Methylnaltrexone (MNTX, brand name Relistor), used in form of methylnaltrexone bromide (INN, USAN, BAN), is a medication that acts as a peripherally acting μ-opioid receptor antagonist that acts to reverse some of the side effects of opioid drugs such as constipation without significantly affecting pain relief or precipitating withdrawals. Because MNTX is a quaternary ammonium cation, it cannot cross the blood–brain barrier, and so has antagonist effects throughout the body, counteracting effects such as itching and constipation, but without affecting opioid effects in the brain such as pain relief.[6] However, since a significant fraction (up to 60%) of opioid analgesia can be mediated by opioid receptors on peripheral sensory neurons, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain,[7] MNTX may increase pain under such circumstances.
Methylnaltrexone is a peripheral acting mu-opioid receptor antagonist, and does not cross the blood brain barrier.[9] Methylnaltrexone has restricted access through the blood brain barrier because it is a quaternary amine, which carries a positive charge when in a solution and more has polarity with lower lipid solubility than a lot of the opioid agonists used for pain treatment.[10] The peripheral action of methylnaltrexone makes it effective for decreasing the constipating effects of opioids, without interfering with the analgesic effects (of opioids) on the central nervous system.[10] This is the primary characteristic that makes methylnaltrexone behave differently than naltrexone.[11]
Furthermore, as methylnaltrexone cannot cross the blood–brain barrier, it does not reverse the pain-killing properties of opioid agonists or cause withdrawal symptoms, but since a small portion of analgesia comes from the peripheral opioid receptors, it can increase pain from inflammatory conditions such as arthritis.[citation needed]
Side effectsEdit
The most common side effects for methylnaltrexone include:[8][10]
Abdominal pain
Dizziness
Vomiting
Nausea
Diarrhea
HistoryEdit
In 1978, a dying friend and colleague presented the late University of Chicago pharmacologist Leon Goldberg with a clinical challenge.[12] Struggling with the pain of prostatic cancer that had metastasized to his bones, the man was now declining the morphine he required for analgesia because of constipation. Research on opioids which would target only the sub-types of receptors associated with pain relief and not with side effects had seen little success outside of in-vitro models. Considering drugs such as loperamide, which acted on the opioid receptors in the gut without acting on the central nervous system, Goldberg proposed a targeted opioid receptor antagonist.[13]
Thousands of opioid-like molecules had been synthesized by pharmaceutical companies looking for the better analgesic - and many of those with no pain-relieving properties had been shelved. Screening these compounds led to the examination of putative antagonists which when modified had properties that suggested they might not readily cross the blood–brain barrier based on their size and charge. One of these compounds, N-methyl-naltrexone (MNTX), was amongst a group of compounds synthesized by Boehringer Ingelheim.[14] The compound looked promising and passed initial screening in which rodents were given opioids along with charcoal meals to track GI transit, and were tested for analgesia.[15] In a 1982 paper by Russell et al., it was first reported that the GI effects of the opioids could be prevented without affecting centrally mediated analgesia in this model.[16] Subsequent preclinical studies also demonstrated this separation of central and peripherally mediated opioid effects for other smooth muscles of the GI tract and the cough reflex.[17][18] Interest also developed in the potential for MNTX to act at the chemoreceptor trigger zone and block the emetic effect of opioids. This blockade of opioid-induced emesis was demonstrated in a canine model.[19][20] Goldberg died before he could see the core of this idea come into clinical practice.
Research on methylnaltrexone continued in the Department of Anesthesiology and Critical Care at the University of Chicago through the 1990s. More recent investigations, however, discovered opioid receptors on peripheral sensory neurons.[21]
In December 2005, Wyeth and Progenics entered into an exclusive, worldwide agreement for the joint development and commercialization of methylnaltrexone for the treatment of opioid-induced side effects, including constipation and post-operative ileus (POI), a prolonged dysfunction of the gastrointestinal tract following surgery. Under the terms of the agreement, the companies are collaborating on worldwide development. Wyeth received worldwide rights to commercialize methylnaltrexone, and Progenics retained an option to co-promote the product in the United States. Wyeth will pay Progenics royalties on worldwide sales and co-promotion fees within the United States.
Methylnaltrexone is being developed in subcutaneous and oral forms to treat opioid induced constipation (OIC).
The use of methylnaltrexone (Relistor) for more than 4 months has not been studied.[22]
Society and cultureEdit
ApprovalEdit
On April 1, 2008, Progenics and Wyeth announced that Health Canada has approved methylnaltrexone for the treatment of opioid-induced constipation.[23] It was later approved by the US FDA on April 24, 2008.[24][25]
FormsEdit
As of 2010, methylnaltrexone is supplied as an injection in trays containing seven one-dose vials containing 0.6 mL of solution. Each tray also contains seven 12 mm (0.47 in) 1 mL 27 gauge needles with retractable tips, and alcohol wipes for home use. A single vial can treat someone who weighs as much as 115 kilograms (254 lb).[11] For hospital use, vials are available separately.
See alsoEdit
Loperamide - an μ-opioid receptoragonist that doesn't cross the BBB in significant amounts, and treats diarrhea (in contrast to methynaltrexone, a Mu-opioid receptor antagonist that doesn't cross the BBB, avoiding opiate withdrawal effects in patients, while treating constipation)
Naloxegol (trade names Movantik and Moventig) - another peripherally selective opioid antagonist used to treat opioid-induced constipation
(+)-Naloxone - a non-opioid drug which also reduces some side effects of opioids without significantly affecting analgesia when used in small oral doses
6β-Naltrexol (6α-hydroxynaltrexone) - another naltrexone derivative that is also a peripherally selective opioid antagonist
ReferencesEdit
^"Methylnaltrexone (Relistor) Use During Pregnancy". Drugs.com. 9 July 2020. Retrieved 21 September 2020.
^Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). from the original on 2023-08-03. Retrieved 2023-08-16.
^"Relistor Product information". Health Canada. 25 April 2012. Retrieved 6 September 2022.
^"Relistor Product information". Health Canada. 25 April 2012. Retrieved 6 September 2022.
^"Relistor Product information". Health Canada. 25 April 2012. Retrieved 6 September 2022.
^National Prescribing Service (1 March 2010). . Archived from the original on 2010-06-01. Retrieved 12 March 2010.
^Stein C (January 1993). "Peripheral mechanisms of opioid analgesia". Anesthesia and Analgesia. 76 (1): 182–91. doi:10.1213/00000539-199301000-00031. PMID 8380316. S2CID 10113604.
^ ab"Highlights of Prescribing Information - Metylnaltrexone bromide" (PDF).
^Thomas J, Karver S, Cooney GA, Chamberlain BH, Watt CK, Slatkin NE, et al. (May 2008). "Methylnaltrexone for opioid-induced constipation in advanced illness". The New England Journal of Medicine. 358 (22): 2332–2343. doi:10.1056/nejmoa0707377. PMID 18509120.
^ abcRotshteyn Y (11 January 2011). "Methylnaltrexone bromide: research update of pharmacokinetics following parenteral administration". Expert Opinion on Drug Metabolism & Toxicology. 7 (2): 227–235. doi:10.1517/17425255.2011.549824. PMID 21222554. S2CID 24993500.
^ ab"Relistor Full Prescribing Information". Retrieved 2009-05-09.[permanent dead link]
^"Drug developed at the University of Chicago wins FDA approval". University of Chicago News. Retrieved 2019-08-15.
^Moss J (January 2019). "Identifying and Treating Opioid Side Effects: The Development of Methylnaltrexone". Anesthesiology. 130 (1): 142–148. doi:10.1097/ALN.0000000000002428. PMID 30277930. S2CID 52908307.
^US patent 3101339, Karl Zeile and Kurt Freter & Freter, Kurt, "Quaternary salts of normorphine and its acylated derivatives", issued 1963-08-20, assigned to C. H. Boehringer Sohn. About Karl Zeile: born 1905. Untersuchungen über häminhaltige Fermente, habilitation treatise, Technische Hochschule, Munich 1933; In 1933 also SS-Member; 1937 NSDAP-Member; ao. (i.e. extra-ordinary) Professor in Göttingen; 1938 Delegate of NS-Dozentenbund; 1942 Prof. Organic Chemistry and biochemistry at Reichsuniversität Straßburg, and military research; after WW II deputy of Science-Dptm at Chemische Fabrik C. H. Boehringer Ingelheim
^US patent 4176186, Goldberg L, Merz H, Stockhaus K, "Quaternary derivatives of noroxymorphone which relieve intestinal immobility", issued 1979-11-27, assigned to Boehringer Ingelheim
^Russell J, Bass P, Goldberg LI, Schuster CR, Merz H (March 1982). "Antagonism of gut, but not central effects of morphine with quaternary narcotic antagonists". European Journal of Pharmacology. 78 (3): 255–61. doi:10.1016/0014-2999(82)90026-7. PMID 7200037.
^Yuan CS, Foss JF, Moss J (March 1995). "Effects of methylnaltrexone on morphine-induced inhibition of contraction in isolated guinea-pig ileum and human intestine". European Journal of Pharmacology. 276 (1–2): 107–11. doi:10.1016/0014-2999(95)00018-G. PMID 7781680.
^Foss JF, Orelind E, Goldberg LI (1996). "Effects of methylnaltrexone on morphine-induced cough suppression in guinea pigs". Life Sciences. 59 (15): PL235-8. doi:10.1016/0024-3205(96)00451-1. PMID 8845013.
^Foss JF, Bass AS, Goldberg LI (August 1993). "Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs". Journal of Clinical Pharmacology. 33 (8): 747–51. doi:10.1002/j.1552-4604.1993.tb05618.x. PMID 8408737. S2CID 217261.
^US patent 4719215, Goldberg LI, "Quaternary derivatives of noroxymorphone which relieve nausea and emesis", issued 1988-01-12, assigned to University of Chicago
^Stein C, Schäfer M, Machelska H (August 2003). "Attacking pain at its source: new perspectives on opioids". Nature Medicine. 9 (8): 1003–8. doi:10.1038/nm908. PMID 12894165. S2CID 25453057.
^. Wyeth. Archived from the original on 2010-08-04. Retrieved 2010-08-12.
^. Archived from the original on 2008-04-11. Retrieved 2008-04-01.
^. Archived from the original on 2008-05-02. Retrieved 2008-04-27.
methylnaltrexone, mntx, brand, name, relistor, used, form, methylnaltrexone, bromide, usan, medication, that, acts, peripherally, acting, opioid, receptor, antagonist, that, acts, reverse, some, side, effects, opioid, drugs, such, constipation, without, signif. Methylnaltrexone MNTX brand name Relistor used in form of methylnaltrexone bromide INN USAN BAN is a medication that acts as a peripherally acting m opioid receptor antagonist that acts to reverse some of the side effects of opioid drugs such as constipation without significantly affecting pain relief or precipitating withdrawals Because MNTX is a quaternary ammonium cation it cannot cross the blood brain barrier and so has antagonist effects throughout the body counteracting effects such as itching and constipation but without affecting opioid effects in the brain such as pain relief 6 However since a significant fraction up to 60 of opioid analgesia can be mediated by opioid receptors on peripheral sensory neurons particularly in inflammatory conditions such as arthritis traumatic or surgical pain 7 MNTX may increase pain under such circumstances MethylnaltrexoneClinical dataTrade namesRelistorOther namesMNTX naltrexone methyl bromideAHFS Drugs comMonographMedlinePlusa608052License dataEU EMA by INN US DailyMed Methylnaltrexone US FDA MethylnaltrexonePregnancycategoryAU B1 1 Routes ofadministrationOral intravenous subcutaneousATC codeA06AH01 WHO Legal statusLegal statusAU S4 Prescription only BR Class C1 Other controlled substances 2 CA only 3 4 5 UK POM Prescription only US only EU Rx onlyPharmacokinetic dataProtein binding11 15 3 MetabolismLiverElimination half life8 hoursExcretionUrine 50 faeces 50 IdentifiersIUPAC name 5a 17 cyclopropylmethyl 3 14 dihydroxy 17 methyl 4 5 epoxymorphinanium 17 ium 6 oneCAS Number916055 93 1 NPubChem CID5361918IUPHAR BPS7563DrugBankDB06800 NChemSpider4514884 YUNII0RK7M7IABEChEMBLChEMBL1186579 NCompTox Dashboard EPA DTXSID30868236ECHA InfoCard100 122 861Chemical and physical dataFormulaC 21H 26N O 4Molar mass356 442 g mol 13D model JSmol Interactive imageSMILES O C6 C H 3Oc1c2c ccc1O C C H 4 C O C 23CC N 4 C CC5CC5 CC6InChI InChI 1S C21H25NO4 c1 22 11 12 2 3 12 9 8 20 17 13 4 5 14 23 18 17 26 19 20 15 24 6 7 21 20 25 16 22 10 13 h4 5 12 16 19 25H 2 3 6 11H2 1H3 p 1 t16 19 20 21 22 m1 s1 YKey JVLBPIPGETUEET GAAHOAFPSA O Y N Y what is this verify Contents 1 Medical uses 2 Mechanism of action 3 Side effects 4 History 5 Society and culture 5 1 Approval 5 2 Forms 6 See also 7 References 8 Further readingMedical uses EditMethylnaltrexone is approved for the treatment of opioid induced constipation in chronic non cancer pain or when ordinary laxatives have failed 8 Mechanism of action EditMethylnaltrexone is a peripheral acting mu opioid receptor antagonist and does not cross the blood brain barrier 9 Methylnaltrexone has restricted access through the blood brain barrier because it is a quaternary amine which carries a positive charge when in a solution and more has polarity with lower lipid solubility than a lot of the opioid agonists used for pain treatment 10 The peripheral action of methylnaltrexone makes it effective for decreasing the constipating effects of opioids without interfering with the analgesic effects of opioids on the central nervous system 10 This is the primary characteristic that makes methylnaltrexone behave differently than naltrexone 11 Furthermore as methylnaltrexone cannot cross the blood brain barrier it does not reverse the pain killing properties of opioid agonists or cause withdrawal symptoms but since a small portion of analgesia comes from the peripheral opioid receptors it can increase pain from inflammatory conditions such as arthritis citation needed Side effects EditThe most common side effects for methylnaltrexone include 8 10 Abdominal pain Dizziness Vomiting Nausea DiarrheaHistory EditIn 1978 a dying friend and colleague presented the late University of Chicago pharmacologist Leon Goldberg with a clinical challenge 12 Struggling with the pain of prostatic cancer that had metastasized to his bones the man was now declining the morphine he required for analgesia because of constipation Research on opioids which would target only the sub types of receptors associated with pain relief and not with side effects had seen little success outside of in vitro models Considering drugs such as loperamide which acted on the opioid receptors in the gut without acting on the central nervous system Goldberg proposed a targeted opioid receptor antagonist 13 Thousands of opioid like molecules had been synthesized by pharmaceutical companies looking for the better analgesic and many of those with no pain relieving properties had been shelved Screening these compounds led to the examination of putative antagonists which when modified had properties that suggested they might not readily cross the blood brain barrier based on their size and charge One of these compounds N methyl naltrexone MNTX was amongst a group of compounds synthesized by Boehringer Ingelheim 14 The compound looked promising and passed initial screening in which rodents were given opioids along with charcoal meals to track GI transit and were tested for analgesia 15 In a 1982 paper by Russell et al it was first reported that the GI effects of the opioids could be prevented without affecting centrally mediated analgesia in this model 16 Subsequent preclinical studies also demonstrated this separation of central and peripherally mediated opioid effects for other smooth muscles of the GI tract and the cough reflex 17 18 Interest also developed in the potential for MNTX to act at the chemoreceptor trigger zone and block the emetic effect of opioids This blockade of opioid induced emesis was demonstrated in a canine model 19 20 Goldberg died before he could see the core of this idea come into clinical practice Research on methylnaltrexone continued in the Department of Anesthesiology and Critical Care at the University of Chicago through the 1990s More recent investigations however discovered opioid receptors on peripheral sensory neurons 21 In December 2005 Wyeth and Progenics entered into an exclusive worldwide agreement for the joint development and commercialization of methylnaltrexone for the treatment of opioid induced side effects including constipation and post operative ileus POI a prolonged dysfunction of the gastrointestinal tract following surgery Under the terms of the agreement the companies are collaborating on worldwide development Wyeth received worldwide rights to commercialize methylnaltrexone and Progenics retained an option to co promote the product in the United States Wyeth will pay Progenics royalties on worldwide sales and co promotion fees within the United States Methylnaltrexone is being developed in subcutaneous and oral forms to treat opioid induced constipation OIC The use of methylnaltrexone Relistor for more than 4 months has not been studied 22 Society and culture EditApproval Edit On April 1 2008 Progenics and Wyeth announced that Health Canada has approved methylnaltrexone for the treatment of opioid induced constipation 23 It was later approved by the US FDA on April 24 2008 24 25 Forms Edit As of 2010 methylnaltrexone is supplied as an injection in trays containing seven one dose vials containing 0 6 mL of solution Each tray also contains seven 12 mm 0 47 in 1 mL 27 gauge needles with retractable tips and alcohol wipes for home use A single vial can treat someone who weighs as much as 115 kilograms 254 lb 11 For hospital use vials are available separately See also EditLoperamide an m opioid receptor agonist that doesn t cross the BBB in significant amounts and treats diarrhea in contrast to methynaltrexone a Mu opioid receptor antagonist that doesn t cross the BBB avoiding opiate withdrawal effects in patients while treating constipation Naloxegol trade names Movantik and Moventig another peripherally selective opioid antagonist used to treat opioid induced constipation Naloxone a non opioid drug which also reduces some side effects of opioids without significantly affecting analgesia when used in small oral doses 6b Naltrexol 6a hydroxynaltrexone another naltrexone derivative that is also a peripherally selective opioid antagonistReferences Edit Methylnaltrexone Relistor Use During Pregnancy Drugs com 9 July 2020 Retrieved 21 September 2020 Anvisa 2023 03 31 RDC Nº 784 Listas de Substancias Entorpecentes Psicotropicas Precursoras e Outras sob Controle Especial Collegiate Board Resolution No 784 Lists of Narcotic Psychotropic Precursor and Other Substances under Special Control in Brazilian Portuguese Diario Oficial da Uniao published 2023 04 04 Archived from the original on 2023 08 03 Retrieved 2023 08 16 Relistor Product information Health Canada 25 April 2012 Retrieved 6 September 2022 Relistor Product information Health Canada 25 April 2012 Retrieved 6 September 2022 Relistor Product information Health Canada 25 April 2012 Retrieved 6 September 2022 National Prescribing Service 1 March 2010 Methylnaltrexone injections Relistor for opioid induced constipation in palliative care Archived from the original on 2010 06 01 Retrieved 12 March 2010 Stein C January 1993 Peripheral mechanisms of opioid analgesia Anesthesia and Analgesia 76 1 182 91 doi 10 1213 00000539 199301000 00031 PMID 8380316 S2CID 10113604 a b Highlights of Prescribing Information Metylnaltrexone bromide PDF Thomas J Karver S Cooney GA Chamberlain BH Watt CK Slatkin NE et al May 2008 Methylnaltrexone for opioid induced constipation in advanced illness The New England Journal of Medicine 358 22 2332 2343 doi 10 1056 nejmoa0707377 PMID 18509120 a b c Rotshteyn Y 11 January 2011 Methylnaltrexone bromide research update of pharmacokinetics following parenteral administration Expert Opinion on Drug Metabolism amp Toxicology 7 2 227 235 doi 10 1517 17425255 2011 549824 PMID 21222554 S2CID 24993500 a b Relistor Full Prescribing Information Retrieved 2009 05 09 permanent dead link Drug developed at the University of Chicago wins FDA approval University of Chicago News Retrieved 2019 08 15 Moss J January 2019 Identifying and Treating Opioid Side Effects The Development of Methylnaltrexone Anesthesiology 130 1 142 148 doi 10 1097 ALN 0000000000002428 PMID 30277930 S2CID 52908307 US patent 3101339 Karl Zeile and Kurt Freter amp Freter Kurt Quaternary salts of normorphine and its acylated derivatives issued 1963 08 20 assigned to C H Boehringer Sohn About Karl Zeile born 1905 Untersuchungen uber haminhaltige Fermente habilitation treatise Technische Hochschule Munich 1933 In 1933 also SS Member 1937 NSDAP Member ao i e extra ordinary Professor in Gottingen 1938 Delegate of NS Dozentenbund 1942 Prof Organic Chemistry and biochemistry at Reichsuniversitat Strassburg and military research after WW II deputy of Science Dptm at Chemische Fabrik C H Boehringer Ingelheim US patent 4176186 Goldberg L Merz H Stockhaus K Quaternary derivatives of noroxymorphone which relieve intestinal immobility issued 1979 11 27 assigned to Boehringer Ingelheim Russell J Bass P Goldberg LI Schuster CR Merz H March 1982 Antagonism of gut but not central effects of morphine with quaternary narcotic antagonists European Journal of Pharmacology 78 3 255 61 doi 10 1016 0014 2999 82 90026 7 PMID 7200037 Yuan CS Foss JF Moss J March 1995 Effects of methylnaltrexone on morphine induced inhibition of contraction in isolated guinea pig ileum and human intestine European Journal of Pharmacology 276 1 2 107 11 doi 10 1016 0014 2999 95 00018 G PMID 7781680 Foss JF Orelind E Goldberg LI 1996 Effects of methylnaltrexone on morphine induced cough suppression in guinea pigs Life Sciences 59 15 PL235 8 doi 10 1016 0024 3205 96 00451 1 PMID 8845013 Foss JF Bass AS Goldberg LI August 1993 Dose related antagonism of the emetic effect of morphine by methylnaltrexone in dogs Journal of Clinical Pharmacology 33 8 747 51 doi 10 1002 j 1552 4604 1993 tb05618 x PMID 8408737 S2CID 217261 US patent 4719215 Goldberg LI Quaternary derivatives of noroxymorphone which relieve nausea and emesis issued 1988 01 12 assigned to University of Chicago Stein C Schafer M Machelska H August 2003 Attacking pain at its source new perspectives on opioids Nature Medicine 9 8 1003 8 doi 10 1038 nm908 PMID 12894165 S2CID 25453057 Relistor Dosage and Administration Wyeth Archived from the original on 2010 08 04 Retrieved 2010 08 12 Wyeth press release Wyeth and Progenics Announce Relistor Receives Canadian Marketing Approval Archived from the original on 2008 04 11 Retrieved 2008 04 01 Wyeth press release Progenics and Wyeth Announce FDA has Approved Relistor Archived from the original on 2008 05 02 Retrieved 2008 04 27 FDA Approves Relistor for Opioid Induced Constipation Food and Drug Administration Retrieved 2009 05 09 Further reading EditHolzer P February 2007 Treatment of opioid induced gut dysfunction Expert Opinion on Investigational Drugs 16 2 181 94 doi 10 1517 13543784 16 2 181 PMID 17243938 S2CID 9838569 Yuan CS Foss JF September 2000 Oral methylnaltrexone for opioid induced constipation JAMA 284 11 1383 4 doi 10 1001 jama 284 11 1383 PMID 10989399 Retrieved from https en wikipedia org w index php title Methylnaltrexone amp oldid 1177264481, wikipedia, wiki, book, books, library,
