DK167340B1 - APPLICATION OF QUATERNARY DERIVATIVES OF NOROXYMORPHONE FOR THE PREPARATION OF MEDICINAL PRODUCTS THAT REMOVE NURSES AND VESSELS - Google Patents

Description

DK 167340 B1

The administration of therapeutic doses of morphine or other clinically useful narcotic analgesics (analgesics) is often accompanied by unpleasant side effects to the gastrointestinal system. Eg. For example, morphine and related opiates such as meperidine and methadone may delay intestinal mobility by causing contractions of the small intestine's circular smooth muscle.

Morphine and related drugs can also cause nausea and increased mobility of the gastrointestinal tract, resulting in vomiting. These side effects are elicited by direct stimulation of the chemoreceptor trigger zone for emesis in the medulla postrema area. (Goodman and Bilman, The Pharmacological Basis of Therapeutics, p. 502 [6th ed. 1980]. Studies have shown that morphine and other drugs induce vomiting in dogs. For example, Wang and Glaviano, JPET 111: 329- 334 (9143) that administration of 0.5 mg / kg of morphine intravenously to 12 dogs caused vomiting in 9 dogs over an average of 2.4 minutes to 20 minutes (mg / kg refers to mg of morphine per kg of body weight).

When 1.0 mg / kg morphine was administered intramuscularly to 13 dogs, 12 of them vomited over an average of 3.5 minutes.

U.S. Patent No. 4,176,186 discloses the treatment of intestinal motility associated with the use of narcotic analgesics in the administration of quaternary noroxymorphone derivatives. It has now been found that the same compounds are also useful in the treatment, both prophylactic and therapeutic, of nausea and vomiting associated with the administration of these drugs.

According to the invention, therefore, nausea and vomiting in warm-blooded animals receiving morphine and related opiates, meperidine, methadone or the like, can be prevented or undone by using methylnaltrexone or other quaternary derivatives of noroxymorphone represented by formula DK 167340 B1 2 f

—A / * ch3 χθ J OH

Wherein H is allyl or a related radical such as chlorallyl, cyclopropylmethyl or propargyl, and X is the anion of an acid, especially a chloride, bromide, iodide or a methylsulfate anion, to produce a drug.

Thus, the invention relates to an application as claimed in claim 1. Suitable embodiments of this use are set forth in claims 2-5.

The said compositions are administered to the animal one before or simultaneously with the administration of the narcotic analgesic. They can be formulated for either enteral or parenteral use. No interaction with the analgesic activity of the opiates has been found.

As used herein, except as otherwise indicated by the use, the term "morphine" refers to any narcotic analgesic.

The compounds are synthesized as described in 30 U.S. Patent No. 4,176,186. A particularly preferred noroxymorphone derivative is methylnaltrexone, but other compounds represented by the above formula are also suitable.

Methylnaltrexone or other noroxymorphone derivatives can be administered to the patient either enterally or parenterally. However, a preferred method of administration DK 167340 B1 3 is injection. Nausea and vomiting may occur after only a single dose of morphine, contrary to intestinal motility, which is usually caused by chronic repeated use of the drug. Therefore, it is considered that the patient is given an injection of methylnaltrexone before operative treatment or on another occasion when morphine is used to treat acute pain.

As illustrated by the following controls and examples, our studies show that methylnaltrexone prevents vomiting when administered either with morphine or before the morphine is administered. It is believed that methylnaltrexone or other quaternary noroxymorphine derivatives can be administered up to 2 hours prior to administration of morphine, but the duration may be different. In our studies, methylnaltrexone was administered intramuscularly by syringe. Methylnaltrexone may also be administered enterally or parenterally by other means. It has been found effective at doses of 0.05 mg / kg to about 1.0 mg / kg 20 for each 1 mg / kg of morphine administered. It was found effective when administered in the same syringe as morphine, and also when administered up to about 1 hour before the administration of morphine.

The effect of methylnaltrexone with respect to full 25 preventing the vomiting effect of morphine is elucidated herein. The unit mg / kg refers to mg of the substance administered per day. kg body weight.

J CONTROL 1 AND EXAMPLE 1 A mg / kg morphine was administered intramuscularly to 5 dogs. Four dogs vomited. In each case, the vomiting occurred within 4 minutes. Another day, the same dose of morphine was administered intramuscularly to the same 5 dogs in the same syringe 35 with in mg / kg methylnaltrexone. None of the dogs vomited.

DK 167340 B1 4 CHECK 2 AND EXAMPLE 2

Six dogs received an intramuscular dose of 1 mg / kg morphine. All six dogs vomited. Another day, the same dose of morphine was combined with 0.5 mg / kg of methyl-5 naltrexone and administered in the same syringe to the same dogs. None of the dogs vomited.

CHECK 3 AND EXAMPLE 3

One mg / kg morphine was administered intramuscularly to three dogs. All three dogs vomited. Another day, the morphine was combined with 0.25 mg / kg of methylnal-trexone and administered in the same syringe. None of the dogs vomited.

CHECK 4 AND EXAMPLE 4

Methylnaltrexone was administered to two dogs before the administration of 1 mg / kg morphine. In a dog, 0.5 mg / kg methylnaltrexone was administered intramuscularly 15 minutes before morphine. No 20 vomiting occurred. In the other dog, the same dose of methylnaltrexone was administered 30 minutes before morphine administration. There was no vomiting.

CHECK 5 AND EXAMPLE 5 0.05 mg / kg of methylnaltrexone was administered intravenously to four dogs one minute before the administration of 1.0 mg / kg of morphine. None of the dogs vomited.

On another day, the same animals received 1.0 mg / kg morphine without methylnaltrexone administration. All four dogs vomited-30.

The administration of methylnaltrexone alone was not found to produce any noticeable effect on the animals. Previous studies with higher doses of methylnaltrexone have shown that, in contrast to the non-quaternary naltrexone, methylnaltrexone does not accelerate withdrawal systems in morphine-tolerant dogs. Russell et al.,

Claims (5)

5 PATENT REQUIREMENTS Use of a compound of the formula f 10 Γ-UcMs / OH 15 m 0 wherein R is allyl or a related radical such as chlorallyl, cyclopropylmethyl or propargyl, and X is the anion of an acid, especially a chloride, bromine, iodide or a methyl sulfate anion, for the preparation of a pharmaceutical composition for preventing or alleviating nausea and vomiting associated with the use of narcotic analgesics in warm-blooded animals. Use according to claim 1, characterized in that the composition is in unit dosage form for administration to the animal in an amount between 0.05 mg / kg and about 1.0 mg / kg of the compound. Use according to claim 1, characterized in that the composition is formulated for enteral administration. Use according to claim 1, characterized in that the composition is formulated for parenteral administration, preferably administration by injection DK 167340 B1. Use according to claim 1, characterized in that the compound is methylnaltrexone.