{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T13:48:57Z","timestamp":1775742537452,"version":"3.50.1"},"reference-count":18,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,3,8]],"date-time":"2013-03-08T00:00:00Z","timestamp":1362700800000},"content-version":"vor","delay-in-days":5910,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[1997,1]]},"abstract":"<jats:p>N\u2010methylnaltrexone bromide (methylnaltrexone) is a quaternary opioid antagonist with a limited ability to cross the blood\u2014brain barrier. In animal models it reverses at peripheral receptors such side effects of opioids as decreased gastrointestinal motility, emesis, and cough suppression without affecting the desired analgesic effect mediated by central nervous system receptors. Methylnaltrexone thus may be a clinically useful compound for the prevention and treatment of opioid\u2010induced side effects. This study was designed to examine the safety and tolerance of methylnaltrexone in healthy human participants over a range of doses and to identify any adverse effects or toxicity associated with methylnaltrexone and the doses at which these adverse effects occur. Healthy male volunteers received intravenous methylnaltrexone in six ascending doses with a placebo randomly inserted into the sequence. Each participant was observed for subjective and hemodynamic changes. Electrocardiogram and laboratory studies were also performed. The dose\u2010limiting adverse effect of methylnaltrexone was orthostatic hypotension at 0.64 mg\/kg (n = 3) or 1.25 mg\/kg (n = 5), which was transient and self\u2010limiting. Plasma levels of methylnaltrexone in excess of 1,400 ng\/mL were observed to be associated with orthostatic hypotension. There were no significant subjective changes, no release of histamine, and no changes in physical examination or laboratory studies during the course of the study. Pharmacokinetic analysis revealed an elimination half\u2010life of 117.5 minutes (\u00b153.2), and a clearance of 38.8 L\/hr (\u00b117.4) with a methylnaltrexone dose of 0.64 mg\/kg. Our results indicate that methylnaltrexone is well tolerated at doses of 0.32 mg\/kg in healthy humans.<\/jats:p>","DOI":"10.1177\/009127009703700105","type":"journal-article","created":{"date-parts":[[2007,6,22]],"date-time":"2007-06-22T00:52:18Z","timestamp":1182473538000},"page":"25-30","source":"Crossref","is-referenced-by-count":46,"title":["Safety and Tolerance of Methylnaltrexone in Healthy Humans: A Randomized, Placebo\u2010Controlled, Intravenous, Ascending\u2010Dose, Pharmacokinetic Study"],"prefix":"10.1002","volume":"37","author":[{"given":"Joseph F.","family":"Foss","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael F.","family":"O'Connor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun\u2010Su","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Moss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael F.","family":"Roizen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,3,8]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(83)90325-9"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(85)90072-3"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(83)90246-0"},{"key":"e_1_2_1_5_2","first-page":"8","article-title":"Independent central and peripheral mediation of morphine\u2010induced inhibition of gastrointestinal transit in rats","volume":"236","author":"Gmerek DE","year":"1986","journal-title":"J Pharm Exp Ther"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.25.040185.001341"},{"key":"e_1_2_1_7_2","article-title":"Effects of methylnaltrexone on morphine\u2010induced cough suppression in guinea\u2010pigs","author":"Foss JF","journal-title":"Life Sci"},{"key":"e_1_2_1_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1993.tb05618.x"},{"key":"e_1_2_1_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02259022"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02261014"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0091-6749(88)90977-3"},{"key":"e_1_2_1_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-198107000-00006"},{"key":"e_1_2_1_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0195-6663(83)80045-2"},{"key":"e_1_2_1_14_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199505000-00007"},{"key":"e_1_2_1_15_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-198903000-00003"},{"key":"e_1_2_1_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(84)90121-0"},{"key":"e_1_2_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0885-3924(92)90092-V"},{"key":"e_1_2_1_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0025-7125(16)30872-0"},{"issue":"7","key":"e_1_2_1_19_2","first-page":"18","article-title":"Relieving constipation and pain in the terminally ill","volume":"91","author":"Fifield MY","year":"1991","journal-title":"Am J Nurs"}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1177%2F009127009703700105","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1177\/009127009703700105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T09:27:09Z","timestamp":1698398829000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1177\/009127009703700105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,1]]},"references-count":18,"journal-issue":{"issue":"1","published-print":{"date-parts":[[1997,1]]}},"alternative-id":["10.1177\/009127009703700105"],"URL":"https:\/\/doi.org\/10.1177\/009127009703700105","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,1]]}}}