JP2625457B2 - Drugs to prevent or reduce nausea or vomiting - Google Patents

Description

BACKGROUND OF THE INVENTION The administration of therapeutic amounts of morphine and other clinically useful narcotic analgesics is often accompanied by unpleasant side effects of the gastrointestinal system.
For example, morphine and related opiates, such as meparidine and methadone, can interfere with intestinal mobility by causing contraction of small intestinal circulatory smooth muscle.

Also, morphine and related anesthetics can cause nausea and increased mobility in the gastrointestinal tract, resulting in vomiting. These side effects are caused by direct stimulation of the chemoreceptor trigger zone for vomiting in the last area of the medulla. [Goodman and Bilman pharmacolo
Zical Basis of Serapeutics (Pharmacol)
ogical Basis of Therapeutics , p.502 (6th edition, 198
0 year edition)]. Studies have shown that morphine and other anesthetics cause vomiting in dogs. See, for example, JPET Vol. 111, Nos. 329-33 by Wang and Glaviano.
On page 4 (9143), when morphine was administered intravenously at a dose of 0.5 mg / kg to 12 dogs, 9 dogs vomited within an average of 2.4 minutes. (Mg / kg refers to milligrams of morphine per kg body weight). When 1.0 mg / kg morphine was administered intramuscularly to 13 dogs, 12 of those dogs vomited within an average of 3.5 minutes.

SUMMARY OF THE INVENTION Our U.S. Pat. No. 4,176,186 discloses a method of treating intestinal fixation associated with the use of an anesthetic analgesic by administration of a quaternary derivative of noroxymorphone. It has now been found that the same compounds are also useful for the prophylactic and therapeutic treatment of nausea and vomiting associated with the administration of these drugs.

According to the present invention, there is provided a medicament for preventing or reducing nausea or vomiting associated with the use of sickness analgesics such as morphine and related opiates, meparizine and methadone in warm-blooded animals. (Wherein R is allyl, chloroallyl, cyclopropyl-
Is a methyl or propargy group, and X is an anion of an acid). Preventing or reducing nausea or vomiting associated with the use of an anesthetic analgesic in a warm-blooded animal containing at least one compound represented by the following formula: A drug is provided. Preferred examples of x are anions selected from the group consisting of chlorine anion, bromine anion, iodine anion and methyl sulfate anion.

Methylnaltrexone represented by the above general formula (R in the above general formula is a cyclopropyl-methyl group) or other quaternary derivative of noroxymorphone is administered before or simultaneously with the administration of an anesthetic analgesic. Administer to animals.
The compounds described above can be administered enterally or parenterally. No interruption of the analgesic activity of the opiates by the above-mentioned compounds was observed.

As used herein, the term "morphine" refers to an anesthetic analgesic unless otherwise indicated.

DETAILED DESCRIPTION The present invention relates to quaternary derivatives of noroxymorphone for preventing or reducing nausea and vomiting associated with the administration of morphine to warm-blooded animals.

Compounds useful as the above drugs are represented by the following general formula.

Wherein R is an allyl, chloroallyl, cyclopropyl-methyl or propargyl group and X is an acid anion, in particular a chloride, bromine, iodine or methyl sulfate anion.

The above compounds are synthesized as described in U.S. Pat. No. 4,176,186. A particularly preferred noroxymorphone derivative is methylnaltrexone, but other compounds represented by the above general formula are also suitable.

Methylnaltrexone or other noroxymorphone derivative can be administered to the patient intestinal or parenteral. However, the preferred method of administration is by injection. Even after a single dose of morphine, nausea and vomiting can occur with the drug. However, chronic repeated use of morphine can usually result in intestinal fixation. Thus, when morphine is used to treat severe injuries in surgery or otherwise, it is contemplated to receive an injection of methylnaltrexone prior to administration of morphine.

The present invention shows that methylnaltrexone suppresses vomiting when methylnaltrexone is administered concurrently with or before administration of morphine, as illustrated by the following Controls and Examples. Methylnaltrexone or other quaternary noroxymorphone derivative can be administered up to 2 hours before the administration of morphine. It is contemplated that the period can be varied. In the present invention, methylnaltrexone was administered intramuscularly by syringe. In addition, methylnaltrexone can be administered to the intestine or extraintestinal tract by other means. A dose in the range of about 0.05 mg / kg to about 1.0 mg / kg for each 1 mg / kg of morphine administered has been found to be effective. It has been found to be effective when administered with the same syringe as morphine and when administered up to about 1 hour prior to morphine administration.

The effect of methylnaltrexone for reversing the emetic properties of morphine is described below. The unit mg / kg relates to the number of milligrams of substance administered per kg body weight.

Control Example 1 and Example 1 Morphine 1 mg / kg was intramuscularly administered to 5 dogs. Four dogs vomited. In each case, vomiting occurred within 4 minutes. On different days, the same amount of morphine was administered intramuscularly in the same five dogs with the same syringe, together with 1 mg / kg of methylnaltrexone. No dogs vomited.

Control Example 2 and Example 2 Six dogs were dosed intramuscularly with a dose of 1 mg / kg morphine. All six dogs vomited. One day later, the same amount of morphine was administered to the same dog with the same syringe in combination with 0.5 mg / kg of methylnaltrexone. None of the dogs vomited.

Control Example 3 and Example 3 Three dogs received 1 mg / kg morphine intramuscularly. 3
All of the dogs vomited. 1 day later, morphine 0.25mg / k
g was combined with methylnaltrexone and administered with the same syringe. None of the dogs vomited.

Control Example 4 and Example 4 Methylnaltrexone was administered to two dogs before administration of 1 mg / kg morphine. One dog was given morphine
Fifteen minutes before, 0.5 mg / kg of methylnaltrexone was administered.
There was no vomiting. The second dog received the same amount of methylnaltrexone 30 minutes prior to morphine administration. Vomiting did not occur. On different days, when the same dog received 1.0 mg / kg morphine without methylnaltrexone, both dogs vomited.

Control Example 5 and Example 5 One minute before administration of 1.0 mg / kg morphine, four dogs were administered 0.05 mg / kg of methylnaltrexone intramuscularly. Vomiting did not occur in all dogs. On different days, the same dog received 1.0 mg / kg morphine without methylnaltrexone. All four dogs vomited.

It was found that administration of methylnaltrexone alone had no significant effect on animals. Previous studies using relatively high doses of methylnaltrexone have demonstrated that, unlike naltrexone, which is not quaternary, methylnaltrexone is not a sediment recovery system for morphine-resistant drugs. Was. Eur. Of Russell et al.
J. Pharmacol. 78, 255-261 (1982). Methylnaltrexone was found not to interfere with the analgesic activity of morphine or anesthetic.

Claims (3)

(57) [Claims] (1) a drug for preventing or reducing nausea or vomiting accompanying the use of an anesthetic analgesic in a warm-blooded animal, (Wherein R is allyl, chloroallyl, cyclopropyl-
A methyl or propargy group, and X is an anion of an acid). Preventing or reducing nausea or vomiting associated with the use of an anesthetic analgesic in a warm-blooded animal containing at least one compound represented by the following formula: Drugs to do. 2. The drug according to claim 1, wherein X is selected from the group consisting of chloride anion, bromine anion, iodine anion and methyl sulfate anion. 3. The drug according to claim 1, wherein the compound comprises methylnaltrexone.