Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-02-03
2002-02-19
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S300000, C530S324000, C530S325000, C530S326000, C530S327000
Reexamination Certificate
active
06348447
ABSTRACT:
This application is a 371 of PCT/SE99/00997 filed Jun. 8, 1999 which claims priority to Swedish application 98 02080-3 filed Jun. 11, 1998.
The present invention relates to a new use of a gastrointestinal peptide hormone or a derivative thereof, to a pharmaceutical composition for the treatment of functional dyspepsia and/or irritable bowel syndrome, and to a method for such treatment.
Functional diseases are characterized by disordered function of the organ or organ system and no obvious structural pathology can be detected neither macroscopically nor microscopically. This should be differentiated from morphologic pathological diseases where the structure of the organ is changed from normality to abnormality. This type of disease can always be diagnosed either macro- or microscopically, and may be followed by functional aberration of the organ.
In the gastrointestinal tract the two most common functional disorders are functional dyspepsia and disordered gastrointestinal motility, commonly known as irritable bowel syndrome (IBS). These two terms are not exclusive determinants for separate disease entities, but instead the most common expressions for various overlapping symptoms emerging from the upper and lower gastrointestinal tract.
Abdominal pain or discomfort is remarkably common in the general population. The annual prevalence of recurrent abdominal pain or discomfort in Western countries is approximately 25%. If frequent heartburn with retrosternal burning pain or discomfort is also considered the prevalence approaches 40% (Locke et al, 1997; Agréus and Talley, 1997; Talley et al, 1992).
The term dyspepsia refers to chronic or recurrent pain or discomfort centered in the upper abdomen. The major organic diseases that cause dyspepsia are gastroduodenal ulcer, gastroesophageal reflux and gastric cancer. Up to 60% of patients with dyspepsia have no definite explanation for their symptoms and are classified as having functional dyspepsia. These patients may respond to reassurance and explanation of the background to their symptoms, and at times anti-secretory or motility regulatory pharmacotherapy. Even though the bacteria Helicobacter pylori may be encountered in patients with functional dyspepsia, it is yet not recommendable to pursue eradication therapy unless a peptic ulcer is found, and is often of limited value in relieving symptoms. In patients with persistent symptoms, other treatments that may be considered include behavioral therapy, psychotherapy, or antidepressant therapy, but these approaches are not of established value.
The management of dyspepsia represents a major issue in clinical practice; 2-5% of all general practice consultations are accounted for by dyspepsia. Yet, as no obvious cause for the disease is at hand, treatment strategies have to be empirical; either aiming at anti-secretory or motility regulatory therapeutic measures.
Among different treatment strategies available for functional dyspepsia these include: motility regulatory agents, antacids, H
2
-receptor antagonists and, often prokinetics.
Gastrointestinal motility disorders are considered a common cause of functional dyspepsia. In cases of slow gastric emptying, motility stimulating agents, so-called prokinetics such as metoclopramide (Albibi et al, 1983) and cispride (Reboa et al, 1984; Delattre et al, 1985; Rösch, 1987; Abell et al, 1990), have been tried with reported symptomatic relief. In spite of this observation there is an undefined relationship between slow gastric emptying and symptoms and it is therefore unclear if the observed symptomatic relief depends on normalization of gastric emptying rate. Recent clinical trials with cisapride have disclosed symptomatic relief in 60-90% of the studied patients with dysmotility-like and gastroesophageal reflux-like dyspepsia, which should be compared to a 5-60% relief in placebo-treated groups (Talley 1991). Treatment with prokinetic drugs may thus be worthwhile, but does not resolve the problem.
Antacids have generally been considered as potentially effective in treatment of dyspeptic symptoms. No reliable data are available on their efficacy in functional dyspepsia (Talley, 1991), and antacids may rather be used as an on-demand treatment than continuous medication against functional dyspepsia.
H
2
-receptor antagonists, such as cimetidine and ranitidine, have been studied in the treatment of functional dyspepsia. About half of the reported studies show paucity of therapeutic response, whereas others have found statistic evidence for a therapeutic response to H
2
-receptor antagonist therapy (Talley, 1991). Mainly, patients with ulcer-like symptoms in the form of burning epigastric pain, may gain some symptomatic relief (Delattre et al, 1985) with H
2
-receptor antagonists. In addition to this, it is an every day experience that patients may benefit from an even more profound anti-secretory treatment by the use of a proton pump inhibitor such as omeprazole, lansoprazole or pantoprazole.
Thus, some symptomatic relief may be achieved with agents that inhibit gastric acid secretion.
IBS is common and involves about 1-2% of the population and accounts for up to one third of doctor's visits in general practice. The disease seems to be life-long with continuous relapsing activity, but it has not yet been studied how the disease affects the subject over a life span. No effective treatment is yet available. One major obstacle for the development of an effective drug is the fact that no reliable diagnostic hallmark of the disease is at hand, and for diagnostic purposes the doctor has to rely on the patient's case history and subjective reports, mainly as pain episodes and variable bowel habits.
During symptomatic periods a pattern of hypermotility, consisting of high-amplitude pressure waves are ten times as common in pain-dominant IBS than in normal subjects, whereas patients with the diarrhea-predominant disorder have normal or lower than normal pressure waves. These observations fit with basic data from recordings of colonic motility of normal subjects and patients with constipation or diarrhea. Such studies have demonstrated that the predominant form of motor activity from the colon consists of segmental contractions, which impede the propulsion of stool and promote mixing and absorption of water. These segmental contractions appear for more than 90% of the recorded time. Augmentation of segmental contractions produces constipation and inhibition of segmentation motor activity produces diarrhea. Studies indicate that contractions over a long segment of the colon may be accompanied by abdominal pain, analogous to diffuse esophageal spasm, the nutcracker syndrome of the esophagus and chest pain. Such high-amplitude contractions over long segments of the gut are often recorded in patients with IBS under episodes of crampy abdominal pain, i.e. the “gut-cracker syndrome”. Hypermotility of the small intestine also has been found in association with pain. Anecdotal evidence speak in favor of spasmodic cramping as the major source of symptoms in irritable bowel syndrome. Thus, regarding the pathophysiology of irritable bowel syndrome, disordered gastrointestinal motility or disturbances in the sensory system, or both, are suggested to be most important factors. However, there are many reports demonstrating disturbed small intestinal motility in patients with IBS in terms of the migrating motor complex activity. In the fasted state this activity includes phase I, displaying quiescence with no motor activity, phase II with sporadic contractions that become more intense over time and precede the characteristic phase III with high amplitude contractions to a level of about 40-50 mm Hg. In irritable bowel syndrome, increased phase II contraction frequency, increased contraction amplitude, and increased clustered contractions have been described (Kellow et al, 1987; Kellow et al, 1990; Lind, 1991; Kellow et al, 1992; Schmidt et al, 1996; Evans et al, 1996; Small et al, 1997). Radiologic studies demonstrate small bowel motor hyperactivity under str
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