Connect public, paid and private patent data with Google Patents Public Datasets

Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids

Download PDF

Info

Publication number
US20090312359A1
US20090312359A1 US12333912 US33391208A US2009312359A1 US 20090312359 A1 US20090312359 A1 US 20090312359A1 US 12333912 US12333912 US 12333912 US 33391208 A US33391208 A US 33391208A US 2009312359 A1 US2009312359 A1 US 2009312359A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
administration
methylnaltrexone
opioid
mg
enteric
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12333912
Inventor
Joseph F. Foss
Michael F. Roizen
Jonathan Moss
Chun-Su Yuan
William Drell
Original Assignee
Foss Joseph F
Roizen Michael F
Jonathan Moss
Chun-Su Yuan
William Drell
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine

Abstract

A method of for preventing or treating gastrointestinal dysfunction and constipation caused by endogenous opioids in a patient who has been chronically taking opioids. The method comprises administering methylnaltrexone or another quaternary derivative of noroxymorphone most preferably by parenteral, intramuscular, intravenous or oral route.

Description

    RELATED APPLICATIONS
  • [0001]
    This application is a continuation of application Ser. No. 10/779,129, filed Feb. 12, 2004, now pending; which is a continuation of application Ser. No. 10/278,630, filed Oct. 23, 2002, abandoned; which is a divisional of application Ser. No. 09/862,169, filed May 21, 2001, now U.S. Pat. No. 6,608,075; which is a continuation of application Ser. No. 09/120,703, filed Jul. 22, 1998, now U.S. Pat. No. 6,274,591; which is a continuation-in-part of application Ser. No. 08/962,742, filed Nov. 3, 1997, now U.S. Pat. No. 5,972,954, the entire contents of each of which are herein incorporated by reference.
  • GOVERNMENT SUPPORT
  • [0002]
    This invention was made with government support under M01 RR00055 awarded by the National Institute of Health. The government has certain rights in the invention.
  • FIELD OF THE INVENTION
  • [0003]
    The present invention is directed at the treatment of certain side effects associated with the use of opioids as analgesics. In particular the present invention is directed at treating opioid-induced dysphoria, opioid-induced pruritus, opioid-induced urinary retention, inhibition of gastric emptying, and decreased gut motility.
  • BACKGROUND OF THE INVENTION
  • [0004]
    Opioids are effective analgesics, however, their use is associated with a number of undesirable side effects. One of these side effects is pruritus, or itching. Pruritus is a common side effect associated with the use of opioids and may be very severe. Pruritus can occur when the opioid is administered intramuscularly, intravenously, transdermally, transmucosally or intrathecally.
  • [0005]
    It is believed that the opioid induced pruritus results from the release of histamine in response to the administration of opioids. Opioids are thought to stimulate histamine release by binding to opioid receptors on the central nervous system. This, in turn, causes peripheral nerves and histamine containing cells to release histamine.
  • [0006]
    Based on this theory a number of treatments have been used to alleviate opioid induced pruritus. The first is the use of antihistamines. However, antihistamines have a variable effect on opioid induced pruritus. Additionally, the use of antihistamines, when effective, only treats the symptom after it has occurred, rather than preventing its occurrence.
  • [0007]
    Another undesirable side effect of opioids is urinary retention, or the patient's inability to spontaneously empty his or her bladder. This urinary retention is a common side effect that can occur when opioids or related compounds are administered intramuscularly, intravenously, transmucosally, transdermally, or intrathecally. It is not clear why opioids cause urinary retention, but it is thought to be related to the central anticholinergic stimulation that opioids induce. Based on this theory, a number of cholinergic-type drugs have been used to treat urinary retention. However, due to the side effects of cholinergic drugs, catheterization of the bladder with a tube to drain urine remains the mainstay of treatment.
  • [0008]
    Another opioid-induced side effect is dysphoria, a feeling of unpleasantness or discomfort. Many subjects, especially those without pain, report unpleasant psychomimetic responses to the administration of an opioid alone. These responses have been previously attributed to activation of centrally located opioid receptors. This opioid-induced dysphoria is commonly treated by the addition of other drugs, such as benzodiazepines, to decrease the dysphoria or to blunt the recall of the dysphoria. These drugs, however are associated with increased levels of sedation and may enhance respiratory depression caused by the opioid.
  • [0009]
    One treatment for side effects such as pruritis, urinary retention and dysphoria is the use of opioid antagonists which cross the blood-brain-barrier, or which are administered directly into the central nervous system. Opioid antagonists such as naltrexone and naloxone have been administered intramuscularly or orally to treat opioid induced pruritus. Naltrexone and naloxone are highly lipid soluble and rapidly diffuse across biological membranes, including the blood-brain-barrier. However, naltrexone, naloxone and other opioid antagonists also reduce the analgesic effect of the opioid being used.
  • [0010]
    Many quaternary amine opioid antagonist derivatives, such as methylnaltrexone, do not reduce the analgesic effect of the opioids. These quaternary amine opioid antagonist derivatives, which have a relatively higher polarity and reduced lipid solubility when compared to the tertiary forms of the drugs, were specifically developed to not traverse the blood-brain-barrier or to traverse it at a greatly reduced rate. Since these quaternary opioid antagonist derivatives do not cross the blood-brain-barrier, peripheral administration of these antagonists would not be expected to be effective in the treatment of an opioid induced side effect caused by the opioid within the central nervous system. In fact, experiments show that to be effective in blocking the opioid receptors in the central nervous system, these antagonists must be injected directly into the central nervous system. However, injection of drugs directly into the central nervous system is undesirable since it increases the possibility of introducing bacterial or viral contamination to the central nervous system.
  • [0011]
    It is desirable in the treatment of many conditions to have oral medications with prolonged effects. Such oral medications are particularly desirable both for the treatment of opioid-induced side effects (such as urinary retention, pruritus, and some forms of constipation) and for the treatment of nonopioid-induced side effects (such as other forms of constipation and delayed gastric emptying from enteric feeding).
  • [0012]
    It is further desirable to develop a method for the prevention of opioid induced dysphoria, opioid induced pruritus, urinary retention, opioid- or nonopioid-induced delayed gastric emptying from enteric feeding, and constipation, which does not counteract the analgesic effects of the opioid, or risk increased levels of pain.
  • SUMMARY OF THE INVENTION
  • [0013]
    The present invention is directed at methods for preventing and treating endogenous opioid induced gastrointestinal dysfunction.
  • [0014]
    The method for preventing endogenous opioid-induced dysfunction, including gastric dysfunction and constipation, comprises administering methylnaltrexone or other quaternary derivatives of noroxymorphone to a patient, wherein the route of administration is selected from the group consisting of parenteral, intramuscular, intravenous and oral administration, in a standard or enterically coated preparation in an effective amount, more preferably in an amount between 0.03 and 1.0 mg/kg.
  • DETAILED DESCRIPTION
  • [0015]
    The present invention is directed at methods for preventing and treating opioid-induced dysphoria, opioid-induced pruritus, opioid-induced urinary retention, opioid- or nonopioid-induced inhibition of gastric emptying by enteric feeding, and opioid- or nonopioid-induced constipation. When used as a treatment for these opioid- and nonopioid-induced side effects, orally administered, particularly if enteric coated, methylnaltrexone (MNTX) or other quaternary derivatives of noroxymorphone (QDMN) provides prolonged relief of the side effects. Furthermore, for treatment or prevention of delayed gastric emptying from enteric feeding and constipation, whether caused by extrinsic or endogenous opioids, enteric coating surprisingly allows for equal or better efficacy despite lower plasma levels. Idiopathic constipation, i.e., that due to causes other than exogenous administration of opioids, may be mediated by opioid sensitive mechanisms. Endogenous opioid receptors have been identified in the gut, and these receptors may modulate gut motility. Thus, administration of an opioid antagonist with peripheral action, such a methylnaltrexone or other quaternary derivatives of noroxymorphone, would block the effects of endogenous opioids.
  • [0016]
    Quaternary derivatives of noroxymorphone are described in full in Goldberg et al., (supra), and in general are represented by the formula:
  • [0000]
  • [0000]
    wherein R is allyl or a related radical such as chlorallyl, cyclopropyl-methyl or propargyl, and X is the anion of an acid, especially a chloride, bromide, iodide or methylsulfate anion.
  • [0017]
    The presently preferred quaternary derivative of noroxymorphone is methylnaltrexone. Methylnaltrexone is a quaternary amine derivative of naltrexone. Methylnaltrexone has been found to have only 2 to 4% of the opiate antagonistic activity of naltrexone in vivo due to its inability to pass the blood-brain-barrier and bind to the opiate receptors in the central nervous system.
  • [0018]
    Opioids are typically administered at a morphine equivalent dosage of: 0.005 to 0.15 mg/kg body weight for intrathecal administration; 0.05 to 1.0 mg/kg body weight for intravenous administration; 0.05 to 1.0 mg/kg body weight for intramuscular administration; 0.05 to 1.0 mg/kg body weight/hour for transmucosal or transdermal administration. By “morphine equivalent dosage” is meant representative doses of other opioids which equal one milligram of morphine, for example 10 mg meperidine, 1 mg methadone, and 80 μg fentanyl.
  • [0019]
    In accordance with the present invention, methylnaltrexone is administered at a dosage of: 0.03 to 1.0 mg/kg body weight for intravenous administration; 0.03 to 1.0 mg/kg body weight for intramuscular administration; 0.03 to 1.0 mg/kg body weight for transmucosal administration and 1.0 to 40.0 mg/kg body weight for oral administration. In accordance with the present invention, enteric coated methylnaltrexone, is administered at a dosage of 1.0 to 80.0 mg/kg body weight for oral administration.
  • [0020]
    The administration of the methylnaltrexone is preferably commenced prior to administration of the opioid to prevent opioid-induced dysphoria, pruritus, urinary retention, inhibition of gastric emptying with enteric feeding, or constipation. It is desirable to commence administration of methylnaltrexone about 5 minutes for parenteral MNTX administration and 20 minutes for enteral MNTX administration prior to administration of opioids in order to prevent these opioid-induced side effects. It is also preferable to administer the methylnaltrexone prior to the onset of nonopioid-induced gastric dysfunction symptoms, inhibition of gastric emptying with enteric feeding or constipation, in order to prevent these symptoms from manifesting. While the prevention of symptoms is preferred, methylnaltrexone administration may also be commenced after the administration of the opioid or after the onset of opioid induced symptoms as a treatment for those symptoms.
  • [0021]
    Methylnaltrexone is rapidly absorbed after oral administration from the stomach and bowel. Initial plasma levels of the drug are seen within 5-10 minutes of the administration of non-enteric coated compound. Addition of an enteric coating which prevents gastric absorption is associated with lower plasma levels of the methylnaltrexone. Surprisingly, the addition of an enteric coating (i.e., a coating which will prevent degradation or release in the stomach, but will release drug in the small and large bowel) appears to enhance the efficacy of methylnaltrexone in the prevention of decreases in gut motility by intravenously administered opioids (morphine).
  • [0022]
    For intravenous administration, methylnaltrexone is formulated with saline or other physiologically acceptable carriers; for intramuscular administration, the methylnaltrexone is formulated with saline or other pharmacologically acceptable carriers; for transmucosal administration the methylnaltrexone is formulated with a sugar and cellulose mix or other pharmacologically acceptable carriers known in the art; and for oral administration, the methylnaltrexone is formulated with pharmacologically acceptable binders to make a tablet or capsule with or without an enteric coating. Methods for such formulations are well known to those skilled in the art.
  • [0023]
    In a preferred embodiment for the prevention and/or treatment of constipation, the MNTX is enterically coated and administered orally.
  • [0024]
    The enteric coating may be made of any suitable composition. Suitable enteric coatings are described, for example, in U.S. Pat. Nos. 4,311,833 to Namikoshi, et al.; 4,377,568 to Chopra; 4,385,078 to Onda, et al.; 4,457,907 to Porter; 4,462,839 to McGinley, et al.; 4,518,433 to McGinley, et al.; 4,556,552 to Porter, et al.; 4,606,909 to Bechgaard et al.; 4,615,885 to Nakagame, et al.; 4,670,287 to Tsuji; 5,536,507 TO Abramowitz, et al.; 5,567,423 to Ying, et al.; 5,591,433 to Michael, et al.; 5,597,564 to Ying, et al.; 5,609,871 to Michael, et al.; 5,614,222 to Kaplan; 5,626,875 to Rodes, et al.; and 5,629,001 to Michael, et al., all of which are incorporated herein by reference.
  • [0025]
    Preferred enteric coating compositions include alkyl and hydroxyalkyl celluloses and their aliphatic esters, e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylethylcellulose, hydroxyprophymethylcellulose, hydroxybutylmethylcellulose, hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succincate; carboxyalkylcelluloses and their salts, e.g., carboxymethylethylcellulose; cellulose acetate phthalate; cellulose acetate trimellitate, polycarboxymethylene and its salts and derivatives; polyvinylalcohol and its esters: polyvinyl acetate phthalate; polycarboxymethylene copolymer with sodium formaldehyde carboxylate; acrylic polymers and copolymers, e.g., methacrylic acid-methyl methacrylic acid copolymer and methacrylic acid-methyl acrylate copolymer; edible oils such as peanut oil, palm oil, olive oil and hydrogenated vegetable oils; polyvinylpyrrolidone; polyethyleneglycol and its esters: natural products such as shellac, and zein.
  • [0026]
    Other preferred enteric coatings include polyvinylacetate esters, e.g., polyvinyl acetate phthalate; alkyleneglycolether esters of copolymers such as partial ethylene glycol monomethylether ester of ethylacrylate-maleic anhydride copolymer or diethyleneglycol monomethylether ester of methylacrylate-maleic anhydride copolymer, N-butylacrylate-maleic anhydride copolymer, isobutylacrylate-maleic anhydride copolymer or ethylacrylate-maleic anhydride copolymer; and polypeptides resistant to degradation in the gastric environment, e.g., polyarginine and polylysine.
  • [0027]
    Mixtures of two or more of the above compounds may be used as desired. The presently preferred enteric coating comprises cellulose acetate phthalate.
  • [0028]
    The enteric coating material may be mixed with various excipients including plasticizers such as triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl subacute, dibutyl tartrate, dibutyl maleate, dibutyl succinate and diethyl succinate and inert fillers such as chalk or pigments.
  • [0029]
    The composition and thickness of the enteric coating may be selected to dissolve immediately upon coated with the digestive juice of the intestine. Alternatively, the composition and thickness of the anterior coating may be selected to be a time-release coating which dissolves over a selected period of time, as is well known in the art.
  • [0030]
    The amount of enteric coating depends on the particular enteric coating composition used and is preferably sufficient to substantially prevent the absorption of MNTX in the stomach.
  • [0031]
    Hydroxyalkyl celluloses and their aliphatic esters, carboxyalkyl celluloses and their salts, polycarboxymethylene and its salts and derivatives, polyvinyl alcohol and its esters, polycarboxymethylene copolymer with sodium formaldehyde carboxylates, polyvinylpyrrolidone, and polyethylene glycol and its esters can be applied as enteric coatings by first dissolving the compound in a minimum amount of water. Alcohol is then added to the point of incipient cloudiness. The mixture can then be applied by conventional techniques.
  • [0032]
    Application of cellulose acetate phthalate may be accomplished by simply dissolving the cellulose acetate phthalate in a minimum amount of alcohol and then applying by conventional techniques. Hydrogenated vegetable oils may be applied by first dissolving the oil in a minimal amount of a non-polymer solvent, such as methylene chloride, chloroform or carbon tetrachloride, then adding alcohol to the point of incipient cloudiness and then applying by conventional techniques.
  • [0033]
    In a particularly preferred embodiment, the MNTX is coated with Eudragit L100 or S100, a methacrylic acid copolymer enteric coating, at a 50% coating level to provide stability at gastric pH and dissolution at gut pH per a US Pharmacopeia (USP) standard for enteric coatings.
  • [0034]
    Any art-known transdermal application may be used, but transdermal administration is preferably via a patch applied to the skin with a membrane of sufficient permeability to allow diffusion of MNTX at a fixed rate in the range of 1.0 to 10.0 mg/hr. The rate of administration may be varied by varying the size of the membrane contact area and/or applying an electrical wiring potential to a drug reservoir. The patch preferably holds 25 mg to 1 gram of available drug in the reservoir plus additional drug as needed for the mechanics of the system.
  • [0035]
    In the above description, methylnaltrexone is used as an example of a particularly effective QDNM. It is apparent that other QDNM's may be used as desired.
  • [0036]
    The following Examples are intended to illustrate aspects of the invention and are not to be construed as limitations upon it. The methylnaltrexone used in the following Examples was manufactured by Mallinckrodt Pharmaceuticals, St. Louis, Mo. The Enteric Coating was manufactured by Coating Place, Inc., Verona, Wis.
  • Example 1
  • [0037]
    Ten patients were treated with morphine sulfate administered directly to the central nervous system or intravenously. The morphine sulfate was administered at 0.1 mg/kg body weight. The patients in the study had been treated for pain resulting from surgery. All the patients exhibited pruritus as a side effect of the morphine sulfate administration. Subsequent to the onset of the pruritus, methylnaltrexone, at a dosage of 0.3 mg/kg of body weight was administered intravenously as a saline solution containing methylnaltrexone in a concentration of 5 mg/ml to each of the patients. Eighty percent of the 10 patients exhibited relief from the pruritus sixty minutes after receiving methylnaltrexone.
  • [0038]
    In a control group, 8 patients were treated with morphine sulfate administered directly to the central nervous system or intravenously. The morphine sulfate was administered at 0.1 mg/kg body weight. The patients in the study had been treated for pain resulting from surgery. All the patients exhibited pruritus as a side effect of the morphine sulfate administration. A placebo, saline at a volume equivalent to the volume administered to patients receiving active drug, was administered intravenously to each of the patients. Only 50% of the patients exhibited relief from the pruritus within sixty minutes.
  • [0039]
    The study indicates that methylnaltrexone was effective in treating pruritus induced by morphine sulfate.
  • Example 2 Efficacy of Enteric Coating of Methylnaltrexone
  • [0040]
    Morphine (0.05) mg/kg intravenous) was administered to three volunteers after the oral administration of placebo, methylnaltrexone (6.4 mg/kg) in a gelatin capsule (which dissolves readily in the stomach), or methylnaltrexone after enteric coating (12.8 mg/kg of substance to yield a mass of 6.4 mg/kg methylnaltrexone incorporated) which has decreased release and absorption in the stomach. Oral-cecal transit time was measured using the lactulose-hydrogen breath test. Plasma levels of methylnaltrexone were measured and after the enteric coated preparation were lower. In each subject morphine alone increased the oral-cecal transit time by 20-70 minutes, methylnaltrexone blocked this effect, and enteric coated methylnaltrexone blocked the effect to a similar or greater extent than the uncoated methylnaltrexone.
  • Example 3 Enhancement of Enteric Feeding
  • [0041]
    Two patients receiving morphine (375 mg/day and 18 mg/day) and receiving enteric tube feedings of 200 ml every four (4) hours were studied. The first patient had residual stomach contents of 50 cc to 100 cc, or 22.0-58.8% of administered feedings measured every 4 hours during a 24 hour control period. Prior to drug administration the residual volume had increased to 260 cc or >100% of previous feeding volume. Methylnaltrexone, 0.45 mg/kg, was administered intravenously every 4 hours for 24 hours, after the control period. After the first dose (4 hours) of MNTX, the residual was 150 cc or 58% of the previous bolus feed, after the 3rd dose (12 hours) the residual was 75 cc or 30% of the previous feed, after the 5th dose (20 hours) the residual was 22 cc or 13% of the previous feed and after the 6th and final dose (24 hours) the residual was 8 cc or 5.5% of previous feed. The follow-up residual sampling after the final drug-tube feed interval had increased to 50 cc or 38% or previous feed.
  • [0042]
    The second patient had greater than 200 cc residual or 100% of previous feedings on two consecutive samplings, that is 8 hrs and 4 hrs before drug administration. After initiation of Methylnaltrexone, 0.45 mg/kg, administered intravenously every 4 hours, the first residual (4 hrs) was 0 cc, the second residual (8 hrs) was 24 cc or 15% of previous bolus feed.
  • Example 4 Treatment of Urinary Retention
  • [0043]
    Subjects receiving morphine at a variety of doses (via patient controlled analgesia—PCA) who experience urinary retention are administered Methylnaltrexone 0.45 mg/kg intravenously or a placebo. Those treated with Methylnaltrexone have resolution of their symptoms, while those administered placebo go on to require additional therapy (usually urinary catheterization).
  • Example 5
  • [0044]
    In a double-blind randomized placebo-controlled study, we evaluated the efficacy of oral methylnaltrexone to decrease subjective effects after administering morphine to 10 normal human volunteers. After intravenous morphine injection (0.05 mg/kg), significant increases in subjective ratings were obtained on “nauseous”, “skin itch”, “stimulated”, and “flushing”. Compared to baseline, significant increases were obtained on “nauseous”, “skin itch”, “stimulated”, and “flushing” ratings after placebo and morphine administration (P<0.05, P<0.05, P<0.01 and P<0.01, respectively). Oral methylnaltrexone (19.2 mg/kg) significantly decreased these four ratings (P<0.05, P<0.05, P<0.01 and P<0.01, respectively) compared to placebo and morphine and resulted in no change when compared to baseline. Plasma methylnaltrexone concentrations were also measured and correlation between pharmacological effects of the compound and its plasma levels was shown. Our results indicate that methylnaltrexone decreases dysphoria and some other undesirable subjective effects associated with opioid medications.
  • [0045]
    The preceding description and Examples are intended to be illustrative. Those skilled in the art to which the invention pertains will appreciate that alterations and changes in the described protocols may be practiced without departing from the meaning, spirit, and scope of this invention. Therefore, the foregoing description should be read consistent with and as support to the following claims, which are to have their fullest and fair scope.

Claims (15)

1-14. (canceled)
15. A method for treating a patient with constipation caused by endogenous opioids, comprising administering to the patient an amount of a quaternary derivative of noroxymorphone effective to treat the constipation.
16. The method of claim 15, wherein the administration is parenteral.
17. The method of claim 15, wherein the administration is intravenous.
18. The method of claim 15, wherein the administration is intravenous. and the amount is between 0.03 and 1.0 mg/kg.
19. The method of claim 15, wherein the administration is intramuscular and the amount is between 0.03 and 1.0 mg/kg.
20. The method of claim 15, wherein the administration is oral.
21. The method of claims 15-20, wherein the quaternary derivative or noroxymorphone is methylnaltrexone.
22. A method for preventing in a patient constipation caused by endogenous opioids, comprising administering to the patient an amount of a quaternary derivative of noroxymorphone effective to treat the constipation.
23. The method of claim 22, wherein the administration is parenteral.
24. The method of claim 22, wherein the administration is intravenous.
25. The method of claim 22, wherein the administration is intravenous and the amount is between 0.03 and 1.0 mg/kg.
26. The method of claim 22, wherein the administration is intramuscular and the amount is between 0.03 and 1.0 mg/kg.
27. The method of claim 22, wherein the administration is oral.
28. The method of claims 22-28, wherein the quaternary derivative or noroxymorphone is methylnaltrexone.
US12333912 1997-11-03 2008-12-12 Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids Abandoned US20090312359A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US08962742 US5972954A (en) 1997-11-03 1997-11-03 Use of methylnaltrexone and related compounds
US09120703 US6274591B1 (en) 1997-11-03 1998-07-22 Use of methylnaltrexone and related compounds
US09862169 US6608075B2 (en) 1997-11-03 2001-05-21 Use of methylnaltrexone and related compounds
US10278630 US20030065003A1 (en) 1997-11-03 2002-10-23 Use of methylnaltrexone and related compounds
US10779129 US20040162308A1 (en) 1997-11-03 2004-02-12 Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids
US12333912 US20090312359A1 (en) 1997-11-03 2008-12-12 Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US12333912 US20090312359A1 (en) 1997-11-03 2008-12-12 Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids

Publications (1)

Publication Number Publication Date
US20090312359A1 true true US20090312359A1 (en) 2009-12-17

Family

ID=26818669

Family Applications (6)

Application Number Title Priority Date Filing Date
US09120703 Expired - Lifetime US6274591B1 (en) 1997-11-03 1998-07-22 Use of methylnaltrexone and related compounds
US09862169 Expired - Lifetime US6608075B2 (en) 1997-11-03 2001-05-21 Use of methylnaltrexone and related compounds
US10278630 Abandoned US20030065003A1 (en) 1997-11-03 2002-10-23 Use of methylnaltrexone and related compounds
US10779129 Abandoned US20040162308A1 (en) 1997-11-03 2004-02-12 Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids
US10962729 Abandoned US20050048117A1 (en) 1997-11-03 2004-10-12 Use of methylnaltrexone and related compounds
US12333912 Abandoned US20090312359A1 (en) 1997-11-03 2008-12-12 Use of methylnaltrexone and related compounds for treatment of gastrointestinal dysfunction induced by endogenous opioids

Family Applications Before (5)

Application Number Title Priority Date Filing Date
US09120703 Expired - Lifetime US6274591B1 (en) 1997-11-03 1998-07-22 Use of methylnaltrexone and related compounds
US09862169 Expired - Lifetime US6608075B2 (en) 1997-11-03 2001-05-21 Use of methylnaltrexone and related compounds
US10278630 Abandoned US20030065003A1 (en) 1997-11-03 2002-10-23 Use of methylnaltrexone and related compounds
US10779129 Abandoned US20040162308A1 (en) 1997-11-03 2004-02-12 Use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids
US10962729 Abandoned US20050048117A1 (en) 1997-11-03 2004-10-12 Use of methylnaltrexone and related compounds

Country Status (4)

Country Link
US (6) US6274591B1 (en)
CA (1) CA2312234C (en)
EP (1) EP1047426B1 (en)
WO (1) WO1999022737A1 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8003794B2 (en) 2005-05-25 2011-08-23 Progenics Pharmaceuticals, Inc. (S)-N-methylnaltrexone
US8247425B2 (en) 2008-09-30 2012-08-21 Wyeth Peripheral opioid receptor antagonists and uses thereof
US8338446B2 (en) 2007-03-29 2012-12-25 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
US8343992B2 (en) 2005-05-25 2013-01-01 Progenics Pharmaceuticals, Inc. Synthesis of R-N-methylnaltrexone
US8471022B2 (en) 2008-02-06 2013-06-25 Progenics Pharmaceuticals, Inc. Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone
US8546418B2 (en) 2007-03-29 2013-10-01 Progenics Pharmaceuticals, Inc. Peripheral opioid receptor antagonists and uses thereof
US8552025B2 (en) 2003-04-08 2013-10-08 Progenics Pharmaceuticals, Inc. Stable methylnaltrexone preparation
US8637538B1 (en) 2012-12-14 2014-01-28 Trevi Therapeutics, Inc. Methods for treatment of pruritis
US8940753B1 (en) 2012-12-14 2015-01-27 Trevi Therapeutics, Inc. Methods for treating pruritis
US8987289B2 (en) 2012-12-14 2015-03-24 Trevi Therapeutics, Inc. Methods for treating pruritus
US9102680B2 (en) 2007-03-29 2015-08-11 Wyeth Llc Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030158220A1 (en) * 1997-11-03 2003-08-21 Foss Joseph F. Use of methylnaltrexone and related compounds to treat chronic opioid use side effects
US6274591B1 (en) * 1997-11-03 2001-08-14 Joseph F. Foss Use of methylnaltrexone and related compounds
US6559158B1 (en) * 1997-11-03 2003-05-06 Ur Labs, Inc. Use of methylnaltrexone and related compounds to treat chronic opioid use side affects
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
DK1041987T3 (en) 1997-12-22 2006-08-21 Euro Celtique Sa An oral pharmaceutical dosage form comprising a combination of an opioid agonist and naltrexone
WO2001013909A3 (en) 1999-08-25 2001-05-25 Barrett R Cooper Compositions and methods for treating opiate intolerance
US6451806B2 (en) 1999-09-29 2002-09-17 Adolor Corporation Methods and compositions involving opioids and antagonists thereof
DK1225897T3 (en) 1999-11-01 2005-01-10 John Rhodes A composition for the treatment of constipation and irritable bowel syndrome
US6469030B2 (en) 1999-11-29 2002-10-22 Adolor Corporation Methods for the treatment and prevention of ileus
WO2001042207A3 (en) 1999-11-29 2002-05-02 Adolor Corp Novel methods for the treatment and prevention of ileus
ES2415407T3 (en) 2000-02-08 2013-07-25 Euro-Celtique S.A. oral formulations of opioid agonists resistant tamper
DE10059415A1 (en) 2000-11-30 2002-06-06 Gruenenthal Gmbh Use of weak opioids and mixed opioid agonist / antagonist for the treatment of urinary incontinence
CA2446550C (en) 2001-05-11 2012-03-06 Endo Pharmaceuticals, Inc. Abuse-resistant controlled-release opioid dosage form
WO2002098422A1 (en) * 2001-06-05 2002-12-12 University Of Chicago Use of methylnaltrexone to treat immune suppression
WO2003007802A3 (en) 2001-07-18 2003-11-27 Christopher D Breder Pharmaceutical combinations of oxycodone and naloxone
WO2003013525A1 (en) 2001-08-06 2003-02-20 Euro-Celtique S.A. Opioid agonist formulations with releasable and sequestered antagonist
WO2004014291B1 (en) * 2002-02-04 2004-09-02 Jonathan Moss Use of methylnaltrexone in treating gastrointestinal dysfunction in equines
EP2319496A1 (en) 2002-04-05 2011-05-11 Euro-Celtique S.A. Pharmaceutical preparation containing oxycodone and naloxone
ES2358151T3 (en) * 2002-08-15 2011-05-06 Euro-Celtique S.A. pharmaceutical compositions comprising an opioid antagonist.
WO2004091622A1 (en) * 2003-04-08 2004-10-28 Progenics Pharmaceuticals, Inc. The use of peripheral opiois antagonists, especially methylnaltrexone to treat irritable bowel syndrome
CA2521420A1 (en) * 2003-04-08 2004-10-28 Progenics Pharmaceuticals, Inc. Combination therapy for constipation comprising a laxative and a peripheral opioid antagonist
ES2341546T3 (en) 2003-04-21 2010-06-22 Euro-Celtique S.A. tamper resistant opioid for delivery products.
WO2005018616A1 (en) * 2003-08-12 2005-03-03 Endo Pharmaceuticals, Inc. Method for deterring abuse of opioids by combination with non-release formulation of emetic
CA2539027C (en) * 2003-09-25 2010-02-23 Euro-Celtique S.A. Pharmaceutical combinations of hydrocodone and naltrexone
JPWO2006064780A1 (en) * 2004-12-14 2008-06-12 塩野義製薬株式会社 Constipation treatment agent
JP2008528497A (en) * 2005-01-20 2008-07-31 プロジェニックス ファーマシューティカルズ,インコーポレーテッド Use for postoperative gastrointestinal disorder of methylnaltrexone and related compounds
US20080194611A1 (en) * 2005-06-03 2008-08-14 Alverdy John C Modulation of Cell Barrier Dysfunction
CN104248763A (en) 2005-03-07 2014-12-31 芝加哥大学 Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US9662325B2 (en) 2005-03-07 2017-05-30 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US8524731B2 (en) 2005-03-07 2013-09-03 The University Of Chicago Use of opioid antagonists to attenuate endothelial cell proliferation and migration
US8518962B2 (en) 2005-03-07 2013-08-27 The University Of Chicago Use of opioid antagonists
US20070185145A1 (en) * 2006-02-03 2007-08-09 Royds Robert B Pharmaceutical composition containing a central opioid agonist, a central opioid antagonist, and a peripheral opioid antagonist, and method for making the same
US20080027579A1 (en) * 2006-07-31 2008-01-31 Van Der Hoop Roland Gerritsen Dosage limiting medication dispensing method and apparatus
JP2009545629A (en) * 2006-08-04 2009-12-24 ワイスWyeth 6-carboxyfluorescein nor morphinan derivatives, their synthesis and use
CN101511342A (en) * 2006-09-08 2009-08-19 惠氏公司 Dry powder compound formulations and uses thereof
US8383649B2 (en) * 2007-07-11 2013-02-26 Mallinckrodt Llc Crystalline forms of naltrexone methobromide
US8748448B2 (en) 2007-10-18 2014-06-10 Aiko Biotechnology Combination analgesic employing opioid agonist and neutral antagonist
EP2214672B1 (en) * 2007-10-18 2012-10-17 Aiko Biotechnology Combination analgesic employing opioid and neutral antagonist
US8685995B2 (en) 2008-03-21 2014-04-01 The University Of Chicago Treatment with opioid antagonists and mTOR inhibitors
CA2729582C (en) 2008-07-01 2017-09-19 University Of Chicago Particles containing an opioid receptor antagonist and methods of use
CA2754853C (en) 2009-03-10 2015-04-28 Euro-Celtique S.A. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
CA2789798A1 (en) 2010-03-11 2011-09-15 Syed M. Shah Oral formulations and lipophilic salts of methylnaltrexone

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4176186A (en) * 1978-07-28 1979-11-27 Boehringer Ingelheim Gmbh Quaternary derivatives of noroxymorphone which relieve intestinal immobility
US4719215A (en) * 1986-03-07 1988-01-12 University Of Chicago Quaternary derivatives of noroxymorphone which relieve nausea and emesis
US6559158B1 (en) * 1997-11-03 2003-05-06 Ur Labs, Inc. Use of methylnaltrexone and related compounds to treat chronic opioid use side affects
US6608075B2 (en) * 1997-11-03 2003-08-19 The University Of Chicago Use of methylnaltrexone and related compounds

Family Cites Families (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US222911A (en) * 1879-12-23 Improvement in book-cases
US1047726A (en) * 1912-03-12 1912-12-17 Anthony J Yoggerst Pipe-cleaner.
US2625457A (en) * 1951-07-26 1953-01-13 Bernard J Baecher Course recorder
JPS5612614B2 (en) 1978-09-04 1981-03-23
US4311833A (en) 1979-03-06 1982-01-19 Daicel Chemical Industries Ltd. Process for preparing ethylcarboxymethylcellulose
US4322426A (en) * 1980-04-28 1982-03-30 E. I. Du Pont De Nemours And Company 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists
US4377568A (en) 1981-08-12 1983-03-22 Merck Sharp & Dohme (I.A.) Corp. Preparation of aqueous alcoholic dispersions of pH sensitive polymers and plasticizing agents and a method of enteric coating dosage forms using same
DK150008C (en) 1981-11-20 1987-05-25 Benzon As Alfred Process for the preparation of a pharmaceutical orally multiple-units
US4987136A (en) 1982-03-16 1991-01-22 The Rockefeller University Method for controlling gastrointestinal dysmotility
JPH045647B2 (en) 1982-03-16 1992-02-03 Univ Rockefeller
US4457907A (en) 1982-08-05 1984-07-03 Clear Lake Development Group Composition and method for protecting a therapeutic drug
US4518433A (en) 1982-11-08 1985-05-21 Fmc Corporation Enteric coating for pharmaceutical dosage forms
US4462839A (en) 1983-06-16 1984-07-31 Fmc Corporation Enteric coating for pharmaceutical dosage forms
US4556552A (en) 1983-09-19 1985-12-03 Colorcon, Inc. Enteric film-coating compositions
EP0143949B1 (en) 1983-11-01 1988-10-12 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Pharmaceutical composition containing urokinase
US5266574A (en) 1984-04-09 1993-11-30 Ian S. Zagon Growth regulation and related applications of opioid antagonists
JPH0466450B2 (en) 1985-07-30 1992-10-23 Shinjiro Tsuji
US4861781A (en) * 1986-03-07 1989-08-29 The University Of Chicago Quaternary derivatives of noroxymorphone which relieve nausea and emesis
US5597564A (en) 1986-08-28 1997-01-28 Enzacor Properties Limited Method of administering a microgranular preparation to the intestinal region of animals
WO1988001512A1 (en) 1986-08-28 1988-03-10 Thomas Ko Sai Ying Animal growth promotant
US4888346A (en) * 1986-10-07 1989-12-19 Bernard Bihari Method for the treatment of persons infected with HTLV-III (AIDS) virus
FR2609632B1 (en) 1987-01-21 1991-03-29 Shelly Marc New therapeutic application of 17- (cyclopropylmethyl) -4,5-epoxy-3,14-dihydroxymorphinon-6-one and pharmaceutical compositions destinies has this use
US4857833A (en) * 1987-08-27 1989-08-15 Teradyne, Inc. Diagnosis of faults on circuit board
EP0306575B1 (en) * 1987-09-10 1992-07-29 The University Of Chicago Quaternary derivatives of noroxymorphone which relieve nausea and emesis
EP0352361A1 (en) 1988-07-29 1990-01-31 The Rockefeller University Method of treating patients suffering from chronic pain or chronic cough
US5102887A (en) * 1989-02-17 1992-04-07 Arch Development Corporation Method for reducing emesis and nausea induced by the administration of an emesis causing agent
US4965269A (en) * 1989-12-20 1990-10-23 Ab Hassle Therapeutically active chloro substituted benzimidazoles
JPH04230625A (en) * 1990-12-27 1992-08-19 Standard Chem & Pharmaceut Corp Ltd Production of finely dispersed tablet composition comprising microcapsule containing spray-dried diclofenac sodium and having enteric coating
US5270328A (en) 1991-03-29 1993-12-14 Eli Lilly And Company Peripherally selective piperidine opioid antagonists
US5159081A (en) * 1991-03-29 1992-10-27 Eli Lilly And Company Intermediates of peripherally selective n-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists
EP0590060B1 (en) 1991-06-21 1997-09-17 University Of Cincinnati Orally administrable therapeutic proteins and method of making
US5614219A (en) * 1991-12-05 1997-03-25 Alfatec-Pharma Gmbh Oral administration form for peptide pharmaceutical substances, in particular insulin
US5512578A (en) 1992-09-21 1996-04-30 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists
USRE36547E (en) 1992-09-21 2000-02-01 Albert Einstein College Of Medicine Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists
US5580876A (en) 1992-09-21 1996-12-03 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US6096756A (en) 1992-09-21 2000-08-01 Albert Einstein College Of Medicine Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US5585348A (en) 1993-02-10 1996-12-17 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Use of excitatory opioid receptor antagonists to prevent growth factor-induced hyperalgesia
US5472943A (en) 1992-09-21 1995-12-05 Albert Einstein College Of Medicine Of Yeshiva University, Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists
DE69305313T2 (en) 1992-12-22 1997-02-20 Univ Cincinnati Oral administration of the immunological active biomolecules and other therapeutic proteins
US5656290A (en) * 1993-02-26 1997-08-12 The Procter & Gamble Company Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery
US5391372A (en) * 1993-06-28 1995-02-21 Campbell; Elizabeth Methods of treating colic and founder in horses
WO1995030774A1 (en) * 1994-05-05 1995-11-16 Beckman Instruments, Inc. Oligonucleotide repeat arrays
WO1995031985A3 (en) 1994-05-24 1996-01-04 Paolo Minoia Pharmaceutical compositions comprising an opiate antagonist and calcium salts, their use for the treatment of endorphin-mediated pathologies
US5536507A (en) 1994-06-24 1996-07-16 Bristol-Myers Squibb Company Colonic drug delivery system
US5866154A (en) * 1994-10-07 1999-02-02 The Dupont Merck Pharmaceutical Company Stabilized naloxone formulations
US5614222A (en) 1994-10-25 1997-03-25 Kaplan; Milton R. Stable aqueous drug suspensions and methods for preparation thereof
US5965161A (en) * 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
ES2094694B1 (en) 1995-02-01 1997-12-16 Esteve Quimica Sa New pharmaceutically stable of a benzimidazole compound formulation and production process.
US6025154A (en) * 1995-06-06 2000-02-15 Human Genome Sciences, Inc. Polynucleotides encoding human G-protein chemokine receptor HDGNR10
US5804595A (en) * 1995-12-05 1998-09-08 Regents Of The University Of Minnesota Kappa opioid receptor agonists
EP0914097B1 (en) 1996-03-12 2002-01-16 Alza Corporation Composition and dosage form comprising opioid antagonist
DE19651551C2 (en) 1996-12-11 2000-02-03 Klinge Co Chem Pharm Fab Opioid antagonist-containing pharmaceutical formulation
US6353004B1 (en) * 1997-07-14 2002-03-05 Adolor Coporation Peripherally acting anti-pruritic opiates
US5972954A (en) 1997-11-03 1999-10-26 Arch Development Corporation Use of methylnaltrexone and related compounds
US20030158220A1 (en) * 1997-11-03 2003-08-21 Foss Joseph F. Use of methylnaltrexone and related compounds to treat chronic opioid use side effects
US6194382B1 (en) 1999-03-03 2001-02-27 Albert Einstein College Of Medicine Of Yeshiva University Method and composition for treating irritable bowel syndrome using low doses of opioid receptor antagonists
WO2001013909A3 (en) * 1999-08-25 2001-05-25 Barrett R Cooper Compositions and methods for treating opiate intolerance
US6451806B2 (en) 1999-09-29 2002-09-17 Adolor Corporation Methods and compositions involving opioids and antagonists thereof
WO2001041705A3 (en) 1999-11-29 2001-12-20 Adolor Corp Novel methods for the treatment and prevention of dizziness and pruritus
WO2001042207A3 (en) 1999-11-29 2002-05-02 Adolor Corp Novel methods for the treatment and prevention of ileus
US6469030B2 (en) * 1999-11-29 2002-10-22 Adolor Corporation Methods for the treatment and prevention of ileus
ES2278647T3 (en) 1999-11-29 2007-08-16 Adolor Corporation New methods and compositions comprising opioids and opioid antagonists.
US6967075B2 (en) * 2000-04-07 2005-11-22 Schering Corporation HCV replicase complexes
EP1284736A2 (en) 2000-05-05 2003-02-26 Albert Einstein College Of Medicine Of Yeshiva University Opioid antagonist compositions and dosage forms
DK1296714T3 (en) * 2000-06-22 2009-12-07 Coley Pharm Gmbh Combination of CpG and antibodies directed against CD19, CD20, CD22 or CD40 for the treatment or prevention of cancer
WO2002098422A1 (en) * 2001-06-05 2002-12-12 University Of Chicago Use of methylnaltrexone to treat immune suppression
WO2003032990A3 (en) * 2001-10-18 2004-02-26 Michael David Bentley Polymer conjugates of opioid antagonists
US20030191147A1 (en) * 2002-04-09 2003-10-09 Barry Sherman Opioid antagonist compositions and dosage forms
DK1615646T3 (en) * 2003-04-08 2015-02-02 Progenics Pharm Inc Pharmaceutical formulations containing methylnaltrexone
WO2004091622A1 (en) * 2003-04-08 2004-10-28 Progenics Pharmaceuticals, Inc. The use of peripheral opiois antagonists, especially methylnaltrexone to treat irritable bowel syndrome
CA2521420A1 (en) * 2003-04-08 2004-10-28 Progenics Pharmaceuticals, Inc. Combination therapy for constipation comprising a laxative and a peripheral opioid antagonist
CA2543077A1 (en) * 2003-10-29 2005-05-12 Allez Physionix Ltd. Method and apparatus for determining an ultrasound fluid flow centerline
JP2008528497A (en) * 2005-01-20 2008-07-31 プロジェニックス ファーマシューティカルズ,インコーポレーテッド Use for postoperative gastrointestinal disorder of methylnaltrexone and related compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4176186A (en) * 1978-07-28 1979-11-27 Boehringer Ingelheim Gmbh Quaternary derivatives of noroxymorphone which relieve intestinal immobility
US4719215A (en) * 1986-03-07 1988-01-12 University Of Chicago Quaternary derivatives of noroxymorphone which relieve nausea and emesis
US6559158B1 (en) * 1997-11-03 2003-05-06 Ur Labs, Inc. Use of methylnaltrexone and related compounds to treat chronic opioid use side affects
US6608075B2 (en) * 1997-11-03 2003-08-19 The University Of Chicago Use of methylnaltrexone and related compounds

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8552025B2 (en) 2003-04-08 2013-10-08 Progenics Pharmaceuticals, Inc. Stable methylnaltrexone preparation
US9669096B2 (en) 2003-04-08 2017-06-06 Progenics Pharmaceuticals, Inc. Stable pharmaceutical formulations of methylnaltrexone
US8003794B2 (en) 2005-05-25 2011-08-23 Progenics Pharmaceuticals, Inc. (S)-N-methylnaltrexone
US9597327B2 (en) 2005-05-25 2017-03-21 Progenics Pharmaceuticals, Inc. Synthesis of (R)-N-methylnaltrexone
US8916581B2 (en) 2005-05-25 2014-12-23 Progenics Pharmaceuticals, Inc. (S)-N-methylnaltrexone
US8343992B2 (en) 2005-05-25 2013-01-01 Progenics Pharmaceuticals, Inc. Synthesis of R-N-methylnaltrexone
US9102680B2 (en) 2007-03-29 2015-08-11 Wyeth Llc Crystal forms of (R)-N-methylnaltrexone bromide and uses thereof
US8853232B2 (en) 2007-03-29 2014-10-07 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
US8546418B2 (en) 2007-03-29 2013-10-01 Progenics Pharmaceuticals, Inc. Peripheral opioid receptor antagonists and uses thereof
US8338446B2 (en) 2007-03-29 2012-12-25 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
US8772310B2 (en) 2007-03-29 2014-07-08 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
US8471022B2 (en) 2008-02-06 2013-06-25 Progenics Pharmaceuticals, Inc. Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone
US8916706B2 (en) 2008-02-06 2014-12-23 Progenics Pharmaceuticals, Inc. Preparation and use of (R),(R)-2,2′-bis-methylnaltrexone
US8822490B2 (en) 2008-09-30 2014-09-02 Wyeth Llc Peripheral opioid receptor antagonists and uses thereof
US8455644B2 (en) 2008-09-30 2013-06-04 Wyeth Peripheral opioid receptor antagonists and uses thereof
US8420663B2 (en) 2008-09-30 2013-04-16 Wyeth Peripheral opioid receptor antagonists and uses thereof
US9492445B2 (en) 2008-09-30 2016-11-15 Wyeth, Llc Peripheral opioid receptor antagonists and uses thereof
US8247425B2 (en) 2008-09-30 2012-08-21 Wyeth Peripheral opioid receptor antagonists and uses thereof
US9180125B2 (en) 2008-09-30 2015-11-10 Wyeth, Llc Peripheral opioid receptor antagonists and uses thereof
US9724343B2 (en) 2008-09-30 2017-08-08 Wyeth, Llc Peripheral opioid receptor antagonists and uses thereof
US8987289B2 (en) 2012-12-14 2015-03-24 Trevi Therapeutics, Inc. Methods for treating pruritus
US8940753B1 (en) 2012-12-14 2015-01-27 Trevi Therapeutics, Inc. Methods for treating pruritis
US8637538B1 (en) 2012-12-14 2014-01-28 Trevi Therapeutics, Inc. Methods for treatment of pruritis

Also Published As

Publication number Publication date Type
US6274591B1 (en) 2001-08-14 grant
WO1999022737A1 (en) 1999-05-14 application
CA2312234A1 (en) 1999-05-14 application
US20030065003A1 (en) 2003-04-03 application
EP1047426A4 (en) 2004-07-14 application
EP1047426B1 (en) 2010-05-12 grant
CA2312234C (en) 2005-03-22 grant
US20020028825A1 (en) 2002-03-07 application
EP1047426A1 (en) 2000-11-02 application
US20040162308A1 (en) 2004-08-19 application
US6608075B2 (en) 2003-08-19 grant
US20050048117A1 (en) 2005-03-03 application

Similar Documents

Publication Publication Date Title
Sarhill et al. Hydromorphone: pharmacology and clinical applications in cancer patients
US4661492A (en) Analgesic compositions
US7026329B2 (en) Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
Choi et al. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation
US6166044A (en) Colonic delivery of nicotine to treat inflammatory bowel disease
EP0631781A1 (en) Opioid formulations having extended controlled release
US20080176955A1 (en) Combined administration of benzonatate and guaifenesin
US6159501A (en) Modified release multiple-units dosage composition for release of opioid compounds
US5846983A (en) Colonic delivery of nicotine to treat inflammatory bowel disease
US6608073B1 (en) Intranasal codeine for the rapid suppression of cough and rapid relief of pain
US20100151014A1 (en) Pharmaceutical composition
US20050106249A1 (en) Once-a-day, oral, controlled-release, oxycodone dosage forms
De Giorgio et al. The pharmacological treatment of acute colonic pseudo‐obstruction
US20100152221A1 (en) Pharmaceutical composition
EP0615749A2 (en) Use of NMDA antagonists for the treatment of pain
Mendelson et al. Clinical and pharmacological evaluation of buprenorphine and naloxone combinations: why the 4: 1 ratio for treatment?
US6825203B2 (en) Topical anesthetic/opioid formulations and uses thereof
Foley et al. β-Endorphin: analgesic and hormonal effects in humans
US5202128A (en) Sustained release pharmaceutical composition
US20040126428A1 (en) Pharmaceutical formulation including a resinate and an aversive agent
US20040259899A1 (en) Combination therapy for constipation
US6238689B1 (en) Intestinal absorption of nicotine to treat nicotine responsive conditions
EP0377518A2 (en) Sustained release pharmaceutical composition
US20050038062A1 (en) Methods and materials for the treatment of pain comprising opioid antagonists
US4582835A (en) Analgesic compositions