WO2008121046A1

WO2008121046A1 - Improvement of gastric emptying in patients suffering from diabetes mellitus

Info

Publication number: WO2008121046A1
Application number: PCT/SE2008/000228
Authority: WO
Inventors: Bodil Ohlsson
Original assignee: Forskarpatent I Syd Ab
Priority date: 2007-03-29
Filing date: 2008-03-28
Publication date: 2008-10-09

Abstract

The present invention relates to the use of oxytocin in the preparation of a pharmaceutical composition for improving gastric emptying in individuals suffering from diabetes mellitus and gastroparesis, as well as a method for alleviating problems in gastric emptying.

Description

TITLE

Improvement of gastric emptying in patients suffering from diabetes mellitus

DESCRIPTION

Technical field

The present invention relates to a new use of oxytoxin in the treatment of problems related to gastric emptying.

Background of the invention

Gastroparesis has previously been regarded as a rare problem in relation to diabetes mellitus. However, this fact has been reconsidered, and delayed gastric emptying represents a frequent, and clinically important, complication of diabetes mellitus.

Gastric motility in patients with diabetes mellitus has usually been quantified by measurement of gastric emptying. Delayed gastric emptying in diabetes was first reported back in 1925, and was studied using radiological techniques in 1937. These latter studies showed that in diabetics the stomach motor responses are weaker than normal; contractions are slow, lack vigour and die out quickly. Later studies have shown that about 50 % of the individuals suffering from diabetes mellitus suffer from gastroparesis.

Our knowledge about the physiology and patophysiology of the gastrointestinal tract is only rudimentary explored. Gastrointestinal dysmotility is a severe clinical problem for the health care system today. It leads to severe pain, recurrent vomiting and impaired bowel habits. The symptoms can be that aggravated that parenteral nutrition is necessary because of severe malnutrition.

The drugs available today to treat patients with gastrointestinal dysmotility have only limited effects, and new drugs are necessary to handle these patients. Many kinds of gastrointestinal dysmotility are idiopathic, but most commonly, they are secondary to diabetes mellitus. As the prevalence of diabetes mellitus is increasing all over the world, the well-known complications to this disease are also increasing. Besides giving the patients symptoms and impaired quality of life, the dysmotility also affects the glucose homeostasis. The blood glucose levels are unstable and it is difficult to get a good control of the disease. This in turn leads to further development of diabetic complications. In a prior study by the present invention the effect of oxytocin on constipation was investigated. Thereby, firstly, the concentration of oxytocin in plasma before and after a meal was assessed by radioimmunoassay. Then, the presence of oxytocin and its receptor in the gastrointestinal tract was examined by PCR and immunofluorescence. The colonic peristalsis rate was evaluated by a barostat method. A double-blind, placebo-control trial was performed to evaluate the role of oxytocin on chronic, refractory constipation. The results showed that oxytocin was released in response to a fatty meal in both sexes in healthy subjects. By contrast, patients suffering from gastro paresis had no postprandial release of oxytocin. Further, if an oxytocin receptor antagonist was administered together with the meal in healthy subjects, the gastric emptying rate was prolonged. Although mRNA for both oxytocin and its receptor was present throughout the gastrointestinal tract, only oxytocin is translated into a fully expressed protein, and was present in the enteric nervous system. Pharmacological administration of intravenous oxytocin led to increased peristalsis in healthy women. When administered by nasal inhalation, no effect was observed on chronic constipation, but abdominal pain decreased and an increased psychological well- being was experienced.

Summary of the present invention

The present invention relates to solving the problem of gastric emptying in individuals suffering from diabetes mellitus and gastroparesis.

Detailed description of the present invention

In particular the present invention relates to use of oxytocin to be used in pharmaceutical preparations for improving gastric emptying in individuals suffering from diabetes mellitus and gastroparesis.

A further aspect of the invention relates to a method for improving gastric emptying in individuals suffering from diabetes mellitus and gastroparesis.

To show the validity of the present invention the effect of oxytocin release was primarily studied in connection with food intake.

Oxytocin levels in relation to food intake

In the first study, eight healthy women and six women suffering from chronic constipation were included. They came to the laboratory after an overnight fast. All went through two separate experiments, which were performed in a randomised order. In one experiment, they ingested a meal consisting of 60 g maize oil and distilled water in a total of 300 ml emulsified oil. In the other experiment, they were given 1 Ivy dog unit (IDU) cholecystokinin (CCK)/kg body weight intravenously (Cholecystokinin Ferring^®, Ferring, Malmό, Sweden). Ten minutes and immediately before the experiment, and 10, 20, 30, 45, 60, 90 and 120 min after the ingestion and injection, blood samples were taken and analyzed by radioimmunoassay for the concentration of oxytocin and CCK.

Ingestion of a fatty meal led, as expected, to a peak rise in CCK levels from 1.0±0.4 to 5.1 ±3.4 pmol/l, p = 0.03, and a rise of oxytocin from 1.0±0.3 to 1.3±0.4 pmol/l, p=0.02, in the healthy subjects. In the constipated women, there was a rise from 0.8±0.5 to 10.6±7.6 pmol/l of CCK, p=0.008, and from 1.0±0.3 to 1.6±0.3 pmol/l of oxytocin, p=0.03. The elevated plasma concentration of CCK preceded the elevation in oxytocin concentration. Injection of exogenous CCK rendered significantly higher CCK and oxytocin levels in plasma than endogenous CCK. There was no difference between the healthy and the constipated women, and although there were higher oxytocin levels in plasma after CCK injection, there was no correlation between CCK and oxytocin levels in the individual subject. These results are in agreement with earlier studies in the rat, which demonstrated how CCK stimulates the secretion of oxytocin through CCK-receptors on afferent vagal neurons. In the hypothalamus, both parvocellular neurons projecting to the dorsal vagal complex, and magnocellular neurons projecting to the pituitary, secrete oxytocin in response to CCK.

After having monitored the presence of mRNA for oxytocin in the Gl tract, the hypothesis was that oxytocin in plasma, apart from originating in the hypophysis, could also be released from the Gl tract. Thus, the next study was conducted, in which eleven women who had undergone colectomy were compared with eleven healthy controls with intact colon. After an overnight fast, they were given 0.2 μg CCK/kg body weight of cholecystokinin octapeptide (CCK-8) (Clinalfa, Switzerland) as an intravenous injection. Blood samples were collected at the same time intervals as above. According to the first study, injection of CCK elevated oxytocin levels in plasma from 1.3±0.1 to 2.8±0.4 pmol/l, p<0.001 , in healthy women and from 1.6±0.2 to 3.3±0.5 pmol/l, p<0.001 , in colectomized women. There was no difference in the plasma concentration of oxytocin between the healthy women and the women who had undergone colectomy. Thus, the conclusion was that the colon is not an important source of the oxytocin released into plasma.

After these two studies to examine oxytocin release in healthy women in response to food and CCK stimulation, it was speculated over the role for oxytocin in the regulation of the gastric emptying process, especially as oxytocin in one human study has been shown to stimulate gastric emptying. Further, Hashmonai has described how postvagotomy-induced gastro paresis was successfully treated with oxytocin.

Therefore 19 patients of both sexes suffering from diabetes mellitus were examined. Nine of these had a delayed gastric emptying when examined by gastric scintigraphy, and were accordingly classified as suffering from gastro paresis. They all ingested a fatty meal consisting of cream and water with an equivalent amount of fat as the emulsified corn oil used in the first study. Blood samples were collected ten minutes before, immediately before and 10, 20, 30, 45, 60, 90, 120, and 180 min afterwards, and analyzed by a radioimmunoassay for the concentration of oxytocin in plasma. The ten diabetics with normal gastric emptying had all, irrespective of sex, a significant elevation of oxytocin concentration in plasma postprandially, which gradually diminished after the meal (Fig 1 C, 2). In contrast, diabetics suffering from gastro paresis had no postprandial elevation, with no fluctuation at all in plasma oxytocin levels over time (Fig 1C, 2).

The presence of oxytocin and its receptor in the gastrointestinal tract

PCR amplification

To examine whether oxytocin and its receptor were present in the Gl tract, full-thickness biopsies from all segments of the entire Gl tract and gallbladder were collected, from surgically removed tissues from patients undergoing surgery for gastric diseases. The biopsies were put into a sterile tube, immediately placed in liquid nitrogen and kept frozen at -70^° C until analyzed. According to histopathological examination, the tissue samples represented normal tissue from various parts of resected intestine or resection margins. All in all, 24 samples from both sexes were processed and analysed for the expression of oxytocin and its receptor mRNA. By PCR-amplification, both oxytocin and receptor mRNA could be detected in almost all segments of the Gl tract but not in the gallbladder (Table 1 ). This gave a morphological basis for the effects observed on the Gl motility. Furthermore, it also explained why oxytocin exerts no effect on human gallbladder strips in vitro.

Immunofluorescence

To examine whether the mRNA found was translated and expressed in corresponding proteins as well, indirect immunofluorescence as earlier described was used. The sections were incubated with polyclonal rabbit anti-oxytocin antibodies (Research Diagnostics Inc, Flanders, NJ, USA), raised against a synthetic oxytocin (Sigma, St. Louis, MO, USA) that displayed less than 1% cross-reactivity with arginine vasopressin. To localize the receptors, tissue sections were incubated with two different antibodies. Firstly, polyclonal rabbit anti-rat oxytocin receptor antibodies (Research Diagnostics Inc), raised against a 20 amino acid peptide sequence within the carboxy terminus (cytoplasmic) domain coupled to KLH, were used. The antibodies display 85% cross-reactivity with human oxytocin receptor. Secondly, a mouse monoclonal anti-human oxytocin receptor IgM antibody, 2F8, raised against the peptide corresponding to the 20^th to 40^th amino acids of the human receptor sequence, was used.

Sections were examined under a Leica epifluorescence microscope (Ernst Leitz, Wetzlar, Germany). Although oxytocin was expressed in myenteric and submucous ganglia throughout the human Gl tract, its expression was most abundant in submucous ganglia in the ileum and colon (Table 2). The oxytocin receptor could not be identified in spite of this examination with two different antibodies. The reason for this can be discussed. Maybe there is no expression of the full protein although its mRNA is expressed, or, which is the most likely explanation, there may be an expression at levels below the detection limit with the antibodies and method used in the present study. As oxytocin has been shown to exert effects on Gl motility (see below), it may be of interest to investigate how this effect is exerted when no receptors are present. One possibility is that oxytocin acts via receptors of vasopressin which is nearly a homologue of oxytocin. Recently, the presence of vasopressin receptors in the gastrointestinal tract has been examined by PCR, and it was found a rich expression of all the different vasopressin receptors throughout the tissues. Another explanation is that oxytocin passes the blood-brain barrier and exerts central effects by affecting vagal neurons in the dorsal vagal complex that is involved in the regulation of the Gl tract. Furthermore, other, as yet unknown, mechanisms may be involved.

In this experiment, it was also examined the presence of oxytocin receptors in rat intestine, but these receptors were not found (unpublished observation). Several studies have described how oxytocin in rats exerts an inhibitory effect on gastric emptying and a stimulatory effect on the colon peristalsis. Wu et al. have described how oxytocin in the rat leads to elevated CCK concentration in the plasma, which in turn activates CCK-receptors with ensuing inhibition of gastric emptying. Whether this pathway is exclusive to the rat, or may be involved also in other species remains to be evaluated.

Effects of oxytocin on gastrointestinal motility

To examine whether oxytocin influences the Gl tract, an open study was first performed where five healthy asymptomatic women and 10 women with chronic severe constipation inhaled 40 U oxytocin (Syntocinon^®, Novartis, Taby, Sweden) twice daily for one week. The colonic transit time and registration of daily stool frequency was performed during this week, as well as during a second week when no oxytocin was inhaled. This study showed that oxytocin increased stool frequency in constipated women from 2 to 4.3 times a week compared to the control period. As the stool frequency was doubled, the constipation trouble was reduced. The colonic transit time did not change during oxytocin treatment. Healthy subjects did not experience any effect of oxytocin.

To study the effect of oxytocin on colonic motility more exactly, an experimental study was started. Fourteen healthy women were investigated. A 6-channel perfusion catheter, with 3 recording points (3 cm apart) proximally and 3 recording points distally to a barostat balloon, was inserted to the splenic flexure by colonoscopy. An intestinal feeding tube was placed in the mid-duodenum. After resting for 1 h, a duodenal lipid infusion of 3 kcal/min was started for 90 min. Thirty minutes after the start of the lipid infusion, the subject randomly received isotonic saline, or 20 mU/min or 40 mU/min of oxytocin (Syntocinon^®) as an intravenous infusion for 90 min. Meanwhile the colonic motility was recorded. The number of antegrade contractions/h was 0.7±0.3 during saline and 3.9±1.4 during oxytocin stimulation (p=0.03), indicating more pronounced lumen-occlusive contractile activity during oxytocin administration. Some of these consisted of specialised or high-amplitude antegrade contractions. This study showed that pharmacological doses of oxytocin stimulated colonic peristalsis.

After these two trials, a double-blind, placebo-controlled, multi-centre trial was started. Fifty-nine women with severe constipation, refractory to conventional therapy were included. The reason to include only patients with severe constipation was that it can never be ethically correct to treat mild constipation with hormonal treatment. After a 2-week period of run-in, the subjects were either treated with saline or oxytocin twice daily in the form of a nasal inhalation. The dose of oxytocin was 40 U (Syntocinon^®) inhaled each time. This dose was chosen as it corresponds to the intravenous dose of oxytocin given in an experimental study, and was the same dose as was given in the open trial performed earlier. The patients had to complete a daily questionnaire about bowel habits, abdominal pain and gas trouble. They also completed the quality of life questionnaires Gastrointestinal Symptoms Rating Scale (GSRS) and Psychological General Well-Being (PGWB) Index. Both in the placebo group and the oxytocin group the constipation was alleviated during the study, but there was no difference between the groups. Thus, oxytocin did not have any effect on constipation in this trial. This may be due to the fact that the doses of oxytocin were inappropriate. However, the dose given was the maximal dose recommended by the drug manufacturer.

Although it has been clinically observed that constipation has in some cases improved during breast feeding, this could not be confirmed when all the women included in our study were asked about their bowel habits during pregnancy and breast feeding. Only 3 of the 38 women who had both been pregnant and had breast fed, had experienced an improvement while lactating, while for one of the women her constipation had grown worse. During pregnancy, two of the women improved, while in 2 their constipation was aggravated. As constipated women had normal oxytocin levels in plasma, the pathophysiology behind constipation may perhaps not involve the oxytocin system.

As it had been found that meal ingestion released oxytocin, and oxytocin has been shown to stimulate gastric emptying, the effects of oxytocin and the recently developed oxytocin receptor antagonist atosiban on gastric emptying were to be examined. Ten healthy volunteers (five men) were examined regarding gastric emptying during three different conditions:

(i) once during oxytocin stimulation using a pharmacological dose; (ii) once during blockage of the oxytocin receptors (which also blocks the vasopressin receptors) and thereby inhibits the action of oxytocin in physiological doses; and (iii) once during saline infusion.

Gastric emptying rate (GER) was assessed and expressed as the percentage reduction in antral cross-sectional area from 15 to 90 min after ingestion of 300 g rice pudding (Scan Risgrynsgrόt; Scan Foods, Johanneshov, Sweden). The assessment was performed by real-time ultrasonography. At the same time, the feeling of satiety was registered using visual satiety scores. Inhibition of the binding of endogenous oxytocin by the receptor antagonist delayed the GER by 37 % compared to saline (Fig 5). In contrast, infusion of oxytocin at a dosage of 40 mU/min did not affect the GER (p=0.610). Satiation scores in healthy subjects after receiving atosiban or oxytocin did not show any significant differences. It may be speculated whether the effect of atosiban was exerted by inhibition of vasopressin and vasopressin receptors, as oxytocin had no effect, and the close homology between vasopressin and oxytocin receptors. However, after this study the vasopressin release after a meal has been analysed as well, and it was found no elevation of vasopressin in plasma postprandially. These results suggest that physiological doses of oxytocin, released after ingestion of a meal, is of importance for the regulation of gastric emptying. The present results, together with the unpublished data of reduced oxytocin secretion in patients with gastro paresis, raise the hypothesis that oxytocin may have a crucial role in the development of gastro paresis. Thus, oxytocin may be of more importance for the proximal than for the distal Gl tract.

Studies in the rat have shown the opposite effects on gastric emptying to our study; oxytocin has in several studies been shown to inhibit gastric emptying. This might be explained by the fact that oxytocin in rats exerts its effect via CCK and CCK-receptors with ensuing inhibition of gastric emptying.

Effects of oxytocin on gastrointestinal sensibility and mood

The role for oxytocin on pain and mood has been examined and debated in many studies. In a double-blind, placebo-controlled multi-centre trial, it was also examined whether oxytocin exerts an effect on abdominal pain and mood. According to the answers in the daily questionnaire, oxytocin showed a tendency to decrease abdominal pain and discomfort, an effect not seen in the placebo group. Extrapolation of standard deviations indicates that a participation of 60-120 patients per group is to be recommended in order to get a difference between placebo and oxytocin over most of the treatment period, at a p value of <0.05 with 80 % power. Subgroup analyses including only patients with irritable bowel syndrome (IBS) revealed a declining trend in the GSRS scores for abdominal pain in the oxytocin group (p=0.05), but not in the placebo group (p=0.78). These results are in accordance with a previous study performed in IBS patients, where oxytocin injection elevated the threshold for visceral pain. Oxytocin receptors have been found on dorsal root ganglia, an important area for joint pain processing, and on enteric nerve plexa and nerve fibres in the bowel wall, which may be the morphological basis of this effect.

Another subgroup analysis in our trial revealed that when only patients with depression were included (8 in the oxytocin and 6 in the placebo group), scores according to PGWB for depressed mood were increased in the oxytocin group (p=0.03) but not in the placebo group (p=0.92), suggesting an antidepressive effect of oxytocin treatment.

Oxytocin has an antidepressive effect on rats, and the administration of selective serotonin re-uptake inhibitors (SSRIs) to these animals was associated with an elevation of the plasma concentration of oxytocin. In rats, the administration of oxytocin produces anti- stress and anti-nociceptive effects that persist for several weeks after the administration. This suggests that secondary, central mechanisms have been activated, especially as oxytocin receptor antagonists are unable to reverse the effects, while the opioid receptor antagonist naloxone does. Further, the effects are exerted by oxytocin in intraventricular injection, and through peripheral administration in 1 000-fold doses. The effects of a reduction in depressed mood and abdominal pain, observed in our study with a small number of patients, may also be a central effect in the same way, activating secondary mechanisms.

Children suffering from recurrent abdominal pain exhibited lower plasma levels of oxytocin than healthy controls. Further, lower values of plasma oxytocin have been reported in patients suffering from dyspepsia and IBS. However, this has not been confirmed in our study when focusing on patients with constipation. Patients suffering from fibromyalgi and depression have also been reported to have lower oxytocin levels. There are clear overlaps between fibromyalgi, IBS and depression. These conditions are all characterized by hyperalgesia, fatigue and depressed mood, symptoms that might be reversed by oxytocin. The role of oxytocin for the development and treatment of these disease entities therefore needs further evaluation.

Table 1. The presence of oxytocin (OT) and oxytocin receptor (OTR) mRNA expression in different segments of the gastrointestinal tract

+=expression of mRNA, -=no expression of mRNA. "Reprinted from Regul Pept, Vo1 119, Monstein et al., Oxytocin and oxytocin receptor mRNA expression in the human gastrointestinal tract: A polymerase chain reaction study, page 39-44,

Table 2. The expression of oxytocin in the gastrointestinal tract

% of cells containing a nucleus stained for oxytocin. As non-stained nerve fibres are very difficult to discover, no quantification was performed in these. Reprinted from Regul Pept, Ohlsson 2006;135:7-11 , Oxytocin is present throughout the human gastrointestinal tract.

A further study was carried out, the aim of which was to measure the concentrations of CCK, gastrin and oxytocin in plasma of patients suffering from diabetes mellitus with dyspeptic symptoms, and to correlate the values to the findings of delayed gastric emptying, oesophageal dysmotility and autonomic neuropathy in this population.

Material & Methods Subjects

Consecutive patients at the diabetes outpatient Department at Malmό University Hospital, who complained of symptoms from the gastrointestinal tract and were supposed to have gastro paresis, were invited to oesophageal manometry, gastric emptying scintigraphy and autonomic nerve function tests. Patients with regular use of opiates and other drugs influencing the gastrointestinal motility or hormonal release were excluded. Twenty patients (10 women) accepted to participate. Out of these, nineteen were further exposed to a fibre- rich meal, where after blood samples were collected and analysed for hormonal concentrations. All (n=19) were investigated with gastric emptying scintigraphy, 17 with an autonomic nerve function test, and 13 with oesophageal manometry. Ten patients had delayed gastric emptying and 7 out of 13 patients showed dysmotility of the oesophagus. Nine showed abnormal expiration/inspiration (E/l) quote as a sign of autonomic neuropathy. All patients were insulin-treated; 17 with type 1 and 2 with type 2 diabetes.

Experimental procedure

All subjects were fasted overnight. In the morning they were given a fat-rich meal containing 15O g cream and 150 g water. This generated 60 g fat and 561 kcal. This meal corresponds to the same content of fat as earlier used to evoke CCK secretion. Blood samples were taken through an intravenous catheter 10 min before and immediately before the injection, and 10, 20, 30, 45, 60, 90, 120, 150 and 180 min after the injection. All blood samples consisted of 8.0 ml whole blood drawn into iced heparinised tubes. The plasma was separated and frozen at -2O⁰C immediately after the experiment.

Plasma analyses

Cholecystokinin and gastrin

The concentrations of CCK in plasma were measured using a highly specific and accurate radioimmunoassay. The limit of detection for his assay is 0.1 pmol/l with intra-assay and interassay variations of less than 5 % and 15 %, respectively, at both 3.7 and 15 pmol/l concentrations. The concentrations of gastrin in plasma were assayed according to (Rehfeld). The radioimmunoassay used was rabbit antibody 2604-8. The tracer, (¹²⁵I- iodinated human gastrin-17, was purified on HPLC (isocratic conditions, 34% acetonitril in 0,1 M phosphate buffer pH 3,5, on a μBondapak C18 column). The bound tracer was separated from the free using goat anti-rabbit antibody. The detection limit was 5 pg/ml and the interassay coefficient of variation was below 8% in the range 10-100 pg/ml.

Oxytocin

Oxytocin was immunoassayed as described by (Uvnas-Moberg). Plasma samples were purified with reversed-phase chromatography using { C18} Waters SEP-PAK cartridges. The antiserum anti-oxytocin (rabbit) for RIA, Ka-19 (Euro Diagonistica, Malmό, Sweden) and the tracer [{¹²⁵ 1}] - {Tyr2} oxytocin (Du Pont NEN Research products, Boston, Mass, USA) were used. The cross-reactivity of the anti-body was less than 0,01% with vasopressin, somatostatin, LH-RH and ACTH. The limit of detection was 2 pmol {1-1}. The intra and inter-assay coefficients of variation were 11 ,2% and 13%, respectively.

Vasopressin

The concentration of vasopressin in plasma was analyzed by a radioimmunoassay described by Rooke & Baylis (1982).

Statistical analyses The values are given as median (interquartile ranges). The basal value is the mean of the 2 samples taken before the meal. Peak value is the highest level measured in plasma after the meal. The area under the curve (AUC) was calculated for all hormones from all samples taken. The Mann-Whitney U test was used for comparisons between groups and the Wilcoxon signed test for comparisons between basal and peak levels within the group. The Spearman test was used for correlations between the different hormones. P<0.05 was considered statistical significant.

Results

Hormonal concentrations in relation to gastric emptying Both CCK and gastrin were secreted in response to the meal. There were no observed differences in the secretion of these hormones between patients with normal respective delayed gastric emptying (Fig 1 A and B). In the same way, there was a significant increase in postprandial oxytocin levels in the group of patients who showed normal gastric emptying (Fig 1 C). In contrast, patients who displayed delayed gastric emptying had no increased oxytocin secretion in response to the meal (Fig 1C). The oxytocin concentration showed no fluctuations over time in the group with delayed gastric emptying, which was seen in patients with normal gastric emptying (Fig 2). The concentration of vasopressin was not increased after the meal in patients with normal gastric emptying (0.7 [0.5-0.8] during basal conditions compared to 0.6 [0.5-1.0] postprandially), why this hormone was not further analysed in women with delayed gastric emptying. There were not any correlations between the plasma levels of the different hormones (data not shown).

Hormonal concentrations in relation to autonomic neuropathy

Patients with autonomic neuropathy showed significantly higher levels of gastrin in plasma than patients without neuropathy. There was difference both in the AUC (Fig 3) and the peak values (22.0 [15.5-57.0] respective 13.5 [11.2-15.0] pmol/l; p<0.046). There was no difference in oxytocin or CCK peak levels between the groups (181.5 [73.6-449.5] respective 211.4 [139.7-346.8] pg/ml oxytocin and 4.4 [3.3-6.6] respective 3.4 [2.8-5.6] pmol/l CCK).

Hormonal concentrations in relation to esophageal dysmotility The basal plasma values of CCK tended to be higher in the group of patients with oesophageal dysmotility compared to those with normal motility (Fig 4), whereas there was no difference in the peak values measured after the meal (3.6 [2.8-5.3] respective 3.4 [2.6- 8.6]).

The oxytocin is often administered in the form of an injectable solution, whereby 20 to 330 mU/min is added as infusion independent of body weight. A U is the same as IE or IU, i.e., international units. A U corresponds to 1.67 microgram of oxytocin. An oral composition of oxytocin will be administered in amounts providing for a similar blood plasma level as the infusion of 20 to 330 mU/min. The oral composition will of the type having a prolonged release of active compound. The oral composition can be in the form of a solution, a syrup, a depot tablet or the similar conventionally used and generally known orally administrable products.

When the oxytocin is administered in the form of an inhalable composition the oxytocin is adsorbed to a carrier, which can be administered by inhalation, and in such amounts as to provide for the same blood serum levels. The inhalable product can be used in self-driven inhalers or gas driven devices.

Abbreviations used herein:

CCK = cholecystokinin

GER = gastric emptying rate

Gl = Gastrointestinal

GSRS = Gastrointestinal Symptoms Rating Scale IBS = Irritable Bowel Syndrome

PGWB = Psychological General Weil-Being Figure legends

Figure 1. The plasma concentration of CCK and gastrin after a meal between patients with normal respective delayed gastric emptying (Fig 1A and B). In the same way, there was a significant increase in postprandial oxytocin levels in the group of patients who showed normal gastric emptying (Fig 1 C). In contrast, patients who displayed delayed gastric emptying had no increased oxytocin secretion in response to the meal (Fig 1C).

Figure 2. The oxytocin concentration showed no fluctuations over time in the group with delayed gastric emptying, which was seen in patients with normal gastric emptying (Fig 2).

Figure 3. Patients with autonomic neuropathy showed significantly higher levels of gastrin in plasma than patients without neuropathy. There was difference both in the AUC (Fig 3) and the peak values (22.0 [15.5-57.0] respective 13.5 [11.2-15.0] pmol/l; p<0.046).

Figure 4. The basal plasma values of CCK tended to be higher in the group of patients with oesophageal dysmotility compared to those with normal motility (Fig 4).

Claims

1. Use of oxytocin in the preparation of a pharmaceutical composition for improving gastric emptying in individuals suffering from diabetes mellitus and Gastroparesis.

2. Use according to claim 1 , wherein the daily dose of oxytocin is mg/kg bodyweight.

3. Use according to claim 1 , wherein the pharmaceutical preparation is an oral composition.

4. Use according to claim 1 , wherein the pharmaceutical preparation is an injectable solution.

5. Use according to claim 1 , wherein the pharmaceutical preparation is an inhalable preparation.

6. Method for improving gastric emptying in individuals suffering from diabetes mellitus, whereby a therapeutically effective amount of oxytocin is administered to such individuals showing reduced gastric emptying motility.