ORAL ADMINISTRATION OF SODIUM CHLORIDE TO PREVENT COMPLICATIONS ASSOCIATED WITH BOWEL CLEANSING WITH STIMULANT LAXATIVES

Abstract

A method for preventing unwanted side effects associated with the administration stimulant laxative such as bisacodyl or sodium picosulphate by orally administering sodium chloride to the patient is disclosed. Said side effects include hyponatraemia, hypokalemia, unwanted fluctuations in blood pressure, hypotension and renal failure. In certain embodiments, the sodium chloride is administered in the form of tablets during the two hours period following the administration of the stimulant laxative. This method is particularly useful in preparing patients for a colonoscopy.

Claims

1. A method to prevent the side effects associated with the administration of a stimulant laxative drug by administering sodium chloride orally to the patient in need thereof to whom said stimulant laxative drug is administered.

2. The method according to claim 1, wherein said stimulant laxative drug is a derivative of triphenylmethane.

3. The method according to claim 2, wherein said stimulant laxative drug selected from the group consisting of ρ,ρ-diacetoxy-diphenyl-2-pyridylmethane, 4,4′-dihydroxydiphenyl-(2-pyridyl)methane, pharmaceutically acceptable salts thereof, prodrugs thereof and any combination thereof.

4. The method according to claim 3, wherein said ρ,ρ-diacetoxy-diphenyl-2-pyridylmethane is bisacodyl.

5. The method according to claim 3, wherein said prodrug of 4,4′-dihydroxydiphenyl-(2-pyridyl)methane is sodium picosulfate.

6. The method according to claim 1, wherein the patient is administered a combination of bisacodyl and sodium picosulfate.

7. The methods according to claims 1, 3 or 6 wherein said patient is administered 10 g of sodium chloride.

8. The method according to claim 7, wherein said patient is administered 15 mg of bisacodyl.

9. The method according to claim 7, wherein said patient is administered 10 mg of sodium picosulfate.

10. The method according to claim 7, wherein the patient is administered said sodium chloride in incremental doses.

11. The method according to claim 10, wherein said patient is administered ten 1 g tablets of sodium chloride.

12. The method according to claim 11, wherein said patient administers said tablets to themselves upon the advice of a treating technician.

13. The method according to claim 5, further comprising administering magnesium oxide and citric acid with said sodium picosulfate.

14. The method according to claim 13, wherein said sodium picosulfate, magnesium oxide and citric acid are in the form of dry ingredients mixed together and contained in a sachet for administration to the patient in need thereof by the patient.

15. The method according to claim 14, wherein said sachet contains 10 mg of sodium picosulfate, 3.5 g of magnesium oxide and approximately 10-12 g of citric acid.

16. The method according to claim 14, wherein two sachets sodium picosulfate, magnesium oxide and citric acid are in the form of dry ingredients are administered to the patient in need thereof.

17. The method of claim 16, wherein said sachets are dissolved in water prior to administration.

18. The method of claim 17, wherein said sachet is dissolved in approximately 250 ml of water.

19. The method according to claim 7, wherein said bisacodyl is a pre-dosed tablet.

20. The method according to claim 19, wherein 3 tablets of bisacodyl are administered to a patient in need thereof.

21. The method according to claim 7, wherein said patient is in need of a bowel cleaning prior to a diagnostic procedure requiring a clean bowel.

22. The method according to claim 19, wherein said diagnostic procedure is a colonoscopy.

23. The method according to claim 7, wherein 3 tablets of bisacodyl, 2 sachets of a combination of sodium picosulfate, magnesium oxide and citric acid and 10 tablets of sodium chloride are administered to a patient in need thereof.

24. The method according to claim 23, comprising the steps of administering orally 3 tablets of bisacodyl with approximately 250 ml of water to a patient in need thereof approximately 24 hours prior to the day said colonoscopy is scheduled; dissolving one sachet containing the sodium picosulfate, magnesium oxide and citric acid combination in approximately 250 ml of water and orally administrating said solution to the patient approximately 2 to 4 hours after the administration of the bisacodyl; administering 1 sodium chloride tablet orally with approximately 250 ml of a clear liquid to the patient every 30 minutes after the administration of said sodium picosulfate, magnesium oxide and citric acid combination for approximately 2 hours; dissolving the second sachet containing the sodium picosulfate, magnesium oxide and citric acid combination in approximately 250 ml of water and orally administrating said solution to the patient approximately 4 to 5 hours before said colonoscopy is scheduled; and administering one sodium chloride tablet orally to the patient every 30 minutes after the administration of said sodium picosulfate, magnesium oxide and citric acid combination for approximately 2 hours.

25. The method according to claim 24, wherein said clear liquid is selected from the group consisting of water, light colored fruit juice without pulp, clear broth, coffee without milk, tea without milk, flavored gelatin, popsicles and soft drinks.

26. The method according to claim 1, wherein said method prevents hyponatremia, hypokalemia, unwanted fluctuation in blood pressure, hypotension and/or renal failure.

27. The method according to claim 1, wherein said side effects are selected from the group consisting of dehydration, diarrhea, dizziness, ocular deviation, decreased urination, bloody stool, seizures, irregular heartbeat, rash, hives, nausea and vomiting, headache, short-term memory loss, confusion, lethargy, fatigue, loss of appetite, irritability, muscle weakness, spasms or cramps, vertigo, fluid and electrolyte imbalance, decreased consciousness, abdominal pain, fainting and any combination thereof.

28. The method according to any one of claims 24 to 26, wherein the patient is elderly or suffering from renal failure.

29. A kit comprising (i) 3 tablets of bisacodyl; (ii) 2 sachets containing the powder forms of sodium picosulfate, magnesium chloride and citric acid; and (iii) 10 1 g tablets of sodium chloride.

30. The kit according to claim 29, further comprising (iv) instructions as to the administration of the components of said kit to a patient to cleanse the bowel of said patient prior to a colonoscopy procedure.

31. The kit according to claim 29, wherein when the contents of said kit are used to cleanse the bowel of a patient prior to a colonoscopy procedure.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0020] Contrary to teachings of the prior art, it was discovered that bisacodyl (Dulcolax®, Boehringer Ingelheim, Ingelheim am Rhein, Germany) could be administered with a sodium picosulfate/magnesium oxide/citric acid combination (Citracleen®, Recordati S.p.A, Milan, Italy) to improve pre-colonoscopy cleaning of the colon. When administering bisacodyl prior to the ingestion of picosulfate/magnesium oxide/citric acid combination by a patient scheduled for a colonoscopy, the bisacodyl removes the bulk of the stool in the colon whereas the picosulfate/magnesium oxide/citric acid combination effectively removes trace solid feces and/or residual brown liquid, thus improving the quality of the following colonoscopy.

[0021] The inventor of the claimed novel method discovered that including the oral ingestion of sodium chloride tablets (Consolidated Midland Corp., Brewster, N.Y.) prevented the onset of blood pressure fluctuation (hypotension), hyponatremia and/or renal failure, as well as obviating a number of side effects observed with the administration of bisacodyl or a sodium picosulfate/magnesium oxide/citric acid combination alone or together. It was discovered that the addition of sodium chloride tablets to a pre-colonoscopy cleansing routine forced patients to drink approximately 2,000 ml (approximately 10 standard drinking glasses) of fluid. It was discovered that the intake of sodium chloride, together with the fluid ingested with said salt dosing, prevented dehydration despite causing watery diarrhea in the patient. Dehydration, which is common side effect caused by the use of stimulant laxatives such as bisacodyl and a sodium picosulfate/magnesium oxide/citric acid combination, can lead to many of the observed, undesirable side effects, and in some cases, particularly in elderly patients and those suffering from renal function issues, can lead to renal failure, an unwanted reduction in blood pressure and an imbalance in electrolytes. The addition of salt tablets to a pre-colonoscopy cleansing regimen maintains hydration, electrolyte balance and normal renal function.

[0022] It was discovered that a specific dosing regimen resulted in the best pre-colonoscopy cleansing without the onset of undesirable side effects, a decrease in blood pressure, electrolyte depletion, or decrease in renal function. The preferred embodiment consists of the following colon cleansing regimen: [0023] administering orally 3 tablets of bisacodyl with approximately 250 ml of water to a patient in need thereof approximately 24 hours prior to the day said colonoscopy is scheduled; [0024] dissolving one sachet containing the sodium picosulfate, magnesium oxide and citric acid combination in approximately 250 ml of water and orally administrating said solution to the patient approximately 2 to 4 hours after the administration of the bisacodyl; [0025] administering 1 sodium chloride tablet orally with approximately 250 ml of a clear liquid to the patient every 30 minutes after the administration of said sodium picosulfate, magnesium oxide and citric acid combination for approximately 2 hours; [0026] dissolving the second sachet containing the sodium picosulfate, magnesium oxide and citric acid combination in approximately 250 ml of water and orally administrating said solution to the patient approximately 4 to 5 hours before said colonoscopy is scheduled; and [0027] orally administering one sodium chloride tablet orally to the patient every 30 minutes after the administration of said sodium picosulfate, magnesium oxide and citric acid combination for approximately 2 hours using a clear liquid selected from the group consisting of water, light colored fruit juice without pulp, clear broth, coffee without milk, tea without milk, flavored gelatin, popsicles or soft drinks.

[0028] As observed, the initial administration of bisacodyl resulted in an initial expulsion of the bulk of the fecal matter found in the lower large intestine, colon and rectum.

[0029] Administration of the sodium picosulfate, magnesium oxide and citric acid combination resulted in the removal of residual stool. The continuous intake of sodium chloride tablets with the accompanying clear liquid maintained the patient's electrolyte levels and renal function, prevented an unwanted decrease in blood pressure, maintained electrolyte levels and prevented dehydration. By maintaining electrolyte levels and keeping the patient hydrated, many of the known side effects cause by stimulant laxative drugs were averted.

[0030] Previous studies have investigated the purgative effect of bisacodyl and sodium picosulfate, alone or in combination with a saline purge and a tap water enema (Fork F-T et al., (1982), Gastrointest Radiol, 7(4):383-9). The Fork study involving 1200 patients indicated that the administration of a contact laxative and a saline purge resulted in a “good cleansing” in 52-80% of the patients tested. The Fork study does not address the problems associated with the use of stimulant laxative drugs. Fork discusses use of saline purge with a water enema as a final step to achieve optimum cleansing, however neither the saline purge nor the water enema is sufficient to maintain the electrolyte levels of the patient and only results in further dehydration of the patient. As noted above, the staggered, yet continuous intake of fluid, keeps the patient well-hydrated and the patient's electrolyte levels constant.

Proof of Concept

[0031] A study to determine the effectiveness of the claimed method to prevent the side effects associated with the administration of a stimulant laxative drug to a patient in need of a bowel cleansing prior to a colonoscopy procedure by administering sodium chloride orally to the patient in need thereof was conducted, in particular, whether adding salt tablets with a specific amount of water in addition to the traditional products used for colon cleansing will result in cleaning the colon without dehydration thus causing minimal changes in blood pressure, weight, urine volume and urine sodium.

[0032] A prospective, open-label study involving four patients scheduled for their regular colonoscopy exam was conducted (Canadian Phase Onward Inc., Toronto, Ontario. CA). (The original study included five patients, however, the subject identified as Patient #1 failed to follow the protocol and was dropped from the study. The selected patients were over the age of 18 and all consented to be part of the study.) After a patient was included in the study, their weight, age, sex, ethnicity, and blood pressure was measured and recorded. In addition to the standard instructions not to eat food and to drink only clear liquids, the selected patients were instructed to do the following on the day before the colonoscopy was to be performed:

[0033] 1. at 10:00 AM orally taking three bisacodyl pills (Dulcolax®, Boehringer Ingelheim, Ingelheim am Rhein, Germany) with water (chewing or crushing the pills was prohibited);

[0034] 2. at 3:00 PM dissolving the contents of a first sachet containing sodium picosulfate/magnesium oxide/citric acid combination (Citracleen®, Recordati S.p.A, Milan, Italy) with cold water and ingesting the solution after carefully stirring the solution to insure that the sodium picosulfate/magnesium oxide/citric acid combination was dissolved completely;

[0035] 3. ingesting approximately 250 ml of a clear fluid with a 1 g sodium chloride tablet every half hour after ingestion of the sodium picosulfate/magnesium oxide/citric acid combination solution;

[0036] 4. repeating step 3 every half hour until five (5) salt tablets have been ingested over a two and half hour period;

[0037] 5. at approximately five hours prior to the time that the patient's colonoscopy is scheduled, dissolving the contents of a second sachet containing sodium picosulfate/magnesium oxide/citric acid combination (Citracleen®, Recordati S.p.A, Milan, Italy) with cold water and ingesting the solution after carefully stirring the solution to insure that the sodium picosulfate/magnesium oxide/citric acid combination was dissolved completely; and

[0038] 6. repeating steps 3 and 4 until five (5) salt tablets have been ingested over a two and half hour period.

[0039] Upon arrival at the clinic on the day of the colonoscopy, the patient's weight was recorded and blood pressure was taken and recorded and an out-patient colonoscopy was performed on each patient (North York Endoscopy Centre Inc., Toronto, Ontario, CA). The quality of the colon cleaning was assessed using the Boston Scale which is a well-established way of identifying the degree of colon cleanliness.

[0040] After the colonoscopy was completed, each patient was given a urine collection container and instructed to collect their urine for the following twenty four (24) hours and return the collected urine to the clinic for analysis.

Patient Case Studies

[0041] Patient #2 is a 72 year old Caucasian male with a medical history of diverticulitis, arthritis, sleep apnea, fatty live disease and distal abnormal aortic ectasia as well as having epidermal cysts removed and surgery on the patient's right hand. The patient takes a daily multi-vitamin as well as Advil® PM for body aches and pains. He was diagnosed as needing a colonoscopy by his treating physician. At the time of information intake, the patient's weight was recorded as 109.5 kg and his blood pressure recorded at 155/90 mmHg. The patient was given bowel cleaning preparation medications: three bisacodyl pills (Dulcolax®, Boehringer Ingelheim, Ingelheim am Rhein, Germany)), two sachets of picosulfate/magnesium oxide/citric acid combination (Citracleen®, Recordati S.p.A, Milan, Italy) and ten 1 g NaCl tablets, as well as instructions to follow the claimed bowel cleansing method as set forth above.

[0042] On the day of the scheduled colonoscopy, the patient confirmed that he followed the instructions provided and ingested all of the proper amounts of the products given to him at the appropriate times as set forth in the instructions provided to the patient. The patient's blood pressure was taken and recorded as 145/80 mmHg and his weight was recorded at 160.4 kg. After completion of the colonoscopy, the Boston Bowel Preparation score was evaluated at a 9. No adverse events were observed.

[0043] The patient was given a urine collection container and instructed to collect his urine for the twenty four (24) hour period following the colonoscopy and return the collected urine to the clinic for analysis. The results of the analysis of Patient #2's urinalysis is presented in Table 1:

TABLE-US-00001 TABLE 1 Patient #2 Urine Analysis Results REFER- TEST NAME ENCE TEST 24 HR URINE RESULT FLAG RANGE UNITS LOC. TOTAL VOLUME 2.80 L/day 10 CREATININE 6.2 3.5-24.5 mmol/L CONCENTRATION CREATININE 17.4 7.8-20.0 mmol/ PER DAY day SODIUM 65 mmol/L CONCENTRATION SODIUM PER DAY 182 40-220 mmol/ day

[0044] Patient #3 is a 45 year old African American female with a medical history of diabetes mellitus type IL, hyperthyroidism, obstructive sleep apnea, fatty liver disease, osteoarthritis of the right knee as well as undergoing a thyroidectomy, oophorectomy and a total hysterectomy. The patient also reported abdominal pain and melena on occasion. She takes 1000 mg metformin and 0.175 levothyroxine daily. She was diagnosed as needing a colonoscopy by her treating physician. At the time of information intake, the patient's weight was recorded as 97.0 kg and her blood pressure recorded at 180/100 mmHg. The patient was given bowel cleaning preparation medications: three bisacodyl pills (Dulcolax®, Boehringer Ingelheim, Ingelheim am Rhein, Germany)), two sachets of picosulfate/magnesium oxide/citric acid combination (Citracleen®, Recordati S.p.A, Milan, Italy) and ten 1 g NaCl tablets, as well as instructions to follow the claimed bowel cleansing method as set forth above.

[0045] On the day of the scheduled colonoscopy, the patient confirmed that she followed the instructions provided and ingested all of the proper amounts of the products given to her at the appropriate times as set forth in the instructions provided to the patient. The patient's blood pressure was taken and recorded as 150/99 mmHg and her weight was recorded at 97.0 kg. After completion of the colonoscopy, the Boston Bowel Preparation score was evaluated at a 9. No adverse events were observed.

[0046] The patient was given a urine collection container and instructed to collect her urine for the twenty four (24) hour period following the colonoscopy and return the collected urine to the clinic for analysis. The results of the analysis of Patient #2's urinalysis is presented in Table 2:

TABLE-US-00002 TABLE 2 Patient #3 Urine Analysis Results REFER- TEST NAME ENCE TEST 24 HR URINE RESULT FLAG RANGE UNITS LOC. TOTAL VOLUME 1.00 L/day 10 CREATININE 16.0 2.5-20.0 mmol/L CONCENTRATION CREATININE 16.0 5.5-17.5 mmol/ PER DAY day SODIUM 194 mmol/L CONCENTRATION SODIUM PER DAY 194 40-220 mmol/ day

[0047] Patient #4 is a 28 year old Caucasian male with a medical history of abdominal pain, left varicocele, genital warts and an allergy to eggs as well as having planter warts removed and acromioclavicular joint surgery. The patient did not report taking any concomitant medications. He was diagnosed as needing a colonoscopy by his treating physician. At the time of information intake, the patient's weight was recorded as 79.0 kg and his blood pressure recorded at 120/70 mmHg. The patient was given bowel cleaning preparation medications: three bisacodyl pills (Dulcolax®, Boehringer Ingelheim, Ingelheim am Rhein, Germany)), two sachets of picosulfate/magnesium oxide/citric acid combination (Citracleen®, Recordati S.p.A, Milan, Italy) and ten 1 g NaCl tablets, as well as instructions to follow the claimed bowel cleansing method as set forth above.

[0048] On the day of the scheduled colonoscopy, the patient confirmed that he followed the instructions provided and ingested all of the proper amounts of the products given to him at the appropriate times as set forth in the instructions provided to the patient. The patient's blood pressure was taken and recorded as 121/74 mmHg and his weight was recorded at 79.2 kg. After completion of the colonoscopy, the Boston Bowel Preparation score was determined to be a 10. No adverse events were observed.

[0049] The patient was given a urine collection container and instructed to collect his urine for the twenty four (24) hour period following his colonoscopy and return the collected urine to the clinic for analysis. The results of the analysis of Patient #4's urinalysis is presented in Table 3:

TABLE-US-00003 TABLE 3 Patient #4 Urine Analysis Results REFER- TEST NAME ENCE TEST 24 HR URINE RESULT FLAG RANGE UNITS LOC. TOTAL VOLUME 1.60 L/day 10 CREATININE 9.2 3.5-24.5 mmol/L CONCENTRATION CREATININE 14.7 7.8-20.0 mmol/ PER DAY day SODIUM 37 mmol/L CONCENTRATION Test repeated and results confirmed. SODIUM PER DAY 59 40-220 mmol/ day

[0050] Patient #5 is a 58 year old Caucasian female with a medical history of constipation, hemorrhoids, recurrent rectal bleeding, recurrent colonic polyps, fatty liver disease, osteopenia, osteoporosis, dyslipidemia, anxiety, varicose veins and diabetes mellitus type II. The patient takes 90 mgs of duloxetine daily and Dulcolax® as needed. She was diagnosed as needing a colonoscopy by her treating physician. At the time of information intake, the patient's weight was recorded as 65.6 kg and her blood pressure recorded at 130/75 mmHg. The patient was given bowel cleaning preparation medications: three bisacodyl pills (Dulcolax®, Boehringer Ingelheim, Ingelheim am Rhein, Germany)), two sachets of picosulfate/magnesium oxide/citric acid combination (Citracleen®, Recordati S.p.A, Milan, Italy) and ten 1 g NaCl tablets, as well as instructions to follow the claimed bowel cleansing method as set forth above.

[0051] On the day of the scheduled colonoscopy, the patient confirmed that she followed the instructions provided and ingested all of the proper amounts of the products given to her at the appropriate times as set forth in the instructions provided to the patient. The patient's blood pressure was taken and recorded as 114/66 mmHg and her weight was recorded at 66.4 kg. After completion of the colonoscopy, the Boston Bowel Preparation score was determined to be a 9. No adverse events were observed.

[0052] The patient was given a urine collection container and instructed to collect her urine for the twenty four (24) hour period following her colonoscopy and return the collected urine to the clinic for analysis. The results of the analysis of Patient #5's urinalysis is presented in Table 4:

TABLE-US-00004 TABLE 4 Patient #5 Urine Analysis Results REFER- TEST NAME ENCE TEST 24 HR URINE RESULT FLAG RANGE UNITS LOC. TOTAL VOLUME 1.00 L/day 10 CREATININE 6.1 2.5-20.0 mmol/L CONCENTRATION CREATININE 6.1 5.5-17.5 mmol/ PER DAY day SODIUM 64 mmol/L CONCENTRATION SODIUM PER DAY 64 40-220 mmol/ day

Kits

[0053] This disclosure also provides kits for conveniently and effectively implementing the methods disclosed herein. Such kits comprise any subject composition, and a means for facilitating compliance with methods disclosed herein. Such kits provide a convenient and effective means for assuring that the subject to be treated self-administers the appropriate active in the correct dosage in the correct manner. The compliance means of such kits includes any means which facilitates administering the actives according to a method disclosed herein. Such compliance means include instructions, packaging, and dispensing means, and combinations thereof. Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods. In other embodiments involving kits, the disclosure contemplates a kit including compositions disclosed herein, and optionally instructions for their use.

EQUIVALENTS

[0054] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0055] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. The terms “comprises,” “comprising,” “has”, “having,” “includes”, “including,” “contains”, “containing” or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises, has, includes, contains a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. An element proceeded by “comprises . . . a”, “has . . . a”, “includes . . . a”, “contains . . . a” does not, without more constraints, preclude the existence of additional identical elements in the process, method, article, or apparatus that comprises, has, includes, contains the element. The terms “a” and “an” are defined as one or more unless explicitly stated otherwise herein. The terms “substantially”, “essentially”, “approximately”, “about” or any other version thereof, are defined as being close to as understood by one of ordinary skill in the art, and in one non-limiting embodiment the term is defined to be within 10%, in another embodiment within 5%, in another embodiment within 1% and in another embodiment within 0.5%.

[0056] The above discussion is meant to be illustrative of the principle and various embodiments of the present invention. Numerous variations and modifications will become apparent to those skilled in the art once the above disclosure is fully appreciated. It is intended that the following claims be interpreted to embrace all such variations and modifications.