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Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids

a technology of endogenous opioids and methylnaltrexone, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocides, etc., can solve the problems of pruritus, or itching, and the use of opioids is associated with a number of undesirable side effects, and may be very sever

Inactive Publication Date: 2009-12-17
FOSS JOSEPH F +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Opioids are effective analgesics, however, their use is associated with a number of undesirable side effects.
One of these side effects is pruritus, or itching.
Pruritus is a common side effect associated with the use of opioids and may be very severe.
Additionally, the use of antihistamines, when effective, only treats the symptom after it has occurred, rather than preventing its occurrence.
Another undesirable side effect of opioids is urinary retention, or the patient's inability to spontaneously empty his or her bladder.
However, due to the side effects of cholinergic drugs, catheterization of the bladder with a tube to drain urine remains the mainstay of treatment.
Many subjects, especially those without pain, report unpleasant psychomimetic responses to the administration of an opioid alone.
These drugs, however are associated with increased levels of sedation and may enhance respiratory depression caused by the opioid.
However, naltrexone, naloxone and other opioid antagonists also reduce the analgesic effect of the opioid being used.
Since these quaternary opioid antagonist derivatives do not cross the blood-brain-barrier, peripheral administration of these antagonists would not be expected to be effective in the treatment of an opioid induced side effect caused by the opioid within the central nervous system.
However, injection of drugs directly into the central nervous system is undesirable since it increases the possibility of introducing bacterial or viral contamination to the central nervous system.

Method used

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  • Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0037]Ten patients were treated with morphine sulfate administered directly to the central nervous system or intravenously. The morphine sulfate was administered at 0.1 mg / kg body weight. The patients in the study had been treated for pain resulting from surgery. All the patients exhibited pruritus as a side effect of the morphine sulfate administration. Subsequent to the onset of the pruritus, methylnaltrexone, at a dosage of 0.3 mg / kg of body weight was administered intravenously as a saline solution containing methylnaltrexone in a concentration of 5 mg / ml to each of the patients. Eighty percent of the 10 patients exhibited relief from the pruritus sixty minutes after receiving methylnaltrexone.

[0038]In a control group, 8 patients were treated with morphine sulfate administered directly to the central nervous system or intravenously. The morphine sulfate was administered at 0.1 mg / kg body weight. The patients in the study had been treated for pain resulting from surgery. All the ...

example 2

Efficacy of Enteric Coating of Methylnaltrexone

[0040]Morphine (0.05) mg / kg intravenous) was administered to three volunteers after the oral administration of placebo, methylnaltrexone (6.4 mg / kg) in a gelatin capsule (which dissolves readily in the stomach), or methylnaltrexone after enteric coating (12.8 mg / kg of substance to yield a mass of 6.4 mg / kg methylnaltrexone incorporated) which has decreased release and absorption in the stomach. Oral-cecal transit time was measured using the lactulose-hydrogen breath test. Plasma levels of methylnaltrexone were measured and after the enteric coated preparation were lower. In each subject morphine alone increased the oral-cecal transit time by 20-70 minutes, methylnaltrexone blocked this effect, and enteric coated methylnaltrexone blocked the effect to a similar or greater extent than the uncoated methylnaltrexone.

example 3

Enhancement of Enteric Feeding

[0041]Two patients receiving morphine (375 mg / day and 18 mg / day) and receiving enteric tube feedings of 200 ml every four (4) hours were studied. The first patient had residual stomach contents of 50 cc to 100 cc, or 22.0-58.8% of administered feedings measured every 4 hours during a 24 hour control period. Prior to drug administration the residual volume had increased to 260 cc or >100% of previous feeding volume. Methylnaltrexone, 0.45 mg / kg, was administered intravenously every 4 hours for 24 hours, after the control period. After the first dose (4 hours) of MNTX, the residual was 150 cc or 58% of the previous bolus feed, after the 3rd dose (12 hours) the residual was 75 cc or 30% of the previous feed, after the 5th dose (20 hours) the residual was 22 cc or 13% of the previous feed and after the 6th and final dose (24 hours) the residual was 8 cc or 5.5% of previous feed. The follow-up residual sampling after the final drug-tube feed interval had inc...

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Abstract

A method of for preventing or treating gastrointestinal dysfunction and constipation caused by endogenous opioids in a patient who has been chronically taking opioids. The method comprises administering methylnaltrexone or another quaternary derivative of noroxymorphone most preferably by parenteral, intramuscular, intravenous or oral route.

Description

RELATED APPLICATIONS[0001]This application is a continuation of application Ser. No. 10 / 779,129, filed Feb. 12, 2004, now pending; which is a continuation of application Ser. No. 10 / 278,630, filed Oct. 23, 2002, abandoned; which is a divisional of application Ser. No. 09 / 862,169, filed May 21, 2001, now U.S. Pat. No. 6,608,075; which is a continuation of application Ser. No. 09 / 120,703, filed Jul. 22, 1998, now U.S. Pat. No. 6,274,591; which is a continuation-in-part of application Ser. No. 08 / 962,742, filed Nov. 3, 1997, now U.S. Pat. No. 5,972,954, the entire contents of each of which are herein incorporated by reference.GOVERNMENT SUPPORT[0002]This invention was made with government support under M01 RR00055 awarded by the National Institute of Health. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention is directed at the treatment of certain side effects associated with the use of opioids as analgesics. In particular the present i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/485
CPCA61K31/485A61P1/00
Inventor FOSS, JOSEPH F.ROIZEN, MICHAEL F.MOSS, JONATHANYUAN, CHUN-SUDRELL, WILLIAM
Owner FOSS JOSEPH F
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