Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-08-25
2002-05-28
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S283000
Reexamination Certificate
active
06395708
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an agent for preventing diarrhea and particularly to a pharmaceutical agent for preventing diarrheal symptoms caused by administration of irinotecan or a salt thereof, particularly in the form of its hydrochloride, or attributed to its active metabolite, SN-38. More particularly, the invention concerns new methods, combination formulations and kits to prevent late diarrhea induced by irinotecan administration.
In the present specification, unless otherwise specified, the term “irinotecan” includes also pharmaceutically acceptable salts, e.g., the hydrochloride salt, and metabolites, such as, e.g. SN-38. In the present specification, unless otherwise specified, the term “octreotide” includes also pharmaceutically acceptable salts of octreotide, e.g., the acetate. By the term “administered” or “administering” as used herein, is meant standard delivery methods, e.g., parenteral administration, including continuous infusion and intravenous, intramuscular and subcutaneous injections, and oral administration.
BACKGROUND OF THE INVENTION
Diarrhea, characterized by the frequent defecation of liquid or liquid-like stools, often develops as a side effect during clinical treatment with chemotherapeutic agents. This adverse effect is most commonly associated with chemotherapeutic agents such as 5-fluorouracil, cisplatin or irinotecan hydrochloride. In particular, late diarrhea due to the administration of irinotecan can be prolonged, may lead to dehydration and electrolyte imbalance and can be, in some cases, sufficiently serious that irinotecan administration must be modified, interrupted or discontinued. Diarrhea poses a problematic symptom for patients, and because it may provoke reductions in irinotecan doses or the frequency of irinotecan administration, diarrhea may compromise the therapeutic efficacy of irinotecan.
While there is a substantial need for development of an agent for preventing diarrhea, particularly late diarrhea caused by irinotecan, no definite and efficacious method for preventing irinotecan-induced diarrhea has been identified. It is therefore an object of the present invention to provide an agent for preventing diarrhea, in particular late diarrhea, induced by irinotecan administration.
SUMMARY OF THE INVENTION
The present invention provides a method for preventing diarrhea caused by the administration of irinotecan. The invention comprises administration of octreotide or a pharmaceutically acceptable salt thereof, in particular octreotide acetate, to patients receiving irinotecan. Optionally, octreotide or a pharmaceutically acceptable salt thereof can be administered together with an anticholinergic agent, e.g., atropine, and/or with one or more antiemetic agents, e.g., dexamethasone, ondansetron or granisetron. Octreotide or a pharmaceutically acceptable salt thereof may be administered simultaneously with irinotecan, or the compounds may be administered sequentially, in any desirable order. Preferably, octreotide is administered before or concurrent with administration of irinotecan.
The present invention is also directed to combining separate pharmaceutical compositions containing irinotecan or, respectively, octreotide or its salts in kit form.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for preventing diarrhea caused by the administration of irinotecan. The invention comprises administration of octreotide to patients receiving irinotecan-containing therapy.
The preparation and use of irinotecan is known (see U.S. Pat. No. 4,604,463). It is available commercially in the form of CAMPTOSAR™ Injection, sold, e.g., by Pharmacia & Upjohn; and as CAMPTO™, sold by Rhone-Poulenc Rorer.
The preparation and use of SN-38 (10-ethyl 7-hydroxy camptothecin) is known (see U.S. Pat. No. 4,473,692). The preparation and use of octreotide is also well known (see U.S. Pat. No. 4,395,403). This is commercially available as the active ingredient in SANDOSTATIN™ and SANDOSTATIN LAR™ Depot, sold by Novartis.
Irinotecan is (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidino-piperidino)carbonyloxy]-1H-pyrano[3′,4′.6,7] indolizino [1,2-b]quinoline-3,14(4H,12H)dione. Irinotecan hydrochloride is a pale yellow to yellow crystalline powder, with the empirical formula C
33
H
38
N
4
O
6
HCl3H
2
O and a molecular weight of 677.19. Irinotecan hydrochloride was clinically investigated as CPT-11. Irinotecan is a prodrug converted in vivo by plasma and tissue carboxylesterases to SN-38 (7-ethyl-10-hydroxy camptothecin), an active metabolite that is an inhibitor of the nuclear enzyme topoisomerase I. Irinotecan has shown activity against a variety of tumor types, and in particular, refractory colorectal tumors.
Late-onset diarrhea, a severe delayed chronic grade 3-4 diarrhea, generally occurring more than 8 hours after administration of irinotecan, is the major dose-limiting toxicity in cancer patients receiving irinotecan therapy. The loss of fluids and electrolytes associated with late diarrhea can result in life-threatening dehydration, renal insufficiency, and electrolyte imbalances. The life-threatening aspects of persistent or severe diarrhea can require aggressive treatment and may lead to hospitalization. Persistent and severe diarrhea can also have negative effect on the patient's quality of life, and interferes with roles and responsibilities and interpersonal relationships and promotes feelings of social isolation. Because it may provoke reductions in irinotecan doses or the frequency of irinotecan administration, diarrhea may also compromise the therapeutic efficacy of irinotecan.
Quick resolution or, more preferably, prevention of late diarrhea is important, not only to prevent hospitalization, but also to improve quality of life and to enable patients to continue chemotherapy treatment at adequate doses in order to obtain the best antitumor effect. A variety of strategies for the control of chemotherapeutic-related diarrhea, particularly for the control of diarrhea induced by irinotecan, have been examined in humans and in animal models.
In humans, intensive, immediate application of loperamide (an agent that slows intestinal motility and affects water and electrolyte movement through the bowel) has been used to reduce or control diarrhea once diarrhea has started (Rougier P, Bugat R. CPT-11 in the treatment of colorectal cancer: clinical efficacy and safety profile. Semin Oncol 1996;23(Suppl 3): 34-41.) Though often successful in reducing the severity of diarrhea, this agent had not reduced the frequency of diarrhea, requires administration at 2-hour intervals following the onset of diarrhea, and is not used prophylactically.
The Chinese herbal medicine, kampo, has also been shown to control diarrhea in rats and humans; baicalin, one component of kampo, has similar activity (see, e.g., Takasuna K, Kasai Y, Kitano Y, Mori K, Kobayashi R, Hagiwara T, Kakihata K, Hirohashi M, Nomura M, Nagai E, et al. Protective effects of kampo medicines and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats. Jpn J. Cancer Res. 1995;86:978-984; and, Sakata Y, Suzuki H, Kamataki T. Preventive effect of TJ 14, a kampo (Chinese herb) medicine, on diarrhea induced by irinotecan hydrochloride (CPT-11), Gan To Kagaku Ryoho 1994; 21:1241-1244.) Though the mechanism is not clearly defined, the anti-diarrheal activity of kampo or baicalin is thought to be through inhibition of beta glucuronidases in the gastrointestinal tract. This enzyme is responsible for the deconjugation of the glucuronide form of the active irinotecan metabolite, SN-38. Deconjugation of the SN-38 glucuronide is thought to release active SN-38 back into the intestinal lumen and produce toxic effects on the intestinal epithelium.
Since most of the intestinal beta-glucuronidase activity is due to microbial flora, antibiotics have also been suggested to have protective effects (Takasuna K, Hagiwara T, Hirohashi M, Kato M, Nomura
Miller Langdon L.
O'Dowd Hugh Michael
Rothermel John David
Criares Theodore J.
Kim Jennifer
McDonnell & Boehnen Hulbert & Berghoff
Novartis A.G.
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