dogs. Lancet, ii, 886-887.
151 GERICH,J.E. & PATTON, G.S. (1978) Somatostatin. Physiology and clinical applications. Medical Clinics of North
America, 2,375-392.
161 HIRSCH, H.J., LOO, S., EVANS,N., CRIGLER,J.F., FILLER,
R.M. & GABBAY,K.H. (1977) Hypoglycaemia of infancy and
nesidioblastosis. Studies with somatostatin. New England
Journal oJMedicine, 296,1323-1326.
65 6
A . J. Barnes er a/.
171 LONG, R.G., PETERS, J.R., BLOOM,S.R., BROWN,M.R., VALE,
W., RIVIER, J.E. & GRAHAME-SMITH,
D.G. (1981) Somatostatin, gastrointestinal peptides and the carcinoid syndrome.
Gut (In press).
181 RIVIER,J., BROWN, M. & VALE, W. (1975) D-Trp'-somatostatin: an analog of somatostatin more potent than the native
molecule. Biochemical atid Biophysical research Communicatioris, 65,746-75 I.
191 BROWN,M., RIVIEKJ. & VALE, W. (1977) Somatostatin:
analogues with selected biological activities. Science, 196,
1467-1469.
I I01 VOYLES,N.R., BHATHENA, S.J., RECANT,L., MEYERS,L.A. &
COY, D.H. (1979) Selective inh,ibition of glucagon and insulin
secretion by somatostatin analogs. Proceedings of the Society
f o r Experimental Biology arid Medicine, 160.76-79.
I I I 1 LONG,R.G., BARNES, A.J., ADRIAN,T.E., MALLINSON,
C.N.,
BROWN, M.R., VALE,W., RIVIER,J.E., CHRISTOFIDES,
N.D. &
BLOOM,S.R. (1979) Suppression of pancreatic endocrine
tumour secretion by long-acting somatostatin analogue.
Lancet, ii, 164-767.
1121 SAIFER,A. & GERSTENFELD,S. (1958) The photometric
microdetermination of blood glucose with glucose oxidase.
Journal of Laborarory and Cliitical Medicine, 5 1,448-460.
I131 JACOBS, H.S. (1969) Use of activated charcoal in the
radioimmunoassay of human growth hormone in plasma.
Journal of Cliitical Pathology, 22,710-7 17.
1141 ALFORD, F.B., BLOOM, S.R. & NABARRO,J.D.N. (1977)
Glucagon levels in normal and diabetic subjects. Use of a
specific immunoabsorbant for glucagon radioimmunoassay.
Diabelologia, 13,l-6.
I 151 ALBANO.J.D., EKINS,R.P., MARITZ,G. & TURNER,R.C.
(1972) A sensitive precise radioimmunoassay of serum insulin
relying on charcoal separation of bound and free hormone
moieties. Acta Endocrinologica, 70,487-509.
1161 ADRIAN,T.E., BLOOM,S.R., BRYANT,M.G., POLAK, J.M.,
HEIK P.H. & BARNES, A.J. (1976) Distribution and release of
human pancreatic polypeptide. Cur, 17,940-944.
1171 RUSSELL,R.C.G., BLOOM,S.R., FIELDING,
L.P. & BRYANT,
M.G. (1976) Current problems in the measurement of gastrin
release. Postgraduate Medical Journal, 52,645-650.
I181 CHRISTOFIDES,
N.D.. MODLIN,I.M., FITZPATRICK,M.L. &
BLOOM,S.R. (1979) Effect of motilin on the rate of gastric
emptying and gut hormone release during breakfast. Gastroenterology, 76,903-907.
I191 SARSON, D.L., BRYANT,M.G. & BLOOM,S.R. (1980) A
radioimmunoassay of gastric inhibitory polypeptide in human
plasma. Journal of Endocrinology, 85,487496.
I201 LONG,R.G., ALBUQUERQUE,
R.H., PRATA,A,, BARNES,A.J.,
ADRIAN,T.E., CHRISTOFIDES,
N.D. & BLOOM,S.R. (1980)
Response of plasma pancreatic and gastrointestinal hormones
and growth hormone to oral and intravenous glucose and
insulin hypoglycaemia in Chagas' disease. Cur, 21,772-777.
1211 TANNENBAUM,
G.S. & COLLE, E. (1980) Ineffectiveness of
protamine zinc somatostatin as a long-acting inhibitor of
insulin and growth hormone secretion. Canadiaii Joirrnal of
Physiology and Pharmacology, 58,95 1-955.
1221 LONG,R.G., ADRIAN,T.E., BARNES,A.J., VALE,W., RIVIER,
J.E., BROWN,M.R. & BLOOM,S.R. (1979) d e ~ - A A l * ~ * ' * ~ . ~ ~ . ' ~ D-Trp'-Somatostatin: a long-acting inhibitor of pancreatic
endocrine tumour and non-tumour derived hormones. Gut, 20,
949.
M., DAVIS,
1231 KREJS,G.J., ORCI, L., CONLON,M., RAVAZZOLA,
G.R., RASKIN, P., COLLINS, S.M., MCCARTHY,D.M.,
BAETENS,D., RUBENSTEIN,
A., ALDOR,T.A.M. & UNGER,
R.H. (1979) Somatostatinoma syndrome. Biochemical,
morphologic and clinical features. New England Journal of
Medicine, 301,285-292.