U.S. patent number RE38,115 [Application Number 10/052,698] was granted by the patent office on 2003-05-06 for dextromethorphan and an oxidase inhibitor for treating intractable conditions.
This patent grant is currently assigned to Center for Neurologic Study. Invention is credited to Jonathan M. Licht, Richard Alan Smith.
United States Patent |
RE38,115 |
Smith , et al. |
May 6, 2003 |
Dextromethorphan and an oxidase inhibitor for treating intractable
conditions
Abstract
Methods are disclosed for increasing the effectiveness of
dextromethorphan in treating chronic or intractable pain, for
treating tinnitus and for treating sexual dysfunction comprising
administering dextromethorphan in combination with a
therapeutically effective dosage of a debrisoquin hydroxylase
inhibitor. A preferred combination is dextromethorphan and the
oxidative inhibitor quinidine.
Inventors: |
Smith; Richard Alan (La Jolla,
CA), Licht; Jonathan M. (San Diego, CA) |
Assignee: |
Center for Neurologic Study (La
Jolla, CA)
|
Family
ID: |
22243021 |
Appl.
No.: |
10/052,698 |
Filed: |
January 18, 2002 |
PCT
Filed: |
September 22, 1994 |
PCT No.: |
PCT/US94/10771 |
PCT
Pub. No.: |
WO96/09044 |
PCT
Pub. Date: |
March 28, 1996 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
464792 |
Sep 19, 1996 |
05863927 |
Jan 26, 1999 |
|
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Current U.S.
Class: |
514/289; 514/305;
514/491; 514/649; 514/651; 514/652; 514/654 |
Current CPC
Class: |
A61P
43/00 (20180101); A61P 15/00 (20180101); A61K
45/06 (20130101); A61P 11/14 (20180101); A61P
25/02 (20180101); A61P 27/16 (20180101); A61P
25/04 (20180101); A61K 31/49 (20130101); A61K
31/485 (20130101); A61P 25/00 (20180101); A61P
17/00 (20180101); A61K 31/49 (20130101); A61K
31/485 (20130101); A61K 31/485 (20130101); A61K
31/415 (20130101); A61K 31/485 (20130101); A61K
31/145 (20130101); A61K 31/485 (20130101); A61K
31/135 (20130101); A61K 31/49 (20130101); A61K
31/485 (20130101); A61K 31/485 (20130101); A61K
2300/00 (20130101); A61K 31/49 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
45/06 (20060101); A61K 45/00 (20060101); A61K
031/44 (); A61K 031/265 (); A61K 031/135 () |
Field of
Search: |
;514/289,305,491,649,651,652,654 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Dickenson, A.H., "A cure for wind up: NMDA receptor antagonist as
potential analgesics," Trends in Pharm. Sci., 11:307-309 (1990).*
.
Dickenson, A.H., et al., "Dextromethorphan and levorphanol on
dorsal horn nociceptive neurones in the rat," Neuropharmacology,
30: 1303-1308 (1991).* .
France, C. P., et al., "Analgesic Effects of Phencyclidine-Like
Drugs in Rhesus Monkeys," J. Pharmacol. Exp. Therapeutics, 250:
197-201 (1989).* .
Mao, J., et al., "Intrathecal treatment with dextrorphan or
ketamine potently reduces pain-related behaviors in a rat model of
peripheral mononeuropathy," Brain Research, 605: 164-168 (1993).*
.
McCarthy, J.P., "Some less familiar drugs of above," Med. J.
Australia 1971 (2): 1078-1081 (1971).* .
McQuay, H. J., et al., "Dextromethorphan for the treatment of
neurophatic pain: a double-blind randomised controlled crossover
trial with integral n-of-1 deisgn," Pain, 59: 127-133 (1994).*
.
Tortella, F.C., et al., "Dextromethorphan and neuromodulation: old
drug coughs up new activities," Trends in Pharm. Sci, 10: 501-507
(1989).* .
Zhang et al. "Dextromethorphan: Enhancing its Systemic Availablity
by Way of Low-dose QWuinidine-mediated Inhibition of Cytochrome
P45O2D6," Clin. Pharm. ? Ther., 51(6) :647-655 (1992)..
|
Primary Examiner: Spivack; Phyllis G.
Attorney, Agent or Firm: Knobbe, Martens, Olson & Bear,
LLP
Parent Case Text
.[.This application is a 371 of PCT/US94/10771, filed Sep. 22,
1994..]. .Iadd.This application is the 35 U.S.C. .sctn.371 national
stage application of PCT application No. PCT/US94/10771 filed Sep.
22, 1994, which is a continuation-in-part of application Ser. No.
08/114,845 filed Sep. 2, 1993, issued as U.S. Pat. No. 5,366,980 on
Nov. 22, 1994, which is a continuation-in-part of application Ser.
No. 07/896,053 filed Jun. 9, 1992, now abandoned..Iaddend.
Claims
We claim:
1. A method of increasing the effectiveness of dextromethorphan in
treating chronic or intractable pain, comprising administering to a
patient suffering from chronic or intractable pain a
therapeutically effective dosage of dextromethorphan or a
pharmaceutically acceptable salt thereof, in combination with a
therapeutically effective dosage of a debrisoquin hydroxylase
inhibitor.
2. The method of claim 1 wherein the debrisoquin hydroxylase
inhibitor is selected from the group consisting of quinidine,
quinine, and pharmaceutically acceptable salts thereof.
3. The method of claim 2 wherein quinidine is administered at a
dosage not exceeding about 300 milligrams per day.
4. The method of claim 1 wherein the debrisoquin hydroxylase
inhibitor is selected from the group consisting of disulfiram,
fluoxetine, propranolol, nortriptyline, and pharmaceutically
acceptable salts thereof.
5. A method of using dextromethorphan to treat chronic or
intractable pain, comprising administering, to a patient suffering
from chronic or intractable pain, dextromethorphan or a
pharmaceutically acceptable salt thereof in combination with a
debrisoquin hydroxylase inhibitor, wherein the dextromethorphan or
salt thereof and the inhibitor are administered at combined dosages
which render the dextromethorphan therapeutically effective in
substantially reducing chronic or intractable pain, without causing
unacceptable side effects.
6. The method of claim 5 wherein the debrisoquin hydroxylase
inhibitor is selected from the group consisting of quinidine,
quinine, and pharmaceutically acceptable salts thereof.
7. The method of claim 6 wherein quinidine is administered at a
dosage not exceeding about 300 milligrams per day.
8. The method of claim 5 wherein the debrisoquin hydroxylase
inhibitor is selected from the group consisting of disulfiram,
fluoxetine, propranolol, nortriptyline, and pharmaceutically
acceptable salts thereof.
9. A method of using dextromethorphan in treating tinnitus,
comprising administering, to a patient suffering from tinnitus,
dextromethorphan or a pharmaceutically acceptable salt thereof in
combination with a debrisoquin hydroxylase inhibitor, wherein the
dextromethorphan or salt thereof and the debrisoquin hydroxylase
inhibitor are administered at combined dosages which render the
dextromethorphan thereof therapeutically effective in substantially
reducing tinnitus without causing unacceptable side effects.
10. The method of claim 9 wherein the debrisoquin hydroxylase
inhibitor is selected from the group consisting of quinidine,
quinine, and pharmaceutically acceptable salts thereof.
11. The method of claim 10 wherein quinidine is administered at a
dosage not exceeding about 300 milligrams per day.
12. The method of claim 9 wherein the debrisoquin hydroxylase
inhibitor is selected from the group consisting of disulfiram,
fluoxetine, propranolol, nortriptyline, and pharmaceutically
acceptable salts thereof.
13. A method for treating sexual dysfunction, comprising
administering to a patient in need thereof dextromethorphan or a
pharmaceutically acceptable salt thereof in combination with a
debrisoquin hydroxylase inhibitor, at combined dosages which render
the dextromethorphan thereof therapeutically effective in treating
the sexual dysfunction.
14. The method of claim 13 wherein the patient is a male who
suffers from priapism or premature ejaculation.
15. The method of claim 13 wherein the debrisoquin hydroxylase
inhibitor is selected from the group consisting of quinidine,
quinine, and pharmaceutically acceptable salts thereof.
16. The method of claim 15 wherein quinidine is administered at a
dosage not exceeding about 300 milligrams per day.
17. The method of claim 13 wherein the debrisoquin hydroxylase
inhibitor is selected from the group consisting of disulfiram,
fluoxetine, propranolol, nortriptyline, and pharmaceutically
acceptable salts thereof.
18. A unit dosage formulation for treatment of chronic or
intractable pain, comprising: (a) dextromethorphan or a
pharmaceutically acceptable salt thereof, and, (b) a debrisoquin
hydroxylase inhibitor, in a combined form that is designed for oral
ingestion by humans, wherein the dextromethorphan or salt thereof
and the debrisoquin hydroxylase inhibitor are present at a combined
dosage which renders the dextromethorphan therapeutically effective
in substantially reducing chronic or intractable pain, without
causing unacceptable side effects.
19. The unit dosage formation of claim 18, comprising a digestible
capsule which encloses the dextromethorphan or pharmaceutically
acceptable salt thereof and the debrisoquin hydroxylase
inhibitor.
20. The unit dosage formulation of claim 18, wherein the
debrisoquin hydroxylase inhibitor is selected from the group
consisting of quinidine, quinine, and pharmaceutically acceptable
salts thereof.
21. The unit dosage formulation of claim 20, wherein the dosage of
quinidine is 300 milligrams/day or less.
22. The unit dosage formulation of claim 18, wherein the
debrisoquin hydroxylase inhibitor is selected from the group
consisting of disulfiram, fluoxetine, propranolol, nortriptyline,
and pharmaceutically acceptable salts thereof.
Description
BACKGROUND OF THE INVENTION
This invention relates to pharmacology. More specifically, the
invention relates to compositions of matter useful for preparing
medicaments for the treatment of various disorders.
A number of chronic disorders have symptoms which are known to be
very difficult to treat, and often fail to respond to safe,
non-addictive, and non-steroid medications. Such disorders, such as
intractable coughing, fail to respond to conventional medicines and
must be treated by such drugs as codeine, morphine, or the
anti-inflammatory steroid prednisone. These drugs are unacceptable
for long-term treatment due to dangerous side-effects, long-term
risks to the patient's health, or the danger of addiction. Other
disorders, such as dermatitis, have no satisfactory treatment for
the severe itching and rash at this time. Drugs such as prednisone
and even tricyclic antidepressants, as well as topical
applications, have been tried, but do not appear to offer
substantial and consistent relief.
Chronic pain due to conditions such as stroke, cancer, trauma, as
well as neuropathic pain resulting from conditions such as diabetes
and shingles (herpes zoster), for example, is also a problem which
resists treatment. Chronic pain is estimated to affect millions of
people. A variety of therapies for this type of pain have been
tried, but there remains a need for safe and effective
treatments.
The compound dextromethorphan, or (+)-3-methoxy-N-methylmorphinan,
has been used as a cough suppressant ingredient in cough syrups.
Dextromethorphan has also been tested as a potential therapeutic
agent for stroke, and progressive neurodegenerative diseases such
as Parkinson's disease, Alzheimer's disease and amyotrophic lateral
sclerosis. However, the effectiveness of dextromethorphan for the
treatment of any disorder has been limited because it is rapidly
broken down by the liver and excreted in most individuals.
It is an object of the present invention to provide a combination
of compounds useful for the preparation of medicaments which will
effectively treat formerly intractable conditions not responsive to
other medications. It is also an object of the present invention to
provide medicaments which are safe, non-addictive, and relatively
free of side-effects for patients suffering from long-term
intractable conditions.
SUMMARY OF THE INVENTION
The present invention provides compounds which are useful in the
preparation of medicaments for the treatment of a variety of
disorders including intractable coughing, dermatitis, chronic pain,
tinnitus and sexual dysfunction. These compounds are a
therapeutically effective dosage of dextromethorphan and a
therapeutically effective dosage of a second agent, an inhibitor of
enzymatic dextromethorphan oxidation. This combination of compounds
can be administered together, or individually. A preferred
combination is dextromethorphan and the oxidative inhibitor
quinidine. Inhibitors which may also be used include quinine,
yohimbine, fluoxetine, haloperidol, ajmaline, lobeline, and
pipamperone.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the relationship between DM oral dosages and DM plasma
concentrations in patients receiving 150 mg/day of quinidine
orally.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions
As used herein the term dextromethorphan (hereinafter, DM) refers
to (+)-3-methoxy-N-methylmorphinan, or therapeutically effective
salts and analogs thereof.
As used herein the term "antioxidants" or "oxidative inhibitors"
refers to inhibitors capable of inhibiting the oxidation of DM by
the liver enzyme debrisoquin hydroxylase.
As used herein, the term "intractable" or "refractory" coughing
refers to coughing that will not respond adequately to
non-addictive, non-steroid medications.
As used herein, the term "dermatitis" or "eczema" refers to a skin
condition which includes visible skin lesions which may be
accompanied by an itching or burning sensation on the skin. This
condition does not readily respond to non-prescription drugs,
lotions, or ointments.
As used herein the term "chronic pain" refers to long-term pain
resulting from conditions such as stroke, cancer and trauma, as
well as neuropathic pain due to deterioration of nerve tissue such
as postherpetic neuralgia (PHN) resulting from herpes zoster
infection, and diabetic neuropathy resulting from long-time
diabetes.
As used herein the term "tinnitus" refers to a syndrome
characterized by a high-pitched ringing in the ears thought to be
induced by loss of motility of the outer hair cells of the cochlea
of the ear.
The present invention provides compositions for use in the
preparation of medicaments for the effective treatment of a variety
of chronic and intractable disorders which failed to respond to
other treatments. These compositions are a therapeutically
effective dosage of dextromethorphan (DM), or a pharmaceutically
acceptable salt or analog thereof, in combination with a
therapeutically effective dosage of an inhibitor of enzymatic
dextromethorphan oxidation by the liver enzyme debrisoquin
hydroxylase. The chronic and intractable disorders which have
responded to medicaments containing a dextromethorphan/antioxidant
combination include intractable coughing, dermatitis, chronic pain
and tinnitus. Relatively potent antioxidants include quinidine and
quinine. Other antioxidants which are milder include yohimbine,
fluoxetine, haloperidol, ajmaline, lobeline, pipamperone.
It has been found that the use of quinidine and other oxidation
inhibitors when administered in conjunction with DM has pronounced
effect in increasing and stabilizing the quantity of DM circulating
in the blood of a patient. This effect is discussed in U.S. Pat.
No. 5,166,207 to Smith, issued Nov. 24, 1992, and in Zhang, Y.,
Clin. Pharmacol. Ther. 51: 647-655 (1992), both of which are herein
incorporated by reference.
Dextromethorphan (hereinafter DM) is the common name for
(+)-3-methoxy-N-methylmorphinan. This compound is described in
detail in Rodd et al., Chemistry of Carbon Compounds, Elsevier
Publ., New York (1960), for example, which is herein incorporated
by reference. DM is a non-addictive opioid having a dextrorotatory
enantiomer (mirror image) of the morphinan ring structure which
forms the molecular core of most opiates.
DM has been used as an ingredient of cough suppressant in
over-the-counter cough syrup. The cough-suppressing activity of DM
is thought to be due primarily to its actions as an agonist on a
class of neuronal receptors known as sigma receptors or
high-affinity dextromethorphan receptors. Although these receptors
are sometimes referred to as sigma opiate receptors, it is not
clear whether they are in fact opiate receptors. Sigma receptors
are inhibitory receptors and the activation of these receptors by
DM or other sigma agonists causes the suppression of certain types
of nerve signals. Dextroinethorphan is also thought to act on
another class of receptors known as N-methyl-D-aspartate (NDMA)
receptors, which are one type of excitatory amino acid (EAA)
receptor. Unlike its agonist activity at sigma receptors, DM acts
as an antagonist at NMDA receptors, suppressing the transmission of
nerve impulses mediated through NMDA receptors. Since NMDA
receptors are excitatory receptors, the action of DM as an NMDA
antagonist also results in the suppression of nerve signals. In
addition, DM has been reported to suppress activity at neuronal
calcium channels. It is the antagonist activity of DM at NMDA
receptors which is through to be one of the common links between
some of the various conditions which respond to medicaments
containing a DM/antioxidant combination.
When used in therapeutic applications, DM disappears rapidly from
the bloodstream of most individuals, as described in Dayer et al.,
Clin. Pharmacol. Ther. 56:34-30 (1989), Vetticaden et al.,
Pharmaceut. Res. 6:13-19 (1989), and Ramachander et al., J. Pharm.
Sci. 66: 1047-1049 (1977), which are herein incorporated by
reference. DM is broken down in the liver into several metabolites.
DM can be oxidized by O-dimethylation, in which one of the methyl
groups is removed and two metabolites, dextrorphan and
3-methoxymorphinan, are produced. If the second methyl group is
removed, the resulting metabolite is 5-hydroxymorphinan.
Dextrorphan is known to have many of the biological activities of
DM. However, dextrorphan and 5-hydroxymorphinan become covalently
bonded to other compounds in the liver, primarily glutathione to
form glucuronide or sulfate conjugates, which can not readily cross
the blood-brain barrier and which are quickly eliminated from the
body in the urine.
The particular enzyme primarily responsible for DM oxidation is
debrisoquin hydroxylase, also known as sparteine monooxygenase, and
also referred to in the literature variously as cytochrome
P-450.sub.DB, as cytochrome P-450db1 (or db1 ), and as cytochrome
P-4502D6. Hereinafter, this enzyme is referred to as debrisoquin
hydroxylase. Debrisoquin hydroxylase belongs to the family
"cytochrome P-450" enzymes, or as "cytochrome oxidase" enzymes.
These enzymes typically found in high concentrations in liver cells
primarily in liver microsomes, and in lower concentrations in
various other organs and tissues such as the lungs. By oxidizing
lipophilic compounds, cytochrome oxidase enzymes eliminate
compounds from the body that might otherwise act as toxins or
accumulate to undesired levels. Typically, oxidation renders
lipophilic compounds more soluble in water and therefore, more
easily eliminated in the urine or in aerosols exhaled out of the
lungs. The debrisoquin hydroxylase enzyme apparently is also
present in brain tissue (Fonne-Pfister et al., Biochem. Biophys.
Res. Communic. 148: 1144-1150 (1987), Niznik et al., Arch. Biochem.
Biophys. 26:424-432 (1990), Tyndate et al., Mol. Pharmacol.
40:63-68 (1991)), although its function in the brain is not fully
understood.
Dextromethorphan is widely available over-the-counter in cough
syrups, at dosages up to about 120 mg/day for an adult. This
invention anticipates DM dosages in the range of about 20 mg/day to
about 200 mg/day, preferably in the range of 20 to 150 mg/day,
depending on factors such as the weight of the patient, the
severity of the disorder, and the potency and dosage of the
antioxidant agent used in conjunction with DM.
Quinidine is a dextrorotatory steroisomer of quinine. Quinidine is
commonly used to treat cardiac arrhythmias, and is considered a
relatively strong cardiac medicine. Quinidine is commercially
available from a number of sources, for example, A H. Robins,
Richmond, Va., but is available to the public only with a doctor's
prescription. Both DM and quinidine are commercially available in
powder form, and capsules of a specific dosage can be prepared as
desired by commercial vendors. The dosage of quinidine which was
found to provide a major increase in DM concentration in the blood
of most patients was equal to or less than 150 mg/day, depending on
the individual. The present invention contemplates dosages ranging
from 50 mg/day to 300 mg/day, preferably from 50 mg/day to 150
mg/day. In some patients a dosage of about 50 mg/day is found to be
effective. In contrast the dosage used for anti-arrhythmic control
in cardiac patients is between 600-1200 mg/day.
A number of antioxidants other than quinidine have already been
identified in the literature, using in vitro screening. These are
reported in Inaba et al., Drug Metabolism and Disposition
13:443-447 (1985), Fonne-Pfister et al., Biochem. Pharmacol.
37:3829-3835 (1988) and Broly et al., Biochem. Pharmacol.
39:1045-1053 (1990), all of which are herein incorporated by
reference. As reported in Inaba et al., agents with a K.sub.i value
(Michaelis-Menton inhibition values) of 50 micromolar or lower
include nortriptyline, chlorpromazine, domperidone, haloperidol,
pipamperone, labetalol, metaprolol, oxprenolol, propranolol,
timolol, mexiletine, quinine, diphenhydramine, ajmaline, lobeline,
papaverine, and yohimbine. Preferred compounds having particularly
potent inhibitory activities include yohimbine, haloperidol,
ajmaline, lobeline, and pipamperone, which have K.sub.i values
ranged from 4 to 0.33 .mu.M. In comparison, the K.sub.i value of
quinidine is 0.06 .mu.M. of these inhibitors quinine sulfate,
disulfiram, cimetidine, fluoxetine, propranolol, and nortriptyline
were tested for the ability to stabilize the concentration of DM in
the blood stream, as described in detail in Example 4 below. As
expected, the results of these studies show an increase in levels
of DM which is not as pronounced as that when DM is co-administered
with quinidine. In addition, the results indicated substantial
variations between individuals in the effect of each antioxidant.
Quinine, having a structure similar to quinidine, was shown to be
effective in increasing DM/DRP ratios in the individuals tested.
Other drugs showed more variability among individuals. This
variability indicates that individual antioxidants would be
pre-tested using the methodology described in Example 4 below,
before using on patients. It should also be noted that a number of
antioxidants have their own pharmaceutical effects, which vary
widely, and which would be taken into consideration by a
prescribing physician. Dosages of other antioxidants will vary with
the antioxidant, and should be determined on an individual basis
using the protocal described in Example 4.
In addition to the antioxidants reported above, it has also been
found that fluoxetine, sold by Eli Lilly and Co. under the trade
name Prozac, is effective in increasing DM concentrations in the
blood of some people. For example, a single patient who was taking
20 mg fluoxetine twice a day registered a blood level of 40 ng/ml
of DM when administered DM according to the testing outlined in
Example 4.
The optimal dosage of both dextromethorphan and any of the
antioxidant to be administered to specific patient can be
determined by administering various dosages of each drug and then
(1) analyzing blood samples to determine the concentration of DM in
the circulating blood, and/or (2) evaluating the patient's progress
to determine which combination of dosages provides the best result
in effectively suppress the symptoms being targeted.
A number of factors influence the dosage of DM and antioxidant
which would be appropriate for a particular individual. One very
important factor is the individual's ability to metabolize DM. It
is known that a substantial fraction of the general public,
estimated from 7 to 10%, do not have a properly functioning gene
encoding the debrisoquin hydroxylase enzyme. These persons are
referred to by doctors and pharmacologists as "poor metabolizers",
while those having the gene encoding debrisoquin hydroxylase are
known as "extensive metabolizers". "Poor metabolizers" are regarded
as somewhat high-risk patients who must be treated with special
care and attention, since they are overly sensitive to certain
drugs that can be prescribed safely to people who have the full set
of cytochrome P450 enzymes.
In addition to the inhibition of debrisoquin hydroxylase, other
cytochrome P450 isozymes are also likely to be suppressed by
quinidine or other inhibitors, with varying levels of binding
affinity. This is described in articles such as Kupfer et al.,
Lancet ii:517-518 (1984) and Guttendorf et al., Ther. Drug. Monit.
10:490-498 (1988), which are herein incorporated by reference. In
addition, cytochrome P-450 enzymes are non-specific to the extent
that a single isozyme can react with numerous substrates having
widely different chemical structures, and various isozymes are
known to have overlapping activity on a single substrate.
Accordingly, even though quinidine exerts its most marked effect on
debrisoquin hydroxylase, it may suppress a number of other
cytochrome P450 enzymes as well, thereby subjecting a patient to a
more general loss of normal and desirable liver activity.
Since DM is considered to be a safe drug which is readily available
as an over-the-counter medication, it can be used as a convenient
tool or probe drug for determining whether a patient is a extensive
metabolizer or a poor metabolizer. Such diagnostic tests are
performed so that a patient who is a "poor metabolizer" can be
identified and protected against various drugs which he or she
cannot metabolize properly. However, if a patient is taking a drug
such as quinidine, the level of enzymes will be inhibited, and the
diagnostic test for identifying "poor metabolizers" will not be
accurate, and will reflect the presence of the inhibitor.
In addition, DM may cause side effects in some people such as
diarrhea, drowsiness, lightheadedness, or loss of appetite, and in
some cases, impotence in male patients. The likelihood and severity
of such side-effects will be increased by antioxidants, in direct
proportion to the potency of the antioxidant used. Therefore, the
DM-quinidine combination or DM-antioxidant combinations disclosed
herein is currently anticipated for use only under the supervision
of a physician, who would determine the appropriateness of the
treatment. All the appropriate precautions should be taken with the
use of any antioxidant, as would be appreciated by a physician and
others of skill in the art. However, the dosage of quinidine that
provides a substantial increase in DM concentration in the blood is
only a fraction of the dosages normally used for anti-arrhythmic
action.
For some patients, combinations of DM and antioxidants other than
quinidine are preferred for preparing medicaments. In some
instances, individual may not tolerate quinidine or quinidine-DM
combinations, for example, when a patient may be allergic to
quinidine, or if a patient is suffering from a heart condition
known as a prolonged QT interval, and therefore cannot tolerate
quinidine. Less potent oxidation inhibitors are also preferred in
combination with DM for example, as a second agent that can be
alternated with quinidine to avoid developing a tolerance that
would require increasing dosages of quinidine; or for patients who
have a moderate condition such as coughing that will not respond
adequately to other treatments, but which is not severe enough to
require a potent enzyme inhibitor.
It was unexpectedly discovered that DM in conjunction with
quinidine was highly effective in reducing the symptoms of
"emotional lability". Emotional lability is a complex problem in
which patients suffering from bilateral neurological damage
typically due to a stroke or head injury or a neurologic disease
such as ALS or Alzheimer's disease are unable to control spasmodic
emotional outbursts such as explosive laughing or uncontrollable
weeping. In patients suffering from brain damage leading to
emotional lability, such outbursts often occur at very
inappropriate times and without provocation. The ability of DM in
conjunction with quinidine to control emotional lability is
described in U.S. Pat. No. 5,206,248, issued on Apr. 27, 1993,
which is herein incorporated by reference. This effect of
DM-quinidine in controlling emotional lability was not observed in
any patients who received DM alone.
It has now been found that the combination of compounds described
above are extremely effective in medicaments for the treatment for
other chronic disorders which do not respond well to other
treatments. A DM/antioxidant combination can be used to effectively
treat severe or intractable coughing, which has not responded
adequately to non-addictive, non-steroid medications. Intractable
coughing is a consequence of respiratory infections, asthma,
emphysema, and other conditions affecting the pulmonary system.
Tests using a DM-quinidine combination to treat intractable
coughing in human patients is described in Example 5 below. In all
patients tested, treatment with a combination of DM and an
antioxidant provided highly beneficial results with minimal
side-effects. These results clearly confirmed the effectiveness and
utility of the use of DM-antioxidant in preparing medicaments for
treatment of intractable coughing.
This invention also discloses the use of DM in combination with an
antioxidant in preparing medicaments for treating dermatitis. As
used herein, "dermatitis" or "eczema" is a skin condition
characterized by visible skin lesions and/or an itching or burning
sensation on the skin. The effectiveness of the DM-quinidine
combination for treating dermatitis was first observed as an
unexpected beneficial side effect during testing on an ALS patient
who happened to suffer from severe dermatitis. This drug
combination showed a beneficial effect on dermatitis when
subsequently tested by a dermatologic specialist on a non-ALS
patient suffering from severe dermatitis. After these initial
results, an additional study was conducted on several patients
suffering from dermatitis, by administering DM-quinidine capsules
orally. The results showed marked relief from the rash and itching.
Topical administration of DM or DM-antioxidant containing
medicaments is contemplated for person suffering from dermatitis.
These results are described in more detail in Example 6.
It is also contemplated that DM alone can be effective in treating
dermatitis for certain patients who are classified as "poor
metabolizers" due to a genetic inability to express functional
copies of the debrisoquin hydroxylase enzyme. For these individuals
DM alone, at safe dosages, will be sufficient to treat the
dermatitis effectively without requiring concomitant use of an
antioxidant to increase DM levels in the blood.
The present invention also provides for the use of DM and an
antioxidant in medicaments for the treatment of chronic pains from
conditions such as stroke, trauma, cancer, and pain due to
neuropathies such as herpes zoster infections, and diabetes.
Neuropathic pain includes postherpetic neuralgia, and diabetic
neuropathy. Postherpetic neuralgia (PHN) is a complication of
shingles and occurs in approximately 10 percent of patients with
herpes zoster. The incidence of PHN increases with age. Diabetic
neuropathy is a common complication of diabetes which increases
with the duration of the disease. The pain for these types of
neuropathies can be described as the following: burning steady pain
often punctuated with stabbing pains, pins and needles pain, or
toothache-like pain. The skin can be sensitive with dysesthetic
sensations to even light tough and clothing. The pain can be
exacerbated by activity, temperature change or emotional upset. The
pain can be so severe as to preclude daily activities or result in
sleep disturbance or anorexia. The mechanisms involving in
producing pain of these types are not well understood, but may
involve degeneration of myelinated nerve fibers. It is known that
in diabetic neuropathy both small and large nerve fibers
deteriorate and therefore the thresholds for tolerance of thermal
sensitivity, pain, and vibration are reduced over time. Dysfunction
of both large and small fiber functions is more severe in the lower
limbs when pain develops. Most of the physiological measurement of
nerves that can be routinely done in patients experiencing
neuropathic pain demonstrate a slowing of nerve conduction over
time. To date, treatment for neuropathic pain has been less than
universally successful.
Human patients suffering from chronic pain due to stroke, diabetes,
and other causes, were placed on a dosage of DM-quinidine taken
orally. All patients experienced some degree of pain relief after
receiving DM-quinidine for two to four weeks. This study is
described in Example 7 below.
It was noted that a side-effect suffered by some of the male
patients in earlier emotionality studies and the dermatitis studies
described in Example 7 included instances of impotence. This
impotence persisted until the patient stopped taking medication
containing DM-quinidine. Therefore, DM-antioxidants containing
medicaments are contemplated for the treatment of sexual
dysfunctions including priapism or premature ejaculation.
One of the patients involved in the pain studies also suffered from
tinnitus, a syndrome characterized by a high pitched ringing in the
ears. After treatment with DM/quinidine, the patient reported that
the ringing had ceased. Therefore, based on this evidence and the
involvement of NMDA receptors in the cochlear system, the use of
DM/antioxidants in the preparation of medicaments for the treatment
of tinnitus is also contemplated by the present invention.
The medicaments used for treating the various disorders described
above are prepared from DM and an appropriate antioxidant, or
alternatively from the salts and analogs of DM and the various
antioxidants. The terms "salt" and "analog" are used in their
conventional pharmaceutical sense, and are limited to
pharmacologically acceptable and therapeutically effective salts
and analogs of dextromethorphan or an antioxidant as discussed
herein. The term "pharmacologically acceptable" embraces those
characteristics which make a salt or analog suitable and practical
for administration to humans; for example, such compounds must be
sufficiently chemically stable under reasonable storage conditions
to have an adequate shelf life, they must be physiologically
acceptable when orally ingested, and they must not be addictive or
cause unacceptable side effects. Acceptable salts can include
alkali metal salts as well as salts of free acids or free bases.
Acids that may be employed to form acid addition salts include
inorganic acids such as sulfate or chloride salts, as well as
organic acids. Alkali metal salts or alkaline earth metal salts
might include, for example, sodium, potassium, calcium or magnesium
salts. All of these salts can be prepared by conventional means.
Various salts of the compounds described herein which are currently
in widespread pharmaceutical use are listed in sources well-known
to those of skill in the art such as The Merck Index. The
constituent used to make a salt of an active drug discussed herein
is not critical, provided that it is non-toxic and does not
substantially interfere with the desired activity.
A pharmaceutical analog refers to a molecule that resembles a
referent compound but which has been modified to replace one or
more moieties of the referent molecule with alternate moieties or
other substituents that do not ionize and dissociate readily, as
occurs in salts. For example, if a hydrogen or chloride moiety is
replaced by a methyl group, the resulting molecule would be
regarded as an analog. To be covered herein, the analog-producing
substituent must not destroy the anti-tussive or anti-dermatitis or
other activities of the referent molecule.
Administration of the medicaments to be prepared from the compounds
described herein can be by any method capable of introducing the
compounds into the bloodstream. Administration can be orally, or by
parenteral, intravenous, or subcutaneous injection, for example, as
well as by topical or inhalant formulations. In particular topical
administration as lotions or ointments is contemplated to treat
dermatitis. Likewise, inhalable aerosols are contemplated for
treating intractable coughing. An injectable, topical, or inhalant
formulation contains a mixture of active compounds with
pharmaceutically acceptable carriers or diluents. Various other
formulations for oral and injectable medicaments have been
described in U.S. Pat. No. 5,166,207 to Smith, which is herein
incorporated by reference.
EXAMPLES
The initial testing described in Examples 1 to 3 were preformed on
patients having amyotrophic lateral sclerosis (ALS, also called Lou
Gehrig's disease). At the time it was thought that DM might have an
effect in arresting the progression of ALS and other neurological
disorders. Although the studies described in Examples 1 to 3 were
done on patients suffering from ALS, most of whom are adults more
than 40 years old, no differences were detected in the metabolism
of DM in ALS patients, compared to reported findings involving
adults who do not have ALS or to one-day tests involving healthy
volunteers as a control population.
Example 1
Urinary DM/DR Ratios
Six patients suffering from ALS were administered orally a single
60 mg dextromethorphan dose. Several hours later, a urine sample
was collected, and the urine concentrations of dextromethorphan
(DM) and dextrorphan (DR) were measured as described below to
determine a DM/DR ratio. A low DM/DR ratio indicates that DM is
being rapidly oxidized to the DR metabolite in that body of that
patient. In a different week, 60 mg of DM and 150 mg of quinidine
were orally administered to the same patients, and urinary DM and
DR levels and DM/DR ratios were determined again.
DM and DR urinary levels without quinidine were determined by
adding 40 mg of thebaine as an internal standard to 1 mL of urine.
To this was added 2000 units of betaglucuronidase in 1 mL of
acetate buffer (0.1M, pH 5.0). The mixture was incubated for 18
hours at 37.degree. C. and then extracted by adding 1 mL of
phosphate buffer (pH 12, 0.10M) and 7 mL of n-butanol/hexane (10:90
v/v). After mixing and centrifugation, the organic layer was
transferred to a clean tube, acidified with 400 uL of 0.01N HCL and
20 microliters (uL) of aqueous phase injected into a high
performance liquid chromatography (HPLC) system. The HPLC used a
phenyl column equilibrated with a mobile phase of
acetonitrile:water (51:49 v/v) containing 10 mM KHPO.sub.4, 10 mM
hexane sulfonic acid, pH 4.0 (flow rate 1.2 mL/min). Detection of
thebaine, dextromethorphan and dextrorphan was achieved by
fluorescence (Kratos FS-980 Fluorometer) with an excitation
wavelength of 228 nm and no emission cutoff filter.
A gas chromatograph/mass spectroscopy (gc/ms) assay was employed
for determining dextromethorphan and dextrorphan levels in the
presence of quinidine. Briefly, 0.5 ml urine samples were spiked
with 500 nanograms (ng) of dimethacrine. The urine pH was adjusted
to 0.5 with 0.1M acetate buffer (usually about 1.0 ml), and
beta-glucuronidase was added (2000 units/ml urine). The mixture was
incubated and shaken at 37.degree. C. for 18 hours. The urine was
subsequently adjusted to pH 10-11 with 1.0 mL of phosphate buffer
and the urine extracted with 5 mL of dichloromethane. The
dichloromethane extract was evaporated under nitrogen,
reconstituted in 300 uL of BSTFA and injected onto a gc/ms analyzer
equipped with a capillary SE-30 column. Gas chromatographic
conditions were: injector and transfer line temperature 250.degree.
C., oven 70.degree. C. to 260.degree. C. at 20.degree. C. per
minute, and source temperature 180.degree. C. Detection was by
selected ion monitoring at m/z 271 for dextromethorphan, 294 for
the internal standard, and 329 for dextrorphan. Typical standard
curves for dextromethorphan and dextrorphan were provided. Assay
sensitivity was 100 ng/ml for dextromethorphan and 400 ng/ml for
dextrorphan.
The results, in Table 1, indicate that quinidine is a potent
inhibitor of dextromethorphan metabolism. The DM/DR ratio in all
test subjects was increased by at least 2 and usually more than 3
orders of magnitude.
TABLE 1 URINGARY DM/DR RATIOS Patient # DM/DR Ratio, DM/DR Ratio, #
no quinidine 150 mg quinidine 1 0.0048 4.090 2 0.0220 3.460 3
0.0002 0.635 4 0.0003 0.420 5 <0.0002 0.631 6 0.054 3.29
Follow up tests were done on more than 50 people, including ALS
patients and healthy controls who volunteered for one-day tests.
The ALS patients received DM and quinidine on a daily basis over
several weeks, while control subjects received only a single dose
of each drug. The results were very similar to the data contained
in Table 1.
Example 2
Plasma Concentrations of DM
Five patients were orally administered 120 mg of DM, with no
co-administration of quinidine. Between 10 and 12 hours later,
blood was sampled, blood plasma was isolated by centrifugation, and
the plasma was analyzed to determine the DM concentration using the
thebaine/HPLC method.
During a different week, the same patients were orally administered
60 mg of DM (half the control dosage) and 150 mg of quinidine.
Between 10 and 12 hours later, blood was sampled and the plasma was
analyzed for DM using thebaine/HPLC.
The results, in Table 2, indicate that quinidine causes a major
increase in the concentration of DM in the blood plasma.
TABLE 2 Effects of 150 mg/day quinidine on plasma dextromethorphan
levels DEXTRO- DEXTRO- QUINIDINE METHORPHAN METHORPHAN DOSE PATIENT
DOSE PLASMA LEVEL (MG/DAY) 1 120 MG/DAY NOT DETECTABLE 0 60 MG ONCE
33 NG/ML 150 2 120 MG/DAY 9.3 NG/ML 0 60 MG ONCE 29.7 NG/ML 150 3
120 MG/DAY NOT DETECTABLE 0 60 MG ONCE 29.0 NG/ML 150 4 120 MG/DAY
16.5 NG/ML 0 60 MG ONCE 28.8 NG/ML 150 5 120 MG/DAY 6.05 NG/ML 0 60
MG ONCE 45.6 NG/ML 150
Subsequently, plasma levels were determined for about 15 other ALS
patients who received dextromethorphan and quinidine over a
prolonged period of time. The results were very similar to the data
in Table 2.
Example 3
Dose-Response Study
Additional studies were undertaken using a range of dosages of DM
to establish a dose-response curve that correlates with plasma
concentrations 10 to 12 hours later (determined as described in
Example 2). All patients received 150 mg of quinidine daily. The
results of those studies are shown in graphical form in FIG. 1,
with mean values shown as open squares and standard deviation
ranges shown by vertical bars. The ascending line through the
median values is a linear approximation; a curve based on more
extensive data would probably show a horizontal asymptote.
The results of the tests described in the foregoing Examples
indicate that if quinidine is co-administered with DM, then DM
circulation in the blood is increased and prolonged, without
causing severe side effects. Accordingly, the co-administration of
an antioxidant compound such as quinidine in conjunction with DM
can increase the effectiveness of DM in any context that depends
upon the concentration of DM circulating in the blood.
Example 4
Use of Other Antioxidants
Since some patients cannot tolerate quinidine well, the ability of
several other candidate antioxidants to inhibit DM oxidation in
various people were tested. In these tests, DM was administered at
a constant dosage to various individuals, all were healthy
volunteers. DM was taken both before and after a candidate
antioxidant was taken, and urine samples were collected at
appropriate times and analyzed to determine the quantity of DM and
its principle metabolite dextrorphan (DRP) in the urine. A DM/DRP
ratio of zero indicated that substantially all of the DM had
metabolized into DRP in that patient. A ratio higher than zero
indicated that the DM had not been completely metabolized, and a
significant quantity of DM remained in the urine.
Twelve healthy volunteers were studied. A first urine sample was
taken after initial DM administration, before any antioxidant was
administered, to determine a baseline value for that person, and
all volunteers were confirmed to be "extensive metabolizers" with
baseline DM/DRP ratios or 0.06 or less, except for one "poor
metabolizer" with a DM/DRP ratio of 1.338, used to provide a
control. Urine samples were analyzed using high performance liquid
chromatography (HPLC) to quantitatively evaluate the areas
contained within the chromatography peaks displayed by DM and its
principle oxidized metabolite (dextrorphan, DRP). A DM/DRP ratio
higher than zero indicated that the DM was not completely
metabolized and that a significant quantity of DM is present in the
urine of the patient; a ratio of 0 indicates that substantially all
of the DM was metabolized into DRP.
After the baseline DM/DRP value for each volunteer had been
determined, a candidate antioxidant was administered. These agents
included quinine sulfate, disulfiram, cimetidine, fluoxetine,
propranolol, and nortriptyline. After an appropriate delay, a
second urine sample was obtained and analyzed. Each agent was
administered to two patients.
The most potent results observed in these tests were from quinamm
(quinine sulfate). In one subject, the DM/DRP ration increased from
0.02 (pre-quinine baseline) to 0.09; in the other subject, the
DM/DRP ration increased from 0.00 to 0.05. When the other candidate
agents were tested, the results indicated high levels of
variability between different individuals. For example, in the two
subjects who took fluoxetine, the DM/DRP ratio for one increased
from 0.00 (pre-drug baseline) to 0.11, while in the other, the
ratio decreased from 0.03 to 0.00. In the two subjects who took
propranolol, the DM/DRP ratio increased from 0.00 to 0.02 in one,
while in the other it decreased from 0.02 to 0.00. In the two
subjects who took disulfiram, the DM/DRP ratio increased from 0.06
to 0.08 in one, while it decreased from 0.06 to 0.00 in other.
These levels of variability were not surprising, since it is well
known that different people have important variations in their
oxidative enzymes.
Example 5
Tests On Patients With Intractable Coughing
Three patients were tested under a doctor's supervision, all of
whom had been suffering from intractable coughing that had
persisted for months. One patient was previously treated with
prednisone, an anti-inflammatory steroid, which has adverse
long-term side effects. A second patient had coughed for 8 months
following a respiratory infection, and would only respond
temporarily to cough syrup containing codeine, which is addictive
and cannot be taken for long periods. A third patient had such
severe coughing following a respiratory infection that he suffered
several broken several ribs. Antibiotics for a respiratory
infection and anti-inflammatory inhalant drugs were prescribed for
a suspected asthmatic condition.
The initial tests on three patients with intractable coughing
indicated highly effective results, with virtually no side
effects.
Patient EAR, a 70 year old female, had suffered from a recurrent
persistent non-productive cough for several years. This cough would
respond to prednisone administration, but it would return shortly
after the prednisone was discontinued, and continuous medication
with prednisone was deemed to be unacceptable. She had tried
various cough syrups, with little benefit, and her cough had not
responded well to albuteral (a beta-adrenergic bronchodilator) or
ipratropium bromide (an anticholinergic bronchodilator); both were
administered using a nebulizer-type inhaler. When she was given 1
capsule per day of 75 mg quinidine and 60 mg DM, the cough
initially stopped but returned after several days. When the dosage
was increased to 2 capsules/day, the cough stopped and did not
return. She reported no side effects.
Patient SP, a 38 year old male nonsmoker with no history of asthma,
had suffered for about 8 months from a persistent non-productive
cough. It receded temporarily when he was given penicillin and a
cough syrup with codeine, but it returned after he stopped taking
codeine. When he began taking 1 capsule per day of 75 mg quinidine
and 60 mg DM, and after a few days, the cough stopped almost
completely, and he coughed only rarely during the day. He reported
no side effects.
Patient RC, a 43 year old male nonsmoker with no history of asthma,
suffered for about 5 months from a cough, which initially began
with an upper respiratory viral infection followed by a bacterial
infection. The coughing became so severe that it led to fractured
ribs. When he first sought medical attention, the cough produced
yellow phlegm. The phlegm was cleared up by antibiotics but the
cough persisted despite inhalation treatment for a suspected asthma
condition with flunisolide (an anti-inflammatory steroid) and
inhalation treatment with albuterol. The cough did not
substantially improve when the patient took only 1 capsule/day, but
when he began taking 2 capsules/day, it improved by roughly 90%
within a few days. Although he occasionally coughed, his condition
improved so much that he sometimes forgot to take his medication.
He reported no side effects.
In all cases, the patients were delighted with the results. The
combined DM-antioxidant treatment was very effective in almost
completely eliminating coughing that could not be treated
adequately by any other medications, and the DM-antioxidant
treatment caused minimum reported side effects. The results clearly
confirm the effectiveness and utility of the invention.
Example 6
Treatment of Dermatitis
During an initial examination, it was discovered that patient BT, a
Caucasian female in her 60's who was suffering from ALS, suffered
from a severe dermatologic condition involving lesions which appear
in small patches. Her condition had been diagnosed as atopic
dermatitis. The etiology is unknown. The patient reported that the
lesions were severely itchy, and she had been suffering from it for
roughly ten years. She had been prescribed a number of drugs
(including various steroids such as prednisone) in an effort to
control the itching; the most recent prescription was "Doxepin," a
tricyclic antidepressant. None of those agents offered much
relief.
The patient began an initial treatment of quinidine alone (150
mg/day) for a week. After it had been established that she did not
have an adverse reaction, she began to receive DM as well,
beginning at 30 mg/day, and increasing after 1 month to 120
mg/day.
During the second monthly visit after beginning the DM/quinidine
treatment, it was found that the patient had obtained an almost
total cessation of any itching sensations, with partial resolution
of her lesions. A follow-up exam some weeks later indicated that
the patient's skin lesions had completely healed with no apparent
evidence of scar tissue.
After seeing this result, additional tests were performed by a
dermatologic specialist at a nearby university. The first test by
the specialist involved a male Caucasian who suffered from severe
but intermittent dermatitis. The relapse resolved in less than two
weeks after starting treatment. Due to the intermittent nature of
the patient's dermatitis, this result could not be conclusively
attributed to the DM-antioxidant combination; nevertheless, the
disappearance of the relapse promptly after DM-antioxidant
treatment began strongly suggested that the DM-antioxidant
combination probably had a substantial beneficial effect.
After the initial successes described above, additional studies to
determine the effectiveness of DM/quinidine for treating dermatitis
were carried out as follows. Patients suffering from dermatitis
were first evaluated as to general physical condition, and also
evaluated by the physician using a "standardized disease activity
scoring" or "lesion score" for the severity of the dermatitis
condition. The standardized disease activity score or lesion score
is completed by the examining physician who scores on a severity
scale of 1 to 5 for both erythema and surface damage for a given
area (1 to 5 in size) on the patient's body. The total score was
then calculated. The patient indicated on a subjective visual scale
the severity of itching and rash due to dermatitis. DM/quinidine
were taken in capsule form of 30 mg DM and 75 mg quinidine per
capsule. The patient was usually re-examined in two weeks, and then
again six weeks or more after the initial exam and receiving the
DM/quinidine capsules.
Patient #1 was a 40 year old female patient who suffered from
atopic eczema since birth, which flares up with stress. The patient
was initially evaluated using the standardized disease activity
scoring system and filling out the subjective itching/rash analysis
forms. The initial score was 42. The patient indicated the initial
itching score as severe, and rash as severe to moderate.
The patient reported side effects of nausea and headache as side
effects, and stopped the drugs after five days. She was then placed
on a reduced dosage of 30 mg/25 mg DM/quinidine per day.
Subsequently, the patent reported the rash and itching almost
totally cleared within five days. The two week evaluation showed
the patients' total standardized disease activity score was reduced
dramatically to 13. The patient's face in particular was strikingly
improved. At two weeks, the patient reported the itching reduced to
moderate to slight and the rash reduced to moderate to slight. Four
weeks later, the patient reported continued headache side effects
even when on a reduced dosage. However, the total standardized
disease activity score remained lower than initially with a total
score of 24. She reported itching in the severe to moderate range,
and rash in the moderate range.
Patient #2 was a fifty five year old male with a 20 year history of
chronic eczema. The rash was located mainly on the thighs. The
initial total standardized disease activity score was initially 12.
The patient received a 30 mg/75 mg dosage of DM/quinidine once a
day for 5 days, then every 12 hours for the duration. The patient
initially reported severe itching and moderate rash. After about 1
month the lesion score remained at 12, but the patient reported
itching was reduced to the low moderate range and the rash was
reduced to the moderate to slight range. The medications were
eventually discontinued due to side effects.
Patient #3 was a fifty four year old male who began suffering from
eczema seven or eight years ago. The initial physical exam showed
fairly generalized excoriated eczematory dermatitis, which was
especially severe on his lower legs. The rash was prone to a
secondary infection. The initial lesion score was 112. The patient
initially rated his itching as moderate and rash as low moderate.
The patient received a 30 mg DM/75 mg quinidine capsule once a day
for five days, then every 12 hours for the duration.
After two and a half months, the patient was again evaluated, and
received a lesion score of 90. The overall appearance was reported
to be improved, and the rash less red. However, the patient
reported the same degree of itching and rashes. The patient
reported some side effects, most of which disappeared after a few
days. However, the patient reported a delay in reaching orgasm, a
side-effect which persisted as long as the medications were
continued.
Due to the reports of side effects in some patients, the
application of DM/quinidine as a topical cream is considered for
the treatment of dermatitis.
Example 7
Treatment of Pain
The following pain studies were undertaken to determine if the
dextromethorphan/quinidine composition moderates or arrests chronic
pain. The effect of the treatment was determined by a patient
questionnaire and clinical assessment of the patients by a study
physician.
The patient questionnaire asks the patient to assess his or her
current level of pain using a linear visual analog scale of 10
where the pain is rated from 10, "pain as bad as it could be" to 0,
"no pain". After taking the medications for several weeks, the
patients are asked to indicate the current level of pain, as well
as to indicate the degree of pain abatement using a linear visual
analog pain relief scale of 10 rated from 10, no pain relief to
complete 0, pain relief.
The DM dosage administered to the subjects of the study were a
total daily dose up to 120 mg of DM, varying with the individual,
taken in a capsule formulation in combination with quinidine.
Quinidine was administered twice daily with DM up to a total daily
dosage 150 mg, varying with the individual subject.
Patient #1 was a 73-year-old female, with a history of diabetes
diagnosed ten years earlier. She reported burning and tingling of
her feet for two years, which had been increasingly bothersome in
the past year. The patient noticed the sensations particularly when
she was walking or standing and also at night. The patient did not
notice any similar sensations in her hands and denied any
significant neck or back pain. The neurological exam was normal,
except for the sensory portion of the exam which showed decreased
appreciation of pinprick, light touch, and vibratory sense in her
distal lower extremities. The neurophysiological assessment
confirmed a diagnosis of sensorimotor polyneuropathy.
Prior to going on medication, the patient filled out a visual
analog scale, describing her level of pain both on April 11 and
shortly before beginning medication on April 25. The patient
initially assessed her pain as 3-4 on the pain scale, with 10
indicating pain as bad as it could be. The patient started her
medication shortly thereafter, taking 30 mg of dextromethorphan and
75 mg of quinidine once a day.
The follow up exam was give approximately a month later on May 9.
The patient reported to be feeling better with much less pain. She
noted the tingling in her feet and pain in her right leg was
alleviated. Her sleep patterns were the same. She reported there
were no side effects taking DM/quinidine at a dosage of 30 mg/75 mg
twice a day. At that point her dosages were increased to 60 mg of
dextromethorphan and 75 mg of quinidine twice a day.
Two weeks later on May 19, the patient filled out a visual analog
pain relief scale, indicating that the level of pain was
substantially improved, now rated as 1 to 2 with 10 rated as pain
as bad as it could be, indicating that she had obtained significant
pain relief. The overall impression was that her pain was much
better. She reported feeling well with no side effects. The
tingling had diminished compared to the past when it occurred 3 to
4 times per week. On May 23 the patient reported her level of pain
as between 0 and 1, which 0 indicating not pain. The patient then
stopped taking the DM/quinidine and reported back on May 27 that
she was well without any significant return of pain. On May 31,
1994 she reported that the tingling in feet and hands had returned
and she was not sleeping as well. The patient then requested to be
placed back on the medication.
Patient #2 was a 53-year-old male with painful sensations on his
right side. This patient had suffered from a stroke in 1991. A CT
scan at the time showed a left posterior cerebral infarct. The
patient also had coronary artery disease and bypass surgery in
1991, and suffered from diabetes and hypertension. Neurological
findings included visual and sensory loss, and right-sided
weakness. Over the past 4 to 5 months, the patient had noted a
buzzing sensation on his right side and an icy or heat sensation,
which affected the right side of his face, arm, chest and leg. His
left side was unaffected. This unpleasant sensation was
particularly bothersome at night occurring for up to five minutes
at a time, and off and on all day long. The buzzing sensation was
generally always present. The sensation was uncomfortable, not very
painful at times, but caused the patient a great deal of anxiety.
In addition, the patient has noted some tingling in the bottom of
both feet from time to time, a high pitched hum in his ears and
lightheadedness when his head was tipped back. In addition, this
patient had reported tinnitus.
The patient was assessed by the examining physician as having
classic symptoms of Dejerine-Roussy Syndrome, which is pain
emanating from a diseased thalamus secondary to stroke.
The patient initially assessed his pain on the visual analog scale
as varying between 9 and 10 at peak period to between 5 and 6 at
other times, with 10 indicating pain as bad as it could be. Six
weeks after being placed on the medication at a dosage of 30 mg
DM/75 mg quinidine twice a day, the patient indicated pain at
between 7 and 8 at peak times, with pain between 3 and 4 at other
times using the visual analog scale. At this time, the patient
indicated the level of pain relief as between 2 and 3, with 0
indicating complete pain relief, and 10 indicating no pain relief.
One week after stopping the medications, the patient indicated a
return to a pain level at between 7 and 8.
Patient #3 was a 63 year old male who had been diagnosed with
diabetes for 25 years. He also suffered from arthritis and
hypertension. The patient complained of numbness in his hands for
two years. In addition, the patient noted that his feet hurt for
the past three years. Throbbing pain interfered with sleep and
required pain pills. He also had pain at the tip of his buttocks
and intermittent neck pain. The neurological examination was
remarkable for markedly decreased pinprick sensation in the
patient's feed and distal fingers, with normal position sense and
slightly decreased vibration sense. The clinical assessment was
that the patient had primarily a sensory neuropathy secondary to
his diabetes.
Prior to starting the DM-quinidine treatment at a dosage of 30 mg
dextromethorphan and 75 mg quinidine at twelve hour intervals, the
patient completed two visual analog scales describing his level of
pain, one on April 11 and one shortly before beginning his
medication on May 9. The patient initially rated his pain at
between 5 and 6, and one month later as between 6 and 7, with 10
indicating the pain was as bad as it could be. The patient began
taking DM-quinidine in the dosage of one tablet of 30 mg of
dextromethorphan and 75 of quinidine twice a day.
On May 16 the patient noted via a telephone conversation that he
felt lightheaded and his stomach was mildly upset, but he otherwise
felt okay and he was continuing on the medication. The patient
followed up in the office on May 23 and at that point, described
that his pain was reduced from occurring nightly to only occurring
occasionally, and was reduced overall to about 70-80% of what was
previously experienced. He was not taking any other types of pain
pills and had awakened only once at night from pain since being on
the medication. He reported still having some intermittent light
pain. Side effects were reported to be a little nausea, but not
every day. At this time he rated his pain relief as between 1 and
2, with 0 indicating complete pain relief, and his current level of
pain at between 1 and 2, with zero indicating no pain. The
examining physician rated the patient's level of pain as much
better.
On May 31 the patient reported pain in each foot during the
previous week. He continued to take one tab of 30/75 DM/Quinidine.
After two more weeks, he stopped taking the medication. On July 19,
the patient completed another visual analog scale describing his
current level of pain. He reported the level of pain as between 2
and 3, which remained lower that his initial assessment, even
though he had discontinued his medication.
Example 8
Treatment of Tinnitus
Patient #2 from the pain study described in Example 7 also had
suffered from chronic ringing in the ears, known as tinnitus, for a
number of years. As a part of the pain study, this patient had
taken 30 mg DM/75 mg quinidine capsules twice a day to relieve
thalamic pain syndrome resulting from a stroke three years earlier.
After about two weeks of taking the DM/quinidine capsules to
relieve his pain, this patient reported an unexpected and total
cessation of his chronic tinnitus. This evidence, together with
published studies that NMDA receptors are found in the cochlear
system which is the presumed site of the tinnitus disorder indicate
that the DM/antioxidant combination is a promising therapy for
tinnitus.
These examples demonstrate that the combination of dextromethorphan
and an antioxidant such as quinidine are effective at treating
intractable disorders, including intractable coughing, chronic
pain, dermatitis, tinnitus and sexual dysfunction. Although this
invention has been described with reference to the presently
preferred embodiments, it is understood that various modifications
can be made without departing from the spirit of the invention.
According, the invention is limited only by the following
claims.
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