U.S. patent application number 10/779129 was filed with the patent office on 2004-08-19 for use of methylnaltrexone and related compounds for treatment of constipation caused by endogenous opioids.
Invention is credited to Drell, William, Foss, Joseph F., Moss, Jonathan, Roizen, Michael F., Yuan, Chun-Sun.
Application Number | 20040162308 10/779129 |
Document ID | / |
Family ID | 26818669 |
Filed Date | 2004-08-19 |
United States Patent
Application |
20040162308 |
Kind Code |
A1 |
Foss, Joseph F. ; et
al. |
August 19, 2004 |
Use of methylnaltrexone and related compounds for treatment of
constipation caused by endogenous opioids
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.
Inventors: |
Foss, Joseph F.; (Chicago,
IL) ; Roizen, Michael F.; (Chicago, IL) ;
Moss, Jonathan; (Chicago, IL) ; Yuan, Chun-Sun;
(Chicago, IL) ; Drell, William; (San Diago,
CA) |
Correspondence
Address: |
Edward R. Gates
Wolf, Greenfield & Sacks, P.C.
600 Atlantic Avenue
Boston
MA
02210
US
|
Family ID: |
26818669 |
Appl. No.: |
10/779129 |
Filed: |
February 12, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10779129 |
Feb 12, 2004 |
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10278630 |
Oct 23, 2002 |
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10278630 |
Oct 23, 2002 |
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09862169 |
May 21, 2001 |
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6608075 |
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09862169 |
May 21, 2001 |
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09120703 |
Jul 22, 1998 |
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6274591 |
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09120703 |
Jul 22, 1998 |
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08962742 |
Nov 3, 1997 |
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5972954 |
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Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61P 1/00 20180101; A61K
31/485 20130101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 031/485 |
Claims
What is claimed is:
1. A method for treating a patient with a gastrointestinal
dysfunction caused by endogenous opioids, comprising administering
to the patient an amount of a quaternary derivative of
noroxymorphone effective to treat the gastrointestinal
dysfunction.
2. The method of claim 1, wherein the administration is
parenteral.
3. The method of claim 1, wherein the administration is
intravenous.
4. The method of claim 1, wherein the administration is intravenous
and the amount is between 0.03 and 1.0 mg/kg.
5. The method of claim 1, wherein the administration is
intramuscular and the amount is between 0.03 and 1.0 mg/kg.
6. The method of claim 1, wherein the administration is oral.
7. The method of claims 1-6, wherein the quaternary derivative or
noroxymorphone is methylnaltrexone.
8. A method for preventing in a patient a gastrointestinal
dysfunction caused by endogenous opioids, comprising administering
to the patient an amount of a quaternary derivative of
noroxymorphone effective to treat the gastrointestinal
dysfunction.
9. The method of claim 8, wherein-the administration is
parenteral.
10. The method of claim 8, wherein the administration is
intravenous.
11. The method of claim 8, wherein the administration is
intravenous and the amount is between 0.03 and 1.0 mg/kg.
12. The method of claim 1, wherein the administration is
intramuscular and the amount is between 0.03 and 1.0 mg/kg.
13. The method of claim 1, wherein the administration is oral.
14. The method of claims 8-13, wherein the quaternary derivative or
noroxymorphone is methylnaltrexone.
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.
Description
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This application is a continuation of application Ser. No.
10/278,630, filed Oct. 23, 2002; which is a divisional of
application Ser. No. 09/862,169, filed May 21, 2001 (herein
incorporated by reference) now U.S. Pat. No. 6,608,075; which is a
continuation of application Ser. No. 09/120,703, filed Jul. 22,
1998 (herein incorporated by reference) 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
disclosures of which are herein incorporated by reference. This
application also claims priority of provisional application Ser.
No. 60/168,480, filed Dec. 1, 1999, also herein incorporated by
reference.
FIELD OF THE INVENTION
[0002] 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
[0003] 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.
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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).
[0011] 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
[0012] The present invention is directed at methods for preventing
and treating endogenous opioid induced gastrointestinal
dysfunction.
[0013] 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
[0014] 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.
[0015] Quaternary derivatives of noroxymorphone are described in
full in Goldberg et al., (supra), and in general are represented by
the formula: 1
[0016] 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 .mu.g 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
acidmethyl 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-butylacrylatemaleic 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
[0040] Efficacy of Enteric Coating of Methylnaltrexone
[0041] 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
[0042] Enhancement of Enteric Feeding
[0043] 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.
[0044] 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
[0045] Treatment of Urinary Retention
[0046] 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
[0047] 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.
[0048] 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.
* * * * *