Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2001-08-01
2004-04-20
Spector, Lorraine (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C530S351000
Reexamination Certificate
active
06723314
ABSTRACT:
FIELD OF INVENTION
The present invention relates to the field of prevention and treatment of gastrointestinal disorders using interleukin-11. More particularly, the present invention relates to preventing or treating gastrointestinal disorders using interleukin-11 to enhance motility of the digestive tract and/or contractility of the lower esophageal sphincter.
BACKGROUND OF THE INVENTION
Motilin, a gut polypeptide hormone, causes contraction of the stomach antrum and relaxation of the pyloric sphincter, thereby promoting gastric emptying. Toyota, K.,
J. Smooth Muscle Res
. (1998) 34:13-22. Central nervous system input (afferent, efferent) is not necessary for cyclic interdigestive activity or cyclic release of motilin. Siadati, M. and M. G. Sarr,
J. Gastrointest. Surg
. (1998) 2:363-72. Motilin reduces fasting gall bladder volume and increases stomach antral contractions in humans. Luiking, Y. C., et al.,
Gut
(1998) 42:830-835. Motilin receptors are distributed throughout the rabbit brain, suggesting a neurotransmitter role for motilin in the brain. Depoortere, I., et al.,
Brain Res
. (1997) 777:103-109.
In man, rabbit and cat, the effects of motilin and motilides are neurally mediated in vivo, whereas in vitro binding and contractility studies suggest the presence of a smooth muscular receptor. Motilin enhances contractions induced by electrical field stimulation in the rabbit antrum by a post-ganglionic interaction with the cholinergic neurotransmission in vitro at low doses and interacts directly with antral smooth muscle at high doses. Van Assche, G., et al.,
Eur. J. Pharmacol
. (1997) 337:267-274. Cholinergic and NANC inhibitory nerves play an important role in human lower esophageal sphincter (LES) contraction, and motilin and cisapride may be clinically useful for improving the impaired LES of patients with gastroesophageal reflux. Tomita, R., et al.,
Surg. Today
(1997) 27:985-992. Induction by motilin of phase III activity in human antrum is dependent on muscarinic mediation and the contractile effect of motilin on human duodenum involves a noncholinergic mechanism, as compared to the antral pathway. Boivin, M., et al.,
Am. J. Physiol
. (1997) 272:G71-6.
Cyclical motor activity of the gastrointestinal tract, normally occurring during the interdigestive period in several mammals, is disrupted in the post-operative ileus. After laparotomy, the cyclical motor activity recovers faster in the distal intestine than in the proximal intestine and the stomach, and that KW-5139 (a motilin derivative), but not PGF
2
-alpha (a naturally-occurring F-series prostaglandin) shortens the reappearance time of the phase III activity in the stomach. Yokoyama, T., et al.,
Neurogastroenterol. Motil
. (1995) 7:199-210.
Motilin is present in human breast milk at 100 pg/ml, and in the stomach its digestion is sufficiently retarded by human milk in the newborn to exert a biological role. De Clercq, P., et al.,
Life Sci
. (1998) 63:1993-2000. Minimal enteral feeding (MEF) favors secretion of gastrointestinal hormones in sick premature infants. Early MEF seems to be preferable to late one since it allows a faster secretion related to volume of the formula. Ordaz-Jimenez, M. R., et al.,
Rev. Invest. Clin
. (1998) 50:37-42. Although the motilin receptor appears to be functionally present beyond 32 weeks of gestation, as assessed by in indirect pharmacologic challenge, hormonal modulation of migrating activity in the neonate by plasma motilin and pancreatic polypeptide is absent. Jadcherla, S. R., et al.,
Pediatr. Res
. (1997) 42:365-9.
The exact pathophysiology of motility disorders, such as those described above, is not well understood. Consequently, a rational therapy for treating these disorders is also not available. Pharmacological agents which enhance the motility in the paralytic gut may be useful in the treatment and prevention of gastrointestinal disorders such as gastroesophageal reflux disease and surgery-induced adynamic ileus (also known as postoperative period ileus). Motility-enhancing agents (also known as gastroprokinetic agents) may also be useful in preventing or treating feeding intolerance in preterm infants.
One common approach to treating gastroesophageal reflux disease involves the use of the antiemetic agent metoclopramide, a benzamide having dopamine D2-receptor antagonist activity. Unfortunately, metoclopramide has several side effects, including an increase in prolactin levels and development of dyskinesia.
Another common practice for treating motility disorders involves the use of macrolide antibiotics, such as erythromycin. However, macrolide antibiotics are know to cause abdominal cramps and diarrhea, thus limiting their clinical application. Whether these side effects are secondary to their antibiotic activity or are due to their effect on gastrointestinal motility and secretion is not known. Various attempts to produce erythromycin derivatives having improved gastroprokinetic properties have met with limited success. See, e.g., Omura et al.,
J. Med. Chem
. (1987) 30(11):1941-1943; and Omura et al.,
J. Antibiotics
(1987) 38(11):1631-1632.
Thus, there remains a need for an effective, clinically applicable means of preventing or treating gastrointestinal disorders characterized by a defective motility pattern.
SUMMARY OF THE INVENTION
Applicants have for the first time determined that interleukin-11 (“IL-11”) increases plasma levels of motilin, a known gastrointestinal prokinetic gut hormone. Thus, IL-11 will enhance motility in the paralytic gut and increase contractility of gastrointestinal muscles, such as the lower esophageal sphincter and stomach antrum. As a result, IL-11 can be used to treat diseases and other conditions which result from defective motility patterns, such as, for example, in treating or preventing gastroesophageal reflux disease, post-operative adynamic ileus, and feeding intolerance in preterm infants.
Provided by the present invention are methods of treating disorders where an increase in plasma level of motilin is shown to be beneficial including, without limitation, gastroesophageal reflux disease, post-operative adynamic ileus, and feeding intolerance in preterm infants.
According to the present invention, IL-11, analogs, and derivatives thereof, are administered to patients, either prophylactically or at the onset of symptoms associated with the aforementioned disorders. IL-11 can be administered in suitable pharmaceutically acceptable carriers either alone or in combination with other conventional agents useful in alleviating the symptoms associated with the aforementioned disorders.
In one embodiment, the invention comprises a method of preventing a gastrointestinal disorder which comprises administering to a mammal, prior to the on-set of symptoms, a therapeutically effective amount of interleukin-11.
In another embodiment, the invention comprises a method of treating a gastrointestinal disorder which comprises administering to a mammal experiencing a gastrointestinal disorder a therapeutically effective amount of interleukin-11.
In preferred embodiments, the therapeutic dose is effective to prevent or treat a gastrointestinal disorder resulting from defective gastrointestinal motility or reduced contractility of the lower esophageal sphincter or duodenum. Preferably, the therapeutically effective amount of interleukin-11 comprises between about 1 and 1000 &mgr;g/kg body weight, and more preferably between about 1 and 100 &mgr;g/kg body weight.
DETAILED DESCRIPTION OF THE INVENTION
The following abbreviations are used herein: interleukin-11 (IL-11); recombinant human IL-11 (rhIL-11); interleukin-12 (IL-12); tumor necrosis factor (TNF); interferon (IFN); trinitrobenzene sulfonic acid (TNBS); substance P (SP); acetylcholine (ACh); non-adrenergic non-cholinergic (NANC); lower esophageal sphincter (LES); and prostaglandin (PG).
All patent and literature references cited are incorporated herein by reference as if fully set forth.
Provided by the present invention are methods of treating disorders where an increase in plasma
Asche G. Van
Depoortere Inge
Keith, Jr. James C.
Peeters Theo L.
Elrifi Ivor R.
Genetics Institute LLC
Jiang Dong
Johnson David E.
Mintz Levin
LandOfFree
Use of interleukin-11 to treat gastrointestinal disorders does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of interleukin-11 to treat gastrointestinal disorders, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of interleukin-11 to treat gastrointestinal disorders will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3224361