WO2000060360A2 - Diagnosis of irritable bowel syndrome - Google Patents

Diagnosis of irritable bowel syndrome Download PDF

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Publication number
WO2000060360A2
WO2000060360A2 PCT/IE2000/000038 IE0000038W WO0060360A2 WO 2000060360 A2 WO2000060360 A2 WO 2000060360A2 IE 0000038 W IE0000038 W IE 0000038W WO 0060360 A2 WO0060360 A2 WO 0060360A2
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ibs
subject
cholinergic
diagnosis
challenge
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PCT/IE2000/000038
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French (fr)
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WO2000060360A3 (en
Inventor
Timothy Gerard Dinan
Paul William Napoleon Keeling
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Malope Company Limited
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Priority to AU36678/00A priority Critical patent/AU3667800A/en
Publication of WO2000060360A2 publication Critical patent/WO2000060360A2/en
Publication of WO2000060360A3 publication Critical patent/WO2000060360A3/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/575—Hormones
    • G01N2333/61—Growth hormones [GH] (Somatotropin)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70571—Assays involving receptors, cell surface antigens or cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor

Definitions

  • This invention relates to the diagnosis and therapy of irritable bowel syndrome (IBS), in particular to classic colonic irritable bowel syndrome.
  • IBS irritable bowel syndrome
  • IBS is the most common reason for referral to gastroenterology clinics and affects 10-12% of the whole population. To date systematic efforts to determine its aetiology have failed. No consistent biochemical or physiological abnormalities have been demonstrated and many gastroenterologists describe it as a functional disorder, without an organic basis.
  • IBS can be described as a condition of the gastrointestinal tract characterised by a disorder of gut motility or rate of movement along the gastrointestinal tract, which may be either delayed or increased. Accordingly, IBS is not characterised by any consistent abnormality in the gut.
  • non-ulcer dyspepsia patients with predominantly upper IBS type symptoms, usually referred to as non-ulcer dyspepsia, have an abnormality involving central serotonergic receptors (Dinan, T.G., Yatham, L.N., Barry, S., Chua, A. and Keeling, P.W.N., Scand. J. Gastroenterol. 1990,25,541-544; EP-B 0 419 237).
  • the abnormality involves increased sensitivity of these receptors and is associated with a delay in solid phase gastric emptying (Dinan T.G. et al, BMJ 1992, 305,280-282)
  • the invention provides an in vitro method for the diagnosis of irritable bowel syndrome (IBS) in a subject suspected of having IBS, which method comprises identifying in said subject a dysfunction of central cholinergic receptors, characterised by the subject's growth hormone response to a cholinergic challenge drug, said response being measured by estimating the level of growth hormone in a sample of blood or a blood fraction obtained from said subject following said challenge, with the proviso that when the subject is a premenopausal female, the diagnosis is carried out during the follicular phase of the menstrual cycle.
  • IBS irritable bowel syndrome
  • the method according to the invention demonstrates that central cholinergic responses are significantly enhanced in patients with IBS thereby providing a means of readily diagnosing a subject suffering from IBS.
  • the cholinergic challenge drug is an acetylcholinesterase inhibitor.
  • Acetylcholine is an important transmitter in the gut and some treatment strategies focus on this peripheral receptor system (Kinnier, W.J., Kachur, J.F., Audia, V.H., Kaiser, C, 1989 Med. Res. Revs. 9, 325-342). It is also an important neurotransmitter in the brain and to date no research has focused on central cholinergic function in IBS.
  • the inventors examined central cholinergic function in patients with a diagnosis of IBS, using a neuroendocrine strategy which they have previously described in detail (O'Keane, V. and Dinan, T.G., 1992, supra).
  • GH growth hormone
  • GHRH GH releasing hormone
  • SS somatostatin
  • the cholinergic challenge drug is pyridostigmine.
  • Example pyridostigmine the acetylcholinesterase inhibitor, was used to enhance cholinergic transmission and thereby stimulate GH release in patients with IBS and appropriate comparison groups.
  • acetylcholinesterase inhibitors such as galanthamine may also be used. Indeed, galanthamine has less side-effects than pyridostigmine.
  • the pyridostigmine when such is used, is preferably administered as a single dose in an amount of at least 60 mg, more especially 120 mg, to effect said cholinergic challenge.
  • the blood fraction is preferably plasma or serum.
  • the GH is suitably measured by an immunoassay method.
  • the GH response is suitably measured by enzyme immunossay or radio immunoassay.
  • immunoassay methods in accordance with the invention may be carried out using any known format, such as, for example, beads, dipsticks, membranes, particles, plates, rods, strips, etc.
  • insolubilised or solid phase antibody as used in accordance with the invention is suitably bound to a bead, dipstick, membrane, plate, particle, rod, tube, well, or the like of plastics material or glass in a manner per se.
  • the insolubilised from of the antibody comprises said antibody adsorbed on a surface adapted for protein adsorption.
  • the surface may be a bead, membrane, particle, plate rod, tube, well or the like and of a material as hereinbefore specified.
  • the surface comprises a plastic microtitration plate or strip adapted for protein adsorption wherein the immunochemical reaction and the estimation of the GH or release of the GH on the insolubilised form of the antibody, depending on the method used.
  • the relevant surface may be coated directly with an optimum dilution of monoclonal antibody or polyclonal antibody.
  • the estimation of the bound GH derived from the sample can be carried out by enzymatic, fluorometric, luminometric or radiometric assay, using enzymes, fluorochromes, light-emitting probes or radio labels, respectively.
  • the labelled agents for use in the assays according to the invention are prepared in conventional manner or are purchased from appropriate suppliers. Such labelled agents are normally in the form of conjugates such as enzyme-labelled antibodies for use in competitive binding assays.
  • the labelled agent is also suitably an antibody covalently linked to a radio label for use in a radiometric assay.
  • the GH response as measured in the method according to the invention is blocked by a muscarinic antagonist.
  • the invention also provides a test kit or pack for diagnosis of IBS in a subject suspected of having IBS, which comprises an amount of a cholinergic challenge drug for administering to one or more subject(s) being investigated for IBS and sufficient to elicit a growth hormone response characteristic of central cholinergic dysfunction.
  • the cholinergic challenge drug is an cetylcholinesterase inhibitor, more especially pyridostigmine.
  • test kit or pack includes a muscarinic antagonist.
  • the accompanying figure shows the growth hormone response to pyridostigmine (120mg) in patients with irritable bowel syndrome ( V), patients with inflammatory bowel disease ( ⁇ ) and healthy comparison subjects (p).
  • Group 1 consisted of 12 age-and-sex matched healthy volunteers.
  • Group 2 consisted of 7 patients with inflammatory bowel disease.
  • test procedure was as follows. An 18g cannula was inserted in a forearm vein at 0830 hours and the subject relaxed for 30 min. before baseline blood for GH estimation was drawn. At this point pyridostigmine 120mg was administered orally and further blood for GH measurement was taken at +60, +90, +120 and +180min. GH was assayed, blind to subject status, by a double antibody radioimmunoassay (Salvatore, R. In: Laron and Butenandt Eds Evaluation of Growth Hormone Secretion Basel: Karger 1983). Visual analogue scales were used to rate patient symptoms during the test.
  • the accompanying figure shows the GH response to pyridostigmine challenge.
  • patients with IBS increased GH levels way in excess of that seen in either healthy volunteers or in patients with inflammatory bowel disease.
  • Measuring response as the increase in GH relative to baseline patients with IBS had a mean ⁇ SEM of 29. l ⁇ 6.8mU/l whilst healthy volunteers had a mean response of 8.9+2.4mU/l and inflammatory bowel disease patients 7.8 ⁇ 2.2mU/l.
  • Eight of the 12 IBS patients experienced an increase in IBS symptoms during the test. No relationship was established between this symptom increase and the GH response.
  • Three of the patients with inflammatory bowel disease developed significant colicky abdominal pain during the test, whilst side-effects in healthy subjects were minimal.
  • Central cholinergic responses are significantly enhanced in patients with IBS. That the method according to the invention does assess central muscarinic response is evidenced by the fact that such response is blocked by muscarinic antagonists.

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Abstract

An in vitro method for the diagnosis of irritable bowel syndrome (IBS) in a subject suspected of having IBS comprises identifying in said subject a dysfunction of central cholinergic receptors, characterised by the subject's growth hormone response to a cholinergic challenge drug more especially an acetylcholinesterase inhibitor such as pyridostigmine or galanthamine. The response is measured by estimating the level of growth hormone in a sample of blood or a blood fraction obtained from said subject following said challenge. When the subject is a premenopausal female, the diagnosis is carried out during the follicular phase of the menstrual cycle.

Description

Description
Diagnosis of irritable bowel syndrome based on demonstrated central cholinergic supersensitivity
Technical Field
This invention relates to the diagnosis and therapy of irritable bowel syndrome (IBS), in particular to classic colonic irritable bowel syndrome.
Background -Art
IBS is the most common reason for referral to gastroenterology clinics and affects 10-12% of the whole population. To date systematic efforts to determine its aetiology have failed. No consistent biochemical or physiological abnormalities have been demonstrated and many gastroenterologists describe it as a functional disorder, without an organic basis.
IBS can be described as a condition of the gastrointestinal tract characterised by a disorder of gut motility or rate of movement along the gastrointestinal tract, which may be either delayed or increased. Accordingly, IBS is not characterised by any consistent abnormality in the gut.
The degree of psychological abnormality attributed to patients with IBS varies from study to study. At the inventors' Clinic using standardised diagnostic criteria (Diagnostic and Statistical Manual- III; American Psychiatric Association, Washington DC) approximately 30% of IBS patients have been found to have psychiatric illness, whilst using less rigorous diagnostic criteria others have found higher rates of illness ( Chaudhury, N.A. and Truelove, S.C., QJMed 1962, 31, 307- 322: Gomez, J. and Dally, P., BMJ 1977, 1, 1451-1453). The most common diagnoses in the group are depression and anxiety disorders.
It has been shown that patients with predominantly upper IBS type symptoms, usually referred to as non-ulcer dyspepsia, have an abnormality involving central serotonergic receptors (Dinan, T.G., Yatham, L.N., Barry, S., Chua, A. and Keeling, P.W.N., Scand. J. Gastroenterol. 1990,25,541-544; EP-B 0 419 237). The abnormality involves increased sensitivity of these receptors and is associated with a delay in solid phase gastric emptying (Dinan T.G. et al, BMJ 1992, 305,280-282)
Lower or colonic IBS frequently runs a chronic course and can result in multiple unpleasant and expensive investigations. Treatment is frequently ineffective and usually involves high fibre diets, colofac and antidepressants. Pharmacological treatments directly target the bowel but are in general rather non-specific, given the fact that the pathophysiology is poorly understood.
Previous studies indicate that the cholinergic release of GH is enhanced in depression and obsessive compulsive disorders (Cooney, J., Lucey, J., O'Keane, V., Dinan, T.G., 1997, Biol. Psychiat. 42, 827- 833). Diagnosis of IBS cannot currently be made with accuracy in patients who suffer from co-existent depression or obsessive compulsion disorder.
Disclosure of Invention
The invention provides an in vitro method for the diagnosis of irritable bowel syndrome (IBS) in a subject suspected of having IBS, which method comprises identifying in said subject a dysfunction of central cholinergic receptors, characterised by the subject's growth hormone response to a cholinergic challenge drug, said response being measured by estimating the level of growth hormone in a sample of blood or a blood fraction obtained from said subject following said challenge, with the proviso that when the subject is a premenopausal female, the diagnosis is carried out during the follicular phase of the menstrual cycle.
The method according to the invention demonstrates that central cholinergic responses are significantly enhanced in patients with IBS thereby providing a means of readily diagnosing a subject suffering from IBS.
The results described herein suggest that drugs which act centrally to block cholinergic receptors, without having any direct action on the gut, may be effective in treating IBS.
In the case of premenopausal females the method should be conducted in the follicular phase of the menstrual cycle, as responses alter throughout the cycle in healthy women (O'Keane, V. and Dinan, T.G., 1992, J. Clin. Endocrinol. Metab. 75, 1 1-14).
Preferably, the cholinergic challenge drug is an acetylcholinesterase inhibitor.
Acetylcholine (ACh) is an important transmitter in the gut and some treatment strategies focus on this peripheral receptor system (Kinnier, W.J., Kachur, J.F., Audia, V.H., Kaiser, C, 1989 Med. Res. Revs. 9, 325-342). It is also an important neurotransmitter in the brain and to date no research has focused on central cholinergic function in IBS. The inventors examined central cholinergic function in patients with a diagnosis of IBS, using a neuroendocrine strategy which they have previously described in detail (O'Keane, V. and Dinan, T.G., 1992, supra).
The release of growth hormone (GH) from the anterior pituitary gland is regulated by GH releasing hormone (GHRH) and somatostatin (SS)(Hartman, M.L., Veldius, J.D., Thorner, M.O., 1993 Horm, Res. 40, 205-235). The former stimulates and the latter inhibits GH release. ACh inhibits, through muscarinic receptors, the release of SS and thereby stimulates GH release.
Further, preferably, the cholinergic challenge drug is pyridostigmine.
As described in the following Example pyridostigmine, the acetylcholinesterase inhibitor, was used to enhance cholinergic transmission and thereby stimulate GH release in patients with IBS and appropriate comparison groups.
Other acetylcholinesterase inhibitors such as galanthamine may also be used. Indeed, galanthamine has less side-effects than pyridostigmine.
The pyridostigmine, when such is used, is preferably administered as a single dose in an amount of at least 60 mg, more especially 120 mg, to effect said cholinergic challenge.
The blood fraction is preferably plasma or serum.
The GH is suitably measured by an immunoassay method.
Thus, the GH response is suitably measured by enzyme immunossay or radio immunoassay.
The immunoassay methods in accordance with the invention may be carried out using any known format, such as, for example, beads, dipsticks, membranes, particles, plates, rods, strips, etc.
For example, insolubilised or solid phase antibody as used in accordance with the invention is suitably bound to a bead, dipstick, membrane, plate, particle, rod, tube, well, or the like of plastics material or glass in a manner per se.
More specifically, the insolubilised from of the antibody comprises said antibody adsorbed on a surface adapted for protein adsorption. The surface may be a bead, membrane, particle, plate rod, tube, well or the like and of a material as hereinbefore specified.
Suitably the surface comprises a plastic microtitration plate or strip adapted for protein adsorption wherein the immunochemical reaction and the estimation of the GH or release of the GH on the insolubilised form of the antibody, depending on the method used.
The relevant surface may be coated directly with an optimum dilution of monoclonal antibody or polyclonal antibody.
The estimation of the bound GH derived from the sample can be carried out by enzymatic, fluorometric, luminometric or radiometric assay, using enzymes, fluorochromes, light-emitting probes or radio labels, respectively.
The labelled agents for use in the assays according to the invention are prepared in conventional manner or are purchased from appropriate suppliers. Such labelled agents are normally in the form of conjugates such as enzyme-labelled antibodies for use in competitive binding assays. The labelled agent is also suitably an antibody covalently linked to a radio label for use in a radiometric assay.
The GH response as measured in the method according to the invention is blocked by a muscarinic antagonist.
The invention also provides a test kit or pack for diagnosis of IBS in a subject suspected of having IBS, which comprises an amount of a cholinergic challenge drug for administering to one or more subject(s) being investigated for IBS and sufficient to elicit a growth hormone response characteristic of central cholinergic dysfunction.
Preferably, the cholinergic challenge drug is an cetylcholinesterase inhibitor, more especially pyridostigmine.
Also preferably the test kit or pack includes a muscarinic antagonist.
Brief Description of Drawing
The accompanying figure shows the growth hormone response to pyridostigmine (120mg) in patients with irritable bowel syndrome ( V), patients with inflammatory bowel disease (Δ) and healthy comparison subjects (p).
The invention will be further illustrated by the following Example.
Mode for Carrying Out the Invention
Example
Twelve patients with IBS were chosen at random from the Gastroenterology Clinic at St. James's Hospital, Dublin and fulfilled the following criteria. They must have had at least 3 months lower abdominal pain and alteration of bowel habit in the absence of endoscopic, ultrasound or X-ray evidence of gastrointestinal structural abnormality. All were negative for occult blood, leucocytes, ova or parasites in stools, endocrine disease, collagen disease, somatic myopathy or any other illness likely to explain symptoms. All were free of present or past psychiatric illness, specifically they were not depressed or suffering from obsessive compulsive disorder. All were medication free for at least 6 weeks prior to testing.
Two groups of comparison subjects were recruited to take part in the study. Group 1 consisted of 12 age-and-sex matched healthy volunteers. Group 2 consisted of 7 patients with inflammatory bowel disease.
The test procedure was as follows. An 18g cannula was inserted in a forearm vein at 0830 hours and the subject relaxed for 30 min. before baseline blood for GH estimation was drawn. At this point pyridostigmine 120mg was administered orally and further blood for GH measurement was taken at +60, +90, +120 and +180min. GH was assayed, blind to subject status, by a double antibody radioimmunoassay (Salvatore, R. In: Laron and Butenandt Eds Evaluation of Growth Hormone Secretion Basel: Karger 1983). Visual analogue scales were used to rate patient symptoms during the test.
The accompanying figure shows the GH response to pyridostigmine challenge. As can be clearly seen patients with IBS increased GH levels way in excess of that seen in either healthy volunteers or in patients with inflammatory bowel disease. Measuring response as the increase in GH relative to baseline patients with IBS had a mean±SEM of 29. l±6.8mU/l whilst healthy volunteers had a mean response of 8.9+2.4mU/l and inflammatory bowel disease patients 7.8 ±2.2mU/l. Eight of the 12 IBS patients experienced an increase in IBS symptoms during the test. No relationship was established between this symptom increase and the GH response. Three of the patients with inflammatory bowel disease developed significant colicky abdominal pain during the test, whilst side-effects in healthy subjects were minimal.
Central cholinergic responses are significantly enhanced in patients with IBS. That the method according to the invention does assess central muscarinic response is evidenced by the fact that such response is blocked by muscarinic antagonists.

Claims

CLAIMS: -
1. An in vitro method for the diagnosis of irritable bowel syndrome (IBS) in a subject suspected of having IBS, which method comprises identifying in said subject a dysfunction of central cholinergic receptors characterised by the subject's growth hormone response to a cholinergic challenge drug, said response being measured by estimating the level of growth hormone in a sample of blood or a blood fraction obtained from said subject following said challenge, with the proviso that when the subject is a premenopausal female, the diagnosis is carried out during the follicular phase of the menstrual cycle.
2. A method according to Claim 1 , wherein the cholinergic challenge drug is an acetylcholinesterase inhibitor.
3. A method according to Claim 1 or 2, wherein the cholinergic challenge drug is pyridostigmine.
4. A method according to Claim 3, wherein the pyridostigmine is administered as a single dose in an amount of at least 60mg to effect said cholinergic challenge.
5. A method according to Claim 3 or 4, wherein the amount of pyridostigmine administered as a single dose to effect the cholinergic challenge is 120mg
6. The method according to any preceding claim, wherein the growth hormone is measured by an immunoassay method.
7. A method according to any preceding claim, wherein the growth hormone response is blocked by a muscarinic antagonist.
8. A test kit or pack for diagnosis of IBS in a subject suspected of having IBS, which comprises an amount of a cholinergic challenge drug for administering to one or more subject(s) being investigated for IBS and sufficient to elicit a growth hormone response characteristic of central cholinergic dysfunction.
9. A test kit or pack according to Claim 8, wherein the cholinergic challenge drug is an acetylcholinesterase inhibitor.
10. A test kit or pack according to Claim 8 or 9, wherein the cholinergic challenge drug is pyridostigmine.
11. A test kit or pack according to any one of Claims 8- 10, which includes a muscarinic antagonist.
12. A method according to Claim 1 for the diagnosis of IBS in a subject suspected of having IBS, substantially as hereinbefore described and exemplified.
PCT/IE2000/000038 1999-04-07 2000-04-06 Diagnosis of irritable bowel syndrome WO2000060360A2 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062345A1 (en) * 2001-02-05 2002-08-15 Janssen Pharmaceutica N.V. Use of galantamine for accelerating transport of intraluminal content

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008146A1 (en) * 1995-08-31 1997-03-06 The State Of Israel Pyridinium derivatives and pharmaceutical compositions containing them
WO1998030243A1 (en) * 1997-01-08 1998-07-16 Warner-Lambert Company Acetylcholinesterase inhibitors in combination with muscarinic agonists for the treatment of alzheimer's disease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008146A1 (en) * 1995-08-31 1997-03-06 The State Of Israel Pyridinium derivatives and pharmaceutical compositions containing them
WO1998030243A1 (en) * 1997-01-08 1998-07-16 Warner-Lambert Company Acetylcholinesterase inhibitors in combination with muscarinic agonists for the treatment of alzheimer's disease

Non-Patent Citations (6)

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Title
CHUA A; KEELING P W N; O'KANE V; DINAN T: "CENTRAL CHOLINERGIC ABNORMALITIES IN PATIENTS WITH THE IRRITABLE BOWEL SYNDROME" GASTROENTEROLOGY , vol. 102, 1992, page A726 XP000938352 *
COLE S J; WATSON L; KIMBER J R; SILK D B A; MATHIAS C J: "Abnormal central sympathetic function in irritable bowel syndrome detected with the clonidine-growth hormone stimulation test" GASTROENTEROLOGY (DIGESTIVE DISEASES WEEK AND THE 99TH ANNUAL MEETING OF THE AMERICAN GASTROENTEROLOGICAL ASSOCIATION; NEW ORLEANS, LOUISIANA, USA; MAY 16-22, 1998), vol. 114, 15 April 1998 (1998-04-15), page A736 XP000949286 *
COLE S J; WATSON L; KIMBER J R; SILK D B A; MATHIAS C J: "Abnormal central sympathetic function in irritable bowel syndrome detected with the clonidine-growth hormone stimulation test" GUT (MEETING OF THE BRITISH SOCIETY OF GASTROENTEROLOGY; HARROGATE, ENGLAND, UK; MARCH 10-13, 1998), vol. 42, March 1998 (1998-03), page A95 XP000949326 *
DINAN T G ET AL: "Assessment of central noradrenergic functioning in irritable bowel syndrome using a neuroendocrine challenge test." JOURNAL OF PSYCHOSOMATIC RESEARCH, (1990) 34 (5) 575-80. , XP000938343 *
GHIGO E; BELLONE J; AIMARETTI G; BELLONE S; LOCHE S; CAPPA M; BARTOLOTTA E; DAMMACCO F; CAMANNI F: "Reliability of provocative tests to assess growth hormone secretory status: Study in 472 normally growing children" JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 81, 1996, pages 3323-3327, XP000938349 *
O'KEANE V; DINAN T G: "SEX STEROID PRIMING EFFECTS ON GROWTH HORMONE RESPONSE TO PYRIDOSTIGMINE THROUGHOUT THE MENSTRUAL CYCLE" JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 75, 1992, pages 11-14, XP000938342 cited in the application *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002062345A1 (en) * 2001-02-05 2002-08-15 Janssen Pharmaceutica N.V. Use of galantamine for accelerating transport of intraluminal content

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