NZ237398A

NZ237398A - A synergistic combination of an analgesic and glucagon and its use in the treatment of colic pain

Info

Publication number: NZ237398A
Application number: NZ23739891A
Authority: NZ
Inventors: Jose Picazo Garzaran
Original assignee: Novo Nordisk As
Priority date: 1991-03-12
Filing date: 1991-03-12
Publication date: 1997-06-24

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £37398 237 3 9 8 Priority Date(s): Complete Specification Filad: Class: Publication Date: P.O. Journal No: ... mi NO DRAWINGS Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION A METHOD AND A PHARMACEUTICAL PREPARATION FOR TREATING PAIN WE, NOVO NORDISK A/S, a Danish company of Novo Alle, DK-2800, Bagsvaerd, DENMARK hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: N.Z. PATENT OFFICE if 12 MAR 1991 received — 1 — (followed by page la) 237398 ®*e prtitnt invention nlttM to & mthod ud • ph«manfirt[^»i ____________ 5 kit suitable for treating pain, especially colic pain such as biliary colic pain. Treating biliary colic pain is extremely difficult as the use of opiates is undesirable and contraindicated due to their spasmogenic action on the biliary tract particularly the 10 sphincter of oddi, and thus rather worsen the pain than alleviating the same. According to Jaffe JH, Martin WR, opioid analgesic and antagonists. In: Goodman A, Goodman LS; Gilman A (eds) the Pharmacological Basis of Therapeutics. New York 1980; Macmillan 15 Publishing Co.: 494-534. (Pages 504-505), therapeutic doses of morphine, codeine, and other morphine surrogates, can c*.u-se a marked increase in pressure in the biliary tract. Some patients with biliary colic pain may experience exacerbation and not relief of pain whan given these drugs. Furthermore, 20 em occasional individual complains of pain in the epigastrium or right hypochondrium after morphine, probably due to duodenal or biliary tract spasm. Spasm of the biliary tract produced by morphine is evident roentgenographically as well as manometrically, and a sharp constriction becomes apparent at 25 the lower end of the common bile duct (sphincter of Oddi). this spasm prevents emptying and thus causes the intraductal pressure to rise. In Martindale, The Extra Pharmacopoeia. Reynolds JEF (ed). 28th edition, London 1982: The Pharmaceutical Press. Pg. 1020 30 this spasmogenic action of opiates (morphine and morphinelike substances) is also pointed out. 3595.500/KMf l/AMu/1991-Q3-01 N.Z. P/VTSiHT ">r r r r It 1332 (followed by page 2£ 2 57 3 9 8 2 Other therapeutic approaches have been the use of anticholinergic agents as spasmolytic substances, which have been widely employed but on an empirical basis, because there is no conclusive evidence that they are efficient. 5 Glucagon has been shown to be efficient in relieving biliary colic pain in several open (Paul F, The role of glucagon in the treatment of biliary tract pathology. In: Picazo J (ed) Glucagon in Gastroenterology. Lancaster 1979; MTP Press: 107-120; Brandstatter G, Kratochvil P, Glukagon Bei Gallenkoli-10 ken. Therapiewoche 1979; 29:3362-3365), and controlled (Hard-castle JD, Stower MJ, Foster GE, The use of glucagon in spastic disorders of the gastrointestinal tract. In: Picazo J (ed) Glucagon in Gastroenterology and Hepatology. Pharmacological, Clinical, and Therapeutic Implications. Lancaster 15 1982; MTP Press: 115-125; Stower MJ, Foster GE, Hardcastle JD, A trial of glucagon in the treatment of biliary tract disease. Br J. Surg 1982; 69:591-592; Grossi E, Broggini M, Quaranta M, Balestrino E, Different pharmacological approaches to the treatment of acute biliary colic. Curr Ther Res 20 1986; 40:876-882) studies, but the relief of pain is not as immediate as it would be desirable. The same thing applies to the results obatined with the use of prostaglandin synthesis inhibitors, i.e. diclofenac sodium (Grossi et al., ibid). Glucagon is known to reverse the biliary spasm induced by 25 narcotics in man (Bordley J, Olson JE, The use of glucagon in operative cholangiography. Surg Gynecol Obstet 1979; 149:-583-584; Jones RM, Fiddian-Green R, Knight PR, Narcotic-induced choledochoduodenal sphincter spasm reversed by glucagon. Anesth Analg 1980: 59:946-947; Jones RM, Coultas RJ, 30 Pollard BJ, Waterland JW, REversal of biliary sphincter spasm with low dose Glucagon during operative cholangiopraphy. Anaesth Intens Care 1983; 11:174-175; McCammon RL, Stoelting R, Madura JA, Reversal of fentanyl induced spasm of the sphincter Oddi. Surg Gynecol obstet 1983; 156:329-324; and Seta- 3595.500/Kim/A«Hu/1991 *03-01 237398 3 kis N, Economou J, Ritsi N, Konidis A, Georgiadis N, Andoniou G, Effect of cimetidine, glucagon, propantheline bromide, morphine, pethidine, naloxone, ethyl alcohol on sphincter of Oddi (Abst). Gut 1990; 31: A488). McCammon et al. have demon-5 strated this by radiomanometric methods and Carr-Locke and Gregg by endoscopic manometry. According to Carr-Locke DL, Glucagon and the human biliary tree. In: Picazo J (ed) Glucagon in 1987. Gastrointestinal and Hepatobiliary Physiology, Diagnosis and Treatment. Lancaster 1987; MTP Press: 67-86 10 (Pages 76-79, 85), as an inhibitor of gastrointestinal motility, glucagon would seem to have opposing effects to opiates, i.e., morphine. In his study, the spasm induced by the intravenous administration of 5 mg morphine was reversed 2 minutes after the intravenous injection of 1 mg Glucagon. 15 This suggests that morphine and glucagon either share a common receptor site or some common pathway of smooth muscle cell control perhaps through their known effects in intracellular cyclic nucleotides. All the above evidence explains why use of analgesics is to a 20 certain extent contraindicated for treatment of biliary colic pain. However, due to the high efficient analgesic effect of opioides it is very desirable to have the possiblity to utilize this effect in relieving the pain in patients suffering from biliary colic pain. Accordingly, in one aspect, this invention provides a pharmaceutical kit suitable for use in the relief of colic pain in a mammal/ the kit comprising an amount of a narcotic sufficient to have an analgesic effect and formulated for administration to the mammal: and a synergistically effective amount of a glucagon to relieve pain and. spasms caused by the narcotic without blocking the analgesic effect of the narcotic, and formulated for administration to the mammal. 3595.500/1011 t/A»H*j/1991-03-01 JNT 0-t;F(C3 26 MAR 1992 4 - 237398 The invention also provides a method of relieving colic p»*r» comprising administering to a subject suffering from the pain an amount of a narcotic affective to relieve the pain an amount of glucagon effective to relieve pain and spasms induced by the narcotic without blocking the analgesic effect of the narcotic. The method is preferably used to treat acuta biliary colic pain as it has been indicated that administration of glucagon together with a narcotic releases the narcotic-induced spasm without blocking the analgesic effect of the narcotic, and a quick relief of the pain can be obtained. It has been alleged that in combination with surgery, glucagon may be used to reverse the spasms of the sphincter of Oddi without counteracting the analgesic effect of narcotics (McCammon et al., 1983 and Carr-Locke, 1987) but there is no experimental support of the allegations. According to the present invention it has been shown that glucagon reverses the spasaogenic effect of opioids without blocking their analgesic effect opening far the use thereof for treating biliary colic pain, and thus a quick relief of the pain can be achieved. (followed, by page 4a) l : zr- 26 MAP 1332 N.Z. PATE." RECEIVD — 4a — 237398 The narcotics which may be used in accordance with the present invention are analgetica e.g. opiates such as morphine, nicomorphine, fentanyl, mepiridine, alfentanile, pethidine, ketobemidon, dextromoramide, or methadone. When working the method of the invention, glucagon and the narcotic may be given in a conventional manner for giving analgesic treatment, e.g. in the form of injection of a preparation as described herein reconstituted in a suitable vehicle for parenteral administration as is conventionally used for the administration of the drug in question. (followed by page 5) N.2. PATENT '•; 26 MAP. j </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 237398 ■ 5 According to the invention the glucagon and the narcotic are given in the form of separate preparations after each other and it is preferred to give the glucagon first and then the narcotic to avoid the spasmogenic effect of the narcotic. In another aspect, this invention provides a method of preparing medication suitable for use in the relief of colic pain in a mammal, comprising selecting and providing a dosage of a narcotic that is effective to relieve the pain; selecting and providing a dosage of glucagon that is synergistically effective in releasing narcotic-induced pain and spasms without blocking the analgesic effect of the narcotic; combining the narcotic with pharmaceutical carriers suitable for administering the narcotic; and combining the glucagon with pharmaceutical carriers suitable for administering the glucagon. 20 The glucagon used in accordance with the present invention is preferably human glucagon and may be derived from a natural source, i.e. being extracted and purified from pancreas, or prepared using genetically transformed microorganisms, preferably yeast, e.g. as described in EP A 189,998. The gluca-25 gon is preferably pure so as to yield a single major band on a polyacryl amide gel. The preparations of comprising glucagon and a narcotic, respectively, to be used according to the present invention may have a composition and be prepared in a manner known per se 30 for the preparation of corresponding known preparations. 3595.500/KNf l/AaHu/1991-03-01 -6- 237398 WHAT WE CLAIM IS:

1. A pharmaceutical kit suitable for use in the relief of colic pain in a mammal, the-kit comprising an amount of a narcotic sufficient to have an analgesic effect curd formulated for administration to the mammal; and a synergistically effective amount of a glucagon to relieve pain and spasms caused by the narcotic without blocking the analgesic effect of the narcotic, and formulated for administration to the mammal.

2. A kit according to claim 1 in which the narcotic and the glucagon are each formulated for parenteral administration.

3. A kit according to claim 1 or claim 2 in which the narcotic is morphine, nicomorphine, fentanyl, mepiridine, alfentanlie, pethidine, ketobemidon, dextromoramide or methadone.

4. A method of preparing medication suitable for use in the relief of colic pain in a mammal, comprising selecting and providing a dosage of a narcotic that is effective to relieve the pain; selecting and providing a dosage of glucagon that is synergistically affective in releasing narcotic—induced paint and spasms without blocking the analgesic effect of the narcotic; combining the narcotic with pharmaceutical carriers suitable for administering the narcotic; and combining the glucagon with, pharmaceutical carriers suitable for admi nisfterf ng the glucagon*;5. A method according to claim 4 in which the narcotic and the glucagon are each formulated for parenteral administration.;5. A method according to claim 4 or claim 5 in which the narcotic is morphine, nicomorphine, fentanyl, mepiridine, alfentanile, pethidine, ketobemidon, dextromoramide or methadone.;7. A method according to any one of claims 4-6, in which the pain is biliary colic pain.;DISK A/S RNEYS ON & CAREY;END OF CLAIMS;i * I J 3 APR 1397 J ... ....... i </div>