JP2012021031A - Prevention, treatment, and amelioration of radiation-induced enteritis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method of ameliorating and/or treating enteritis induced by radiation therapy, alone or in combination with other therapies.SOLUTION: The method for the treatment of, for example, gastrointestinal malignancies, including colorectal, appendiceal, anal, or small bowel cancers; urogenital malignancies, including prostate, bladder, testicular, or penile cancers; gynecologic malignancies, including cervical, endometrial, ovarian, vaginal, or vulvar cancers; or osteogenic and other sarcomatous malignancies in which pelvic structures are involved, includes a step of administering a therapeutically effective amount of balsalazide to a patient in need thereof.

Description

(Related application)
This application claims priority from US patent application Ser. No. 10 / 856,348, filed May 28, 2004. This US patent application was converted to US Provisional Patent Application No. 60 / 608,951 on October 26, 2004. Both of these applications are incorporated herein by reference in their entirety.

(Field of Invention)
The present application relates to the use of balsalazide to treat, prevent or ameliorate enteritis. More specifically, the present invention relates to the use of balsalazide for treating radiation-induced enteritis caused by radiation therapy alone or in combination with other therapies.

(Background of the Invention)
Various pelvic therapies, including radiation therapy, chemotherapy, and surgery (sometimes referred to as “pelvic therapy”) are either adjuvant or primary treatment for subjects with pelvic disorders (eg, tumors). As such, it is used in a wide variety of clinical situations. This treatment can result in intestinal toxicity and other side effects (eg, acute radiation enteritis). For example, approximately 80% of patients who receive pelvic radiation therapy experience acute radiation enteritis.

  The side effects of these various pelvic therapies can cause discomfort and reduce the therapeutic benefit of the treatment due to the need for occasional interruptions in the therapy. Thus, it would be beneficial to have a treatment that prevents, ameliorates or otherwise treats the side effects of pelvic therapy.

(Summary of the Invention)
Disclosed herein are methods for preventing, ameliorating and / or treating radiation-induced enteritis. Further disclosed is a method of treating radiation-induced enteritis caused by a combination of radiation therapy and chemotherapy and / or surgery. In general, subjects who may benefit from treatment with balsalazide include subjects who are scheduled to begin radiation therapy or are undergoing radiation therapy, particularly in the pelvic region. Is mentioned. Subjects that may particularly benefit from this treatment include subjects who have or may be susceptible to enteritis. For example, the subject may be in the immediate vicinity of receiving radiation therapy, may be receiving radiation therapy, or may have received radiation therapy. The subject may also have received a combination of pelvic treatments. Subjects include, for example, gastrointestinal malignancies including colorectal cancer, appendix cancer, anal cancer, or small intestine cancer; genitourinary malignancies including prostate cancer, bladder cancer, testicular cancer, or penile cancer; cervical cancer, intrauterine It may be affected by gynecological malignancies including membrane cancer, ovarian cancer, vaginal cancer, or vulvar cancer; or osteogenic and other sarcomatous malignancies involving pelvic structure.

  The present invention provides a new treatment for radiation-induced enteritis.

  In accordance with one aspect of the invention, a method of treating radiation-induced enteritis includes administering a therapeutically effective amount of balsalazide to a subject in need of treatment for radiation-induced enteritis.

  In certain embodiments, balsalazide is administered at least one day prior to the first dose of radiation therapy for the subject. In a related embodiment, balsalazide is administered at least 5 days prior to the first dose of radiation therapy for the subject.

  In certain other embodiments, balsalazide is administered from at least one day before the first dose of radiation therapy to at least one day after the cessation of radiation therapy.

  According to certain preferred embodiments, balsalazide is administered to a subject twice daily.

  In another embodiment, between about 3000 mg to about 5000 mg of balsalazide is administered to the subject daily.

  In certain embodiments, the balsalazide is administered at least one day prior to the subject's radiation therapy, the first dose of chemotherapy, or at least one day prior to undergoing surgery.

  Certain other embodiments include balsalazide administered at least 5 days prior to the subject's radiation therapy, the first dose of chemotherapy, and / or at least 5 days prior to undergoing surgery.

  Other embodiments include balsalazide administered during radiation therapy, chemotherapy, or the above surgery.

  In certain preferred embodiments, balsalazide is administered from at least one day prior to administration of pelvic treatment to at least one day after pelvic treatment. For example, before radiation therapy, the first dose of chemotherapy, and / or before undergoing surgery.

  According to another aspect, a method of protecting against radiation-induced enteritis comprises administering a therapeutically effective amount of balsalazide to a subject in need of protection from radiation-induced enteritis.

  In another aspect, a method of protecting the colonic mucosa from radiation-induced injury comprises administering a therapeutically effective amount of balsalazide to a subject in need of protection from radiation-induced injury of the colonic mucosa. .

  In yet another aspect, a method of protecting against radiation-induced colorectal inflammation includes administering a therapeutically effective amount of balsalazide to a subject in need of protection from radiation-induced colorectal inflammation.

Other embodiments of the invention are disclosed below.
For example, the present invention provides:
(Item 1)
A method of treating radiation-induced enteritis, comprising administering a therapeutically effective amount of balsalazide to a subject in need of treatment for radiation-induced enteritis.
(Item 2)
The method of claim 1, wherein the balsalazide is administered at least one day prior to the first dose of radiation treatment of the subject.
(Item 3)
The method of claim 1, wherein the balsalazide is administered at least 5 days prior to the first dose of radiation treatment of the subject.
(Item 4)
The method of item 1, wherein the balsalazide is administered during radiation therapy.
(Item 5)
The method of item 1, wherein the balsalazide is administered for at least one day after cessation of radiation therapy.
(Item 6)
2. The method of item 1, wherein the balsalazide is administered for 14 days after cessation of radiation therapy.
(Item 7)
2. The method of item 1, wherein the balsalazide is administered from at least one day prior to the first dose of radiation therapy to at least one day after a cessation of radiation therapy.
(Item 8)
Gastrointestinal malignant tumor including colorectal cancer, appendix cancer, anal cancer, or small intestine cancer; genitourinary malignant tumor including prostate cancer, bladder cancer, testicular cancer, or penile cancer; cervical cancer, endometrium Gynecological malignancies including cancer, ovarian cancer, vaginal cancer, or vulvar cancer; or receiving radiation therapy as a result of treatment for osteogenic and other sarcomatous malignancies involving pelvic structure The method according to item 1.
(Item 9)
The method of claim 1, wherein the balsalazide is administered to the subject twice daily.
(Item 10)
2. The method of item 1, wherein between about 3000 mg and about 5000 mg of balsalazide is administered to the subject daily.
(Item 11)
The method of claim 1, wherein the balsalazide is administered to the subject between about 8 weeks and about 12 weeks.
(Item 12)
The method of item 1, wherein the subject has acute radiation enteritis.
(Item 13)
The method of item 1, wherein the radiation-induced enteritis is caused by radiation therapy in combination with chemotherapy or surgery.
(Item 14)
14. The method of item 13, wherein the balsalazide is administered at least one day before the subject's radiation therapy, the first dose of chemotherapy, or at least one day before undergoing surgery.
(Item 15)
14. The method of item 13, wherein the balsalazide is administered at least 5 days before the first dose of radiation therapy, chemotherapy, or at least 5 days before undergoing surgery.
(Item 16)
14. The method of item 13, wherein the balsalazide is administered during radiation therapy, chemotherapy, or the surgical procedure.
(Item 17)
14. The method of item 13, wherein the balsalazide is administered for at least one day after radiation therapy, chemotherapy cessation, or at least one day after surgery.
(Item 18)
14. The method of item 13, wherein the balsalazide is administered for at least 14 days after radiation therapy, chemotherapy cessation, or at least 14 days after surgery.
(Item 19)
The balsalazide is administered from at least one day before the first dose of radiation therapy, chemotherapy or at least one day before undergoing surgery, to at least one day after radiation therapy, chemotherapy cessation, or at least one day after surgery. 14. The method according to item 13.
(Item 20)
Gastrointestinal malignant tumor including colorectal cancer, appendix cancer, anal cancer, or small intestine cancer; genitourinary malignant tumor including prostate cancer, bladder cancer, testicular cancer, or penile cancer; cervical cancer, endometrium Gynecological malignancies including cancer, ovarian cancer, vaginal cancer, or vulvar cancer; or radiation therapy, chemistry as a result of treatment for osteogenic and other sarcomatous malignancies involving pelvic structure 14. The method according to item 13, which has undergone therapy or surgery.
(Item 21)
14. The method of item 13, wherein the balsalazide is administered to the subject twice daily.
(Item 22)
14. The method of item 13, wherein between about 3000 mg and about 5000 mg of balsalazide is administered to the subject daily.
(Item 23)
14. The method of item 13, wherein the balsalazide is administered to the subject between about 8 weeks and about 12 weeks.
(Item 24)
A method of protecting against radiation-induced enteritis comprising administering to a subject a therapeutically effective amount of balsalazide before, during and / or after receiving radiation therapy.
(Item 25)
A method of protecting the colonic mucosa from radiation-induced injury comprising administering to a subject a therapeutically effective amount of balsalazide before, during and / or after receiving radiation therapy.
(Item 26)
A method of protecting against radiation-induced colorectal inflammation comprising administering to a subject a therapeutically effective amount of balsalazide before, during and / or after receiving radiation therapy.

FIG. 1 shows symptom indices for balsalazide-treated patients and placebo-treated patients, according to one embodiment of the present invention.

(Detailed description of the invention)
Disclosed herein are methods for treating radiation-induced enteritis.

  Radiation therapy and radiotherapy are used interchangeably herein and are external and internal (also referred to as brachytherapy, intracavitary brachytherapy, or interstitial radiation therapy). Is included. Contemplated sources of radiation include pure gamma rays, pure beta rays, and combinations of irradiation.

  As used herein, the terms “chemotherapy” and “chemotherapeutic agent” are used interchangeably and refer to a chemotherapeutic or chemotherapeutic agent that exhibits an anti-cancer effect and a malignant tumor Used in the treatment of.

  The inventors have surprisingly found that administration of balsalazide to patients experiencing radiation-induced enteritis reduces the symptoms of the condition. The success of balsalazide in the treatment of radiation enteritis is surprising from the failure of other related 5-ASA drugs (eg, osalazine and mesalamine) in clinical trials.

  Balsalazide is a 2-hydroxy-5-phenylazobenzoic acid derivative (in which the aminosalicylic acid moiety (5-aminosalicylic acid (5-ASA) (mesalamine)) is a carrier molecule (4-aminobenzoyl-*-alanine (4- ABA)) is a generic name for which is attached via an azo bond. Balsalazide disodium is highly water soluble and is cleaved in the colon to release the therapeutically active portion of this molecule, mesalamine, and the carrier portion, 4-aminobenzsol-alamine. Mesalamine is 5-aminosalicylic acid and appears to act locally.

  The use of balsalazide to treat radiation-induced enteritis is particularly beneficial. This is because it is metabolized to the active form of 5-ASA by the gut microbiota, thus ensuring optimal delivery of the active drug to the gut without loss through absorption closer to the gut. Balsalazide also exhibits fewer side effects than other 5-ASA prodrugs and can be administered to subjects with sulfur allergies. Balsalazide is also beneficial because the active ingredient has been demonstrated to directly remove free radicals, which can reduce subsequent inflammatory responses. Without wishing to be bound by any particular theory, the inventors have shown that balsalazide protects against radiation-induced enteritis by blocking inflammation mediators and free radical release in the rectal mucosa. I think I will get.

  As used herein, radiation-induced enteritis includes radiation-induced damage to the pelvic region due to irradiation of the pelvic region. Irradiation often causes acute radiation enteritis or colorectal toxicity. Symptoms can include diarrhea, proctitis, fecal incontinence, loose stool, increased number of bowel movements per day, tenesmus, mucus production, abdominal pelvic pain, and perirectal discomfort. Acute radiation enteritis mostly results from irritation of the sigmoid colon and rectum.

  Yet another aspect of the invention relates to a method of treating a subject in need of balsalazide treatment (eg, a mammal, human, horse, dog, cat) with balsalazide. Identification of a subject in need of such treatment can be at the subject's or health care provider's discretion and is subjective (eg, opinion) or objective (eg, measurable by a test or diagnostic method) It can be.

  Balsalazide can be used in various treatment regimes. These regimens can vary depending on the subject and the type of treatment.

  Balsalazide can be administered before treatment therapy, during treatment therapy, and / or after treatment therapy. Balsalazide can be administered, for example, twice a day, three times a day, or four times a day. Balsalazide can be administered, for example, in a volume between about 2000 mg BID and about 2500 mg TID. Another example is administering between about 4.0 g / day and about 7.25 g / day of balsalazide. Balsalazide can be administered, for example, in tablet form, powder form, liquid for capsules or liquid in capsules.

  Subjects in need of these include subjects who receive radiation therapy alone or in combination with other pelvic therapies that can induce enteritis. This need may be evident in: Before undergoing radiation therapy, chemotherapy, pelvic surgery, or a combination of therapy; Subjects receiving radiation therapy, chemotherapy, pelvic surgery, or a combination of therapies Body; and subject after receiving radiation therapy, chemotherapy, pelvic surgery, or a combination of therapies. For example, a subject may be up close, receiving or receiving radiation therapy in combination with chemotherapy or surgical procedures.

  Also included are subjects who are enteritis or may be susceptible to enteritis. The subject may have, for example, the following: gastrointestinal malignancy (including colorectal cancer, appendix cancer, anal cancer, or small intestine cancer); genitourinary malignancy (prostate cancer, bladder cancer, Testicular cancer or penile cancer); gynecological malignancies (including cervical cancer, endometrial cancer, ovarian cancer, vaginal cancer or vulvar cancer); or osteogenic involvement in pelvic structure Malignant tumors and other sarcomatous malignancies.

  As used herein, a therapeutically effective amount is an effective amount (eg, acute) when administered to a human or non-human subject to provide a therapeutic benefit (eg, improvement in symptoms). Effective amount to reduce symptoms of radiation enteritis).

  According to certain embodiments, balsalazide can be administered prior to radiation therapy. Balsalazide may be administered, for example, at least 1 day prior to the first dose of radiation therapy for the subject, at least 5 days prior to the first dose of radiation therapy for the subject, at least 5 days after withdrawal of radiation therapy, and at least 14 days after withdrawal of radiation therapy. Can be administered. Administration at least 5 days prior to treatment includes daily administration, daily administration prior to pelvic treatment, administration of a majority of days prior to treatment, administration on the treatment day, or no administration on the treatment day.

  Certain preferred embodiments include administering balsalazide from at least one day before the first dose of radiation therapy to at least one day after discontinuation of radiation therapy. Pre-radiotherapy treatment allows 5-ASA to be present at its site of action while the cause of the disorder is present.

  In certain embodiments, balsalazide is administered to a subject for a period of between about 2 weeks to about 6 weeks, between about 8 weeks to about 12 weeks, or between 1 day to about 7 days. . Balsalazide can be administered intermittently or continuously during the course of treatment. The length of treatment may vary depending on the radiation therapy, the type and length of chemotherapy, and / or the type of surgery, and the appropriate length of treatment will be determined by those skilled in the art having the benefit of this disclosure. It can be easily determined.

  For any embodiment, balsalazide can be administered to a subject, for example, once a day, twice a day, three times a day, or four times a day. In some particularly preferred methods of the invention, administering balsalazide to a subject twice a day is included. This is because, for example, side effects can be minimized and patient compliance can be increased.

  The dosage ranges from between about 3000 mg to about 5000 mg of balsalazide administered daily according to certain preferred embodiments. For example, a dose of 2250 mg can be administered to a subject twice a day. Other suitable dosages for the method according to the invention can be determined by a health care professional or by the subject. The amount of balsalazide administered daily can be increased or decreased based on the subject's weight, age, sex, or medical condition. One of ordinary skill in the art can determine the appropriate dose for a subject based on the present disclosure.

  For a subject undergoing multiple treatments, for example, balsalazide may be administered as follows: radiation treatment of the subject, at least one day before the first dose of chemotherapy, and / or at least one day before undergoing surgery; Body radiation therapy, at least 5 days prior to the first dose of chemotherapy, and / or at least 5 days before undergoing surgery; during radiation therapy, chemotherapy, and / or surgery; at least one of radiation therapy, withdrawal of chemotherapy 1 day after surgery, or at least 1 day after surgery; radiation therapy, at least 14 days after withdrawal of chemotherapy, or at least 14 days after surgery.

  It is often preferred to administer balsalazide to a subject before treatment, during treatment, and after treatment is discontinued. For example, balsalazide may be administered at least one day prior to radiation therapy, first dose of chemotherapy, and / or at least one day prior to surgery, until at least one day after radiation therapy, chemotherapy cessation, or at least one day after surgery. Can be administered.

  Application is as a result of treatment for cervical cancer, prostate cancer, appendix cancer, colon cancer, intestinal cancer, rectal cancer or other gastrointestinal malignancies, or prostatectomy, radiation therapy, chemotherapy administration, and / or surgery Includes subjects undergoing surgery.

  According to certain embodiments, balsalazide can be administered in combination with other compounds. Other compounds include, for example: chemotherapeutic agents, anti-inflammatory agents, antipyretic agents, radiosensitizing agents, radioprotectants, urological agents, antiemetics, and / or diarrhea. Stopping agents (e.g., cisplatin, carboplatin, docetaxel, paclitaxel, fluorouracil, capecitabine, gemcitabine, irinotecan, topotecan, etoposide, mitomycin, gefitinib, vincristine, vinblastine, doxorubicebide, coxidobofibine , Naproxen, ketoprofen, dexamethasone, prednisone, prednisolone, hydrocortisone, acetaminophen, misonidazo , Amifostine, tamsulosin, phenazopyridine, ondansetron, granisetron, alosetron, palonosetron, promethazine, prochlorperazine, trimethobenzamide, aprepitant (aprepitant) And / or loperamide).

  The methods disclosed herein also provide for protecting a subject against radiation-induced enteritis by administering a therapeutically effective amount of balsalazide to a subject in need of protection against radiation-induced enteritis. Useful. For example, a prophylactic dose can be administered before a patient receives radiation.

  The methods disclosed herein provide radiation to the colonic mucosa by administering a therapeutically effective amount of balsalazide to a subject in need of protection against radiation-induced damage to the colonic mucosa and radiation-induced colorectal inflammation. Useful to protect subjects against induced disorders and against radiation-induced colorectal inflammation.

  It should be understood that the invention is not to be construed as limited to the examples set forth herein. Rather, the present invention should be construed to include any and all applications provided herein and any equivalent modifications within the skill of the art.

(Clinical trial of balsalazide to treat radiation enteritis)
Subjects included patients treated for FIGO stage IB2-IVA cervical cancer, or patients treated for biochemical failure after prostatectomy. In a 4-field technique up to at least 40 Gy, radiation therapy was delivered to the subject and the tumor dose was at least 64 Gy for prostate patients and 75 Gy for cervical patients. Brachytherapy boost was allowed.

Patients were given 2250 mg BSZ or placebo with the same appearance twice daily. This began 5 days prior to radiation therapy and continued for 2 weeks after completion. Toxicity, NCI Common
According to Toxicity Criteria, weekly for each of the following: proctitis, diarrhea, dysuria, weight loss, fatigue, nausea, and vomiting. A symptom index was formulated for each toxicity. This consists of a numerical grade of toxicity times the number of days experienced. This was summed for each grade. Therefore, patients with Grade 1 proctitis for 7 days, Grade 2 proctitis for 14 days, and Grade 3 proctitis for 7 days [(1 * 7) + (2 * 14) + (3 * 7)] Had a proctitis index of 56. A higher index indicates worse toxicity.

  Patients were randomized by a sealed envelope decision (only the protocol coordinator knows the outcome of the randomization). After randomization, study subjects or identical-looking placebos were given to study subjects, with explanations regarding dosage and dosing schedule.

As described above, toxicity was assessed weekly during the course of radiation treatment and then for at least 6 months after completion of radiation therapy. The National Cancer Institute (NCI) common toxicity criteria was used to grade the severity of radiation-induced acute enterotoxicity.
Using diarrhea as the primary endpoint, the following were evaluated:
Grade 0-No diarrhea or increased bowel frequency Grade 1-2 2-3 bowel movements / day grade 2 4-6 bowel movements / day increase, or night bowel movement grade 3-7-9 Increased bowel movements / day, or nighttime bowel movement grade 4-> 10 bowel movements / day increase, or gross hemorrhagic diarrhea observed baseline hemorrhoidal bleeding was not considered grade 4.
Secondary endpoints included proctitis. This was assessed using the guidelines outlined by NCI Common Toxicity Criteria. These guidelines include the following:
Grade 0-None Grade 1-Increased frequency of bowel movements, sometimes stool with linear bleeding
tools), or rectal discomfort, no need for medication Grade 2-increased bowel frequency, bleeding, mucus release, or rectal discomfort grade requiring medication 3-increased frequency of bowel movement / requires parenteral support Diarrhea, rectal bleeding requiring infusion, or persistent mucus release grade requiring padding 4-perforation, bleeding or necrosis, or other life-threatening complications requiring surgical intervention.

  Clinical experience has shown that the only statistically significant side effect of balsalazide disodium was abdominal pain (this was seen in 11% of patients receiving the drug versus patients receiving placebo) In 0%). Adverse events reported in the balsalazide trial were comparable to those seen in patients receiving placebo (adverse events included headache, nausea, diarrhea, bloating, and fatigue).

  Except for nausea / vomiting seen in 2 patients with balsalazide and 1 patient with placebo, all toxicities were significantly lower in patients taking balsalazide. Proctitis was most effectively prevented, with a mean index of 35 in balsalazide patients versus 77 in placebo patients (p = 0.04). Patients on balsalazide did not experience grade 4 diarrhea. On the other hand, two placebo patients experienced. The average weight loss in plush exceeded 3 pounds, while on average balsalazide patients gained weight. The fatigue index in balsalazide patients was 20, while the placebo patients averaged 49. Unexpectedly, dysuria was also quite low in balsalazide patients. FIG. 1 is a bar graph showing the symptom index comparing subjects who received balsalazide and subjects who received placebo.

Claims (1)

The invention described herein.

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