CA2114267C - Use of oxidase inhibitor with dextromethorphan to treat intractable coughing and dermatitis - Google Patents

Abstract

This invention discloses a method for increasing the effectiveness of dextromethorphan (DM) in treating either severe coughing or dermatitis which do not respond to other drug treatments. This method involves the administration, to a patient who is an extensive metabolizer of dextromethorphan and who is suffering from severe coughing or dermatitis, of dextromethorphan along with a second agent that inhibits the enzymatic activity of debrisoquin hydroxylase (also called sparteine monooxygenase, cytochrome P450DB, and cytochrome P450-2D6). Quinidine is an especially potent inhibitor of enzymatic DM oxidation, but it is not well tolerated by everyone. Other antioxidants which are less potent and better tolerated by some patients include quinine, yohimbine, fluoxetine, haloperidol, ajmaline, lobeline, and pipamperone.
Since people have major variations in their oxidative enzyme activities, screening tests should be undertaken under the supervision of a physician to select a preferred antioxidant for each particular patient. In tests described herein, patients suffering from intractable coughing or dermatitis which did not respond adequately to any other safe and non-addictive drugs reported excellent results and virtually complete elimination of their coughing or dermatitis. In addition, the treated patients did not report any adverse side effects such as drowsiness, fatigue, or nausea.

Description

USE OF OXIDASE INHIBITOR WITH DEXTROMETHORPHAN
TO TREAT INTRACTABLE COUGHING AND DERMATITIS
BACKGROUND OF THE INVENTION
This invention relates to pharmacology and biochemistry.
Dextromethorphan (frequently abbreviated as DM) is the common name for (+)-3-methoxy-N-methylmorphinan. It widely used as a cough syrup, and is described in references such as Rodd 1960 (full citations to articles are provided below) and Goodman and Gilman's Pharmacological Basis of Therapeutics.
Briefly, DM is a non-addictive opioid comprising a dextrorotatory enantiomer (mirror image) of the morphinan ring structure which forms the molecular core of most opiates.
The cough-suppressing activity of DM is believed to be due primarily to its activity at a class of neuronal receptors known as sigma receptors. These are often referred to as sigma opiate receptors, but there is some question as to whether they are opiate receptors, so many researchers refer to them simply as sigma receptors, or as high-affinity dextromethorphan receptors. They are inhibitory receptors, which means that their activation by DM or other sigma agonists causes the suppression of certain types of nerve signals, apparently including the signals that mediate coughing.
Dextromethorphan also acts at another class of receptors known as N-methyl-D-aspartate (NMDA) 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, which means that DM suppresses the transmission of nerve impulses mediated via NMDA receptors.
Since NMDA receptors are excitatory receptors, the activity of DM as an NMDA antagonist also leads to the suppression of certain types of nerve signals, which may also be involved in some types of coughing.
DM has also been reported to suppress activity at neuronal calcium channels (Carpenter et al 1988). The various receptors and ion channels involved with DM are discussed in more detail in articles such as Tortella et al 1989, Ferkany et al 1988, George et al 1988, Prince & Feeser 1988, Feeser et al 1988, Craviso and Musacchio 1983, and Musacchio et al 1988.
Due to its activity as an NMDA antagonist, DM and one of its metabolites, dextrorphan, are being actively evaluated as possible treatments for certain types of excitotoxic brain damage caused by ischemia (low blood flow) and hypoxia (inadequate oxygen supply), which are caused by acute crises such as stroke, cardiac arrest, drowning, head injury, etc. The anti-excitotoxic activity and blockade of NMDA receptors by DM
and dextrorphan are discussed in items such as Choi 1987, Wong et al 1988, Steinberg et al 1988, and US patent 4,806,543 (Choi 1989).
In addition to being evaluated as a treatment for stroke and other crises, DM has also been evaluated by a number of research teams as a potential therapy to treat progressive neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS, also called Lou Gehrig's disease), all of which are suspected of containing an excitotoxic aspect of their etiology.
Accordingly, the Applicant, a neurologist who specializes in working with ALS patients, began studying DM to determine whether it might be able to retard the progress of ALS.
Regrettably, DM was not able to slow down the progressive loss of strength, slurring of speech, and other muscular symptoms suffered by ALS patients. However, during the course of that study, other important findings emerged, as discussed below.

Dextromethorphan Metabolism Before his study began, the Applicant was aware that in most people, DM disappears fairly rapidly from the bloodstream (see, e.g., Dayer et al 1989, Vetticaden et al 1989, and Ramachander et al 1977). DM is converted in the liver to two metabolites called dextrorphan and 3-methoxymorphinan, by an enzymatic process called O-demethylation; in this process, one of the two pendant methyl groups is replaced by hydrogen. If the second methyl group is removed, the resulting metabolite is called 5-hydroxymorphinan. Dextrorphan and 5-hydroxy-morphinan are covalently bonded to other compounds in the liver (primarily glucuronic acid or sulfur-containing compounds such as glutathione) to form glucuronide or sulfate conjugates, which are eliminated fairly quickly from the body via urine.
During his initial studies with ALS patients, the Applicant confirmed that the same process of rapid oxidation and elimination occurs in such patients. No difference in the metabolism of dextromethorphan was detected in ALS patients compared to previously reported data for healthy adults.
The rapid metabolism of DM makes it very difficult to correlate DM quantities administered to a patient, with DM
quantities circulating in the patient's blood. Since the Applicant wanted to stabilize blood concentrations of DM in order to improve the reliability and statistical significance of any results in ALS patients, he did a literature search on the metabolic pathways that cause DM to disappear from the bloodstream.
That search quickly identified a particular enzyme that is primarily responsible for DM oxidation. That enzyme is usually called debrisoquin hydroxylase, since it was discovered a number of years ago to carry out a hydroxylation reaction on debrisoquin. It apparently is identical to an enzyme called sparteine monooxygenase, which was shown years ago to metabolize sparteine; it was not until recently that scientists realized a single isozyme apparently is responsible for oxidizing both debrisoquin and sparteine; after that discovery was published, debrisoquin hydroxylase became the common name, while "sparteine monooxygenase" apparently fell into general disuse. This same isozyme is also referred to in some articles as cytochrome P-450DB (where DB refers to debrisoquin), as cytochrome P-450dbl (or dbl), and as cytochrome P-4502D6.
Debrisoquin hydroxylase belongs to a family of enzymes known as "cytochrome P-450" enzymes, or as "cytochrome oxidase"
enzymes. These enzymes are found at high concentrations in liver cells (primarily in microsomes, which are organelles inside the liver cells), and at lower concentrations in various other organs and tissues such as the lungs 1990. By oxidizing lipophilic compounds, cytochrome oxidase enzymes help eliminate compounds that would otherwise act as toxins or accumulate to undesired levels. Typically, oxidation renders lipophilic compounds more soluble in water; this helps the body eliminate them in urine or in aerosols exhaled out of the lungs. The debrisoquin hydroxylase enzyme apparently is also present in brain tissue (Fonne-Pfister et al 1987, Niznik et al 1990, Tyndale et al 1991), although its function in the brain is not fully understood.
A follow-up literature search by the Applicant revealed that a number of compounds inhibit the activity debrisoquin hydroxylase (see, e.g., Inaba et al 1985, Broly et al 1990, and Fonne-Pfister and Meyer 1988). The most powerful inhibitor identified to date is quinidine, a dextrorotatory stereoisomer of quinine; it is normally used to treat cardiac arrhythmias.
Inaba et al 1986 and Nielsen et al 1990 discuss the ability of quinidine to inhibit the oxidation of sparteine in in vivo animal tests, and Brinn et al 1986, Brosen et al 1987, Broly et al 1989, and Broly et al 1990 discuss the ability of quinidine to inhibit DM metabolism in liver cell preparations.
After studying Inaba et al 1985, which rated quinidine as the most potent inhibitor of sparteine monooxygenase, and after recognizing that sparteine monooxygenase appears to be the same enzyme referred to elsewhere as debrisoquin hydroxylase, the Applicant realized that quinidine might be a useful adjunct for co-administration along with DM, in order to prolong the life and increase the concentration of DM in the circulating blood.
When he tested that hypothesis, using quinidine in conjunction with DM (both administered orally), the Applicant discovered that quinidine does indeed have a pronounced effect in increasing and stabilizing the quantity of DM circulating in the blood of a patient. That discovery is discussed in U.S.
patent number 5,166,207, issued on November 24, 1992; it is also discussed in Zhang et al 1992, which was co-authored by the Applicant, and which was limited to studies on ALS
patients.

The Applicant also discovered that DM in conjunction with quinidine had a remarkable and unexpected side effect: it was highly effective in reducing the symptoms of "emotional lability" in several ALS patients involved in the Applicant's initial studies. 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) become 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. This makes it very difficult for such patients to go out in public or interact comfortably with friends and family, and they often generate severe feelings of self-directed anger, inadequacy, and depression. The ability of DM
in conjunction with quinidine to control emotional lability is discussed in US patent 5,206,248, issued on April 27, 1993.
This unexpected beneficial effect in controlling emotional lability was not observed in any patients who received only DM.
All patients who became involved in the study initially received DM by itself at the beginning of their participation in the study, to ensure that DM would not adversely affect them. Quinidine was added to the treatment regime only after a tolerance and dosage range for DM had been established for a patient, and the benefits of DM in suppressing emotional lability did not become apparent until after one of the patients also began taking quinidine.
This unexpected discovery caused the Applicant to focus even more attention on the combination of DM and quinidine.
During a careful study of the prior art, a question repeatedly occurred to him: since quinidine and certain other antioxidant drugs had been shown in the prior art to suppress the metabolism and elimination of dextromethorphan, why hadn't anyone else ever administered quinidine or other antioxidants as a way to increase DM concentrations in the blood of patients being treated with DM?

The answer to that question emerged when several facts were correlated:
1. A substantial fraction of the general public (estimated to be roughly 7 to 10%) does not have a properly functioning gene which encodes the debrisoquin hydroxylase enzyme.
2. People who do not have the properly functioning debrisoquin hydroxylase enzyme are classified and referred to by doctors and pharmacologists as "poor metabolizers." Such patients 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 (such people are usually referred to as "extensive metabolizers" or "good metabolizers").
3. In addition to the inhibition of debrisoquin hydroxylase, which is exceptionally potent and easily demonstrated, other cytochrome P450 isozymes are also likely to be suppressed by quinidine, with varying levels of binding affinity. Cytochrome P-450 enzymes are notoriously non-specific; 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. This is consistent with their role in eliminating lipophilic toxins, and it is illustrated by the ability of debrisoquin hydroxylase to metabolize numerous different substrates, including dextromethorphan, debrisoquin, and sparteine (which have very different structures). Accordingly, even though quinidine exerts its most marked effect on debrisoquin hydroxylase, it is likely to 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.
4. Since DM is a relatively safe drug which can be administered without a prescription, it can be used as a convenient tool (often called a probe drug) during clinical tests to determine whether a patient is a good 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.
These issues are documented in articles such as Guttendorf et al 1988, Kupfer et al 1984, and Koppel et al 1987, which discuss poor metabolizers. In light of these facts and correlations, reports such as Broly et al 1989 are actually warnings calling attention to the fact that if a patient is taking quinidine, the patient becomes a high-risk "poor metabolizer" who must be protected against the dangers that affect poor metabolizers. In addition, these articles warn doctors that if a patient is taking a drug such as quinidine, then the diagnostic test for identifying "poor metabolizers"
will not give accurate results and should not be used.
Other factors shed still more light on why other physicians and researchers apparently were not interested in using antioxidants to increase DM concentrations in patients being tested for things such as DM's ability to slow the progression of neurodegenerative diseases. First, to the best of anyone's knowledge, DM's activities were believed to be exactly the same as the activities of its primary metabolite, dextrorphan. Both molecules suppress activity at NMDA
receptors, both inhibit ion flow through neuronal calcium channels, and both have the same protective effects in laboratory models of stroke or epilepsy (see, e.g., Choi 1987, Wong et al 1988, Steinberg et al, 1988, and Carpenter et al 1988). Some items even state that the dextrorphan metabolite has even greater neurologic activity than the DM substrate; for example, Wong et al 1988 states, "In the doses used, DM
[dextromethorphan] did not appear to be as effective an anticonvulsant as DX [dextrorphan], a finding consistent with previous observations on the relative potencies of these drugs"
(pages 262-263). Since debrisoquin hydroxylase creates a metabolite that was presumed to have the same (or even more potent) neurological activities as DM, there was no apparent reason to try to suppress that oxidative reaction.
Another factor involves adverse side effects. In some people, DM causes various unwanted effects such as diarrhea, drowsiness, lightheadedness, or loss of appetite. Presumably, any antioxidant that increases DM levels in the blood could aggravate such side effects, by increasing the percentage of people who suffer from such side effects, and by increasing the severity of such side effects in any affected person.
As evidence of the apparently complete lack of any interest among neurologists in using oxidase inhibitors in conjunction with dextromethorphan, it should be noted that a number of recent studies have been performed to evaluate DM in patients suffering neurological diseases (Walker and Hunt 1989, Albers et al 1991, and Applebaum et al 1991). Although all of these researchers clearly recognized the problem of rapid DM
oxidation, none of their reports made any mention whatever of using any oxidation inhibitors to slow down the degradation of DM.
Despite the relevant facts and prevailing beliefs in this field of research, the work by the Applicant has disclosed that co-administration of quinidine in conjunction with DM leads to an important therapeutic benefit (i.e., the suppression of emotional lability, as discussed above). This benefit was clear and remarkably effective in patients treated with both drugs, but it was not detectable in any of the patients when they were treated with dextromethorphan alone.
Shortly after observing the highly effective results of a DM-antioxidant combination in controlling emotional lability in certain patients, the Applicant also observed another highly useful and unexpected therapeutic benefit from the same combination, in a different patient. This patient had been suffering for years from a severe form of dermatitis, characterized by severe itching and discolored skin lesions.
Neither the itching nor the discoloration had responded adequately to any prior medications, but they both responded with remarkable efficacy to the DM-antioxidant combination.
After seeing those beneficial and unexpected results in treating both emotional lability and intractable dermatitis, the Applicant began to suspect that an oxidase inhibitor might also be able to increase the effectiveness of DM as an antitussive agent (i.e., as a cough suppressant). Accordingly, he arranged for research on human volunteers suffering from intractable coughing (i.e., severe coughing that had not responded adequately to any other drug treatment). The results were outstanding and surpassed anyone's expectations. When co-administered with a quinidine, dextromethorphan far surpassed the effectiveness of any other known drug or combination of drugs, and just as importantly, the combination caused virtually no adverse side effects (such as nausea, drowsiness, fatigue, depression, irritability, etc).
Accordingly, one object of the subject invention is to disclose that dextromethorphan, when co-administered with a cytochrome P450 inhibitor such as quinidine, is far more effective than DM by itself in suppressing severe coughing which is intractable to other treatments.
Another object of the subject invention is to disclose a method of treating severe coughing.
Another object of the subject invention is to disclose a method of treating severe coughing with minimal adverse side effects.
Another object of the subject invention is to disclose a method of treating severe dermatitis.

SUMMARY OF THE INVENTION
This invention discloses a method for increasing the effectiveness of dextromethorphan (DM) in treating either severe coughing or dermatitis which do not respond to other drug treatments. This method involves the administration, to a patient who is an extensive metabolizer of dextromethorphan and who is suffering from severe coughing or dermatitis, of dextromethorphan along with a second agent that inhibits the enzymatic activity of debrisoquin hydroxylase (also called sparteine monooxygenase, cytochrome P450D6, and cytochrome P450-2D6). Quinidine is an especially potent inhibitor of enzymatic DM oxidation, but it is not well tolerated by everyone. Other antioxidants which are less potent, and better tolerated by some patients, include quinine, yohimbine, fluoxetine, haloperidol, ajmaline, lobeline, and pipamperone.
Since people have major variations in their oxidative enzyme activities, screening tests should be undertaken under the supervision of a physician to select a preferred antioxidant for any patient. Patients suffering from intractable coughing or dermatitis which did not respond adequately to any other safe and non-addictive drug reported excellent results and virtually complete elimination of their coughing or dermatitis, when treated as described herein. In addition, the treated patients did not report any adverse side effects such as drowsiness, fatigue, or nausea.

BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 is a graph depicting 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
This invention discloses a method for increasing the effectiveness of dextromethorphan (DM) in treating patients suffering from severe coughing or dermatitis which will not respond adequately to other drugs. This method involves co-administering dextromethorphan (DM), or a pharmaceutically acceptable salt thereof, with a second agent that inhibits the oxidative activity of debrisoquin hydroxylase, an enzyme in the cytochrome P-450 family. Relatively potent antioxidants include quinidine and quinine; other antioxidants which are milder, and which might promote additional therapeutic benefits in certain patients, include yohimbine, fluoxetine, haloperidol, ajmaline, lobeline, and pipamperone. A DM-plus-quinidine combination was tested in humans and shown to be highly effective in treating both severe coughing that had been refractory to other non-narcotic, non-steroid drug treatments, and in treating severe dermatitis that had not responded to any other drugs. Just as importantly, the DM-antioxidant combination displayed no adverse side effects in the patients treated for coughing or dermatitis.

Treatment of Severe Coughing (Anti-Tussive) As summarized in the Background section, the Applicant (who specializes as a neurologist) initially began testing DM
with antioxidants in ALS patients, in the hope that it might slow down the neurodegeneration caused by ALS. After observing certain unexpected but highly beneficial results involving the treatment of emotional lability and dermatitis in several ALS
patients, and after noting that similar benefits had not been detected when those patients were treated with DM alone, the Applicant began to suspect that a DM-antioxidant combination might also be more effective than DM alone in treating coughing.
To test that hypothesis, he contacted a physician whom he knew to be working with patients suffering from intractable coughing. As used herein, "intractable" coughing (also referred to as refractory coughing) refers to coughing that will not respond adequately to non-addictive, non-steroid medications.
Any patient will stop coughing if treated ("doped up") with sufficient quantities of narcotics such as codeine or morphine, but narcotics are addictive and they interfere with normal functioning, so physicians are very reluctant to prescribe them, particularly for any sustained period. Similarly, patients with severe coughing that involves tracheal, bronchial, or pulmonary inflammation will sometimes respond to anti-inflammatory steroids such as prednisone, but steroids can create unacceptable side effects, especially if taken for prolonged periods. Many thousands of people suffer from severe and intractable coughing, despite the best efforts of doctors to treat them, and despite the best efforts of pharmaceutical companies to find effective treatments. The goal that has stymied all prior efforts has been to find a treatment that is effective without causing unacceptable side effects or long-term risks to the patient's health.
At the Applicant's request, the cooperating physician tested three patients, all of whom had been suffering from intractable coughing that had persisted for months. One patient had responded to treatment with prednisone, an anti-inflammatory steroid, but the physician was unwilling to continue prednisone administration because of its adverse long-term side effects. A second patient had coughed for 8 months following a respiratory infection; the cough would respond temporarily to cough syrup with codeine, but codeine is addictive and cannot be taken for long periods, and the cough returned when he stopped taking codeine. A third patient had broken several ribs from coughing so hard, following a respiratory infection; antibiotics had helped control the infection, but his coughing had persisted for months despite taking anti-inflammatory inhalant drugs for a suspected asthmatic condition.
In all three patients, treatment with a combination of DM
and an antioxidant provided highly beneficial results with no side effects. In all three cases, the patients were delighted with the outcome. These results clearly confirmed the effectiveness and utility of the DM-antioxidant.
Treatment of Severe Dermatitis This invention also discloses the use of DM in combination with an antioxidant for treating severe dermatitis. As used herein, "severe dermatitis" includes visible skin lesions and/or an itching or burning sensation on the skin that do not respond adequately to any non-prescription drug, lotion, or ointment.
The ability of the DM-quinidine combination to treat severe dermatitis was first observed as an unexpected beneficial side effect during testing on an ALS patient who happened to suffer from severe dermatitis. When the drug combination was subsequently tested by a dermatologic specialist on a patient suffering from severe dermatitis but not ALS, it also showed a major beneficial effect on the dermatitis. These results are described in more detail in Example 6.

This invention discloses, for the first time, that DM can be effective in treating dermatitis. Among some patients suffering from dermatitis (particularly among patients classifiable as "poor metabolizers" due to a genetic inability to express functional copies of the debrisoquin hydroxylase enzyme), 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.

Dosages 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, depending on factors such as the weight of the patient, the severity of the cough, and the potency and dosage of the antioxidant agent used in conjunction with DM.
The dosage of quinidine that was found (in the initial experiments described herein) to provide a major increase in DM
concentration in the blood was only a fraction of the dosage normally used for anti-arrhythmic action. Quinidine dosages of 600-1200 mg/day are commonly taken by cardiac patients; by contrast, dosages of only 150 mg/day were shown to be effective in increasing DM concentrations and in controlling coughs in at least some patients. It is believed by the Applicant that even lower dosages, such as about 50 mg/day, probably will be effective in at least some patients.
If desired, a doctor can determine an optimal dosage of both quinidine and dextromethorphan for a specific patient being treated for chronic and/or severe coughing, 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 suppressing coughing.
As discussed in the Background section, the activity of DM
in suppressing nerve signals is believed to involve at least two and possibly more types of neuronal receptors (sigma receptors and NMDA receptors), and DM may also suppress nerve impulses mediated by other neuronal mechanisms, such as calcium channels. All of these neuronal interactions involve direct contact of DM molecules with receptors on the surfaces of neurons. Accordingly, any significant antioxidant mediated increase or stabilization of DM concentration in the blood of a patient will directly increase the ability of DM to carry out functions that depend on contact between circulating DM
molecules and neuronal receptors.
Quinidine Usage Quinidine, a very potent antioxidant, suffers from a number of potential drawbacks, and it is available only by prescription. In addition to being a relatively strong cardiac medicine, it converts "extensive metabolizers" into "poor metabolizers," as described in articles such as Kupfer et al 1984 and Guttendorf et al 1988. It is also known that some patients cannot tolerate quinidine well. For example, one ALS
patient being tested by the Applicant suffered an allergic reaction to quinidine.
In addition, DM is known to cause side effects in some people (such as diarrhea, drowsiness, lightheadedness, or loss of appetite, as noted in the Background section), and the likelihood and severity of such side effects will be increased by antioxidants, in direct proportion to the potency of the antioxidant used. For example, one ALS patient being tested by the Applicant using a DM-quinidine combination suffered an episode of severe disorientation that resembled the effects of phencyclidine, a highly potent NMDA antagonist which is often abused as a hallucinogen under the street name "angel dust."
Like phencyclidine, DM is an NMDA antagonist, and apparently, use of an antioxidant with the potency of quinidine caused a severe adverse reaction in a hypersensitive individual.
Accordingly, even though none of the patients treated for coughing or dermatitis reported any side effects, the DM-quinidine combination disclosed herein is currently anticipated for use only under the supervision of a physician, and in most cases it should be used only for treating severe and/or chronic coughing that cannot be adequately treated by dextromethorphan alone, such as in patients suffering from pulmonary or bronchial disease or other severe distress. However, as noted above, 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.
Accordingly, a combination of DM in a relatively low antitussive dosage, along with a relatively small quantity of quinidine (or a less potent oxidation inhibitor, as discussed below), may be safe enough for over-the-counter sale and use.
In view of the fact that contagious diseases are often spread by coughing, optimal public benefit might be achieved by making a combination of DM and an antioxidant available over-the-counter, in a "maximum strength" formulation. The spread of coughing-borne diseases has become of major concern recently, since extremely dangerous and lethal antibiotic-resistant forms of tuberculosis, pneumonia, and other diseases are emerging.
Regardless of how it is sold, anyone taking an antioxidant should be warned that these drugs reduce the body's ability to metabolize and eliminate various drugs, pollutants, and intoxicants. Accordingly, anyone taking an antioxidant should be advised to avoid alcohol and other non-essential drugs, and any drugs that suppress liver functioning. In addition, physicians prescribing antioxidants should be alerted of potential interactions between antioxidants and other drugs, such as certain types of anticoagulants.

Other Antioxidants As mentioned above, some patients cannot tolerate quinidine or quinidine-DM combinations. Some people are allergic to quinidine, and people who suffer from a heart condition known as a prolonged QT interval cannot use quinidine safely. In addition, quinidine has a potent effect in converting patients into "poor metabolizers" as described in articles such as Guttendorf et al 1988 and Koppel et al 1987.

Accordingly, doctors may prefer to use less potent oxidation inhibitors in various situations, such as (1) in patients who cannot tolerate quinidine; (2) as a second agent that can be alternated with quinidine to avoid developing a tolerance that would require increasing dosages of quinidine; (3) for patients who have moderate coughing that will not respond adequately to other treatments, but which is not severe enough to require a potent enzyme inhibitor.
A number of drugs have been identified in in vitro studies as being effective in inhibiting debrisoquin hydroxylase; Inaba et al 1985 (which refers to debrisoquin hydroxylase as sparteine monooxygenase) contains an extensive list, while Fonne-Pfister and Meyer 1988 and Broly et al 1990 contain additional lists. Agents with Michaelis-Menton inhibition values (K1) of 50 micromolar or lower (as reported in Inaba et al 1985) included nortriptyline, chlorpromazine, domperidone, haloperidol, pipamperone, labetalol, metaprolol, oxprenolol, propranolol, timolol, mexiletine, quinine, diphenhydramine, ajmaline, lobeline, papaverine, and yohimbine. In general, K.
values indicate the quantity of a drug required to inactivate a standard quantity of an enzyme, so a low Ki value indicates a potent inhibitor. Especially potent compounds included yohimbine, haloperidol, ajmaline, lobeline, and pipamperone;
these had K, values ranging from 4 down to 0.33 (the K; value of quinidine was 0.06).
It should also be noted that the liver preparations reported in Inaba et al 1985 were obtained from two human cadavers (both apparently died due to kidney problems) who had "similar" sparteine monooxygenase activities (i.e., similar to each other). Other enzyme preparations from other humans would provide different oxidative profiles; therefore, the values listed in Inaba et al 1985 should be regarded as data from two individuals rather than as a broad index of oxidative activity in all humans.
In addition to the antioxidants studied by Inaba et al 1985 and Broly et al 1990, the Applicant also discovered that fluoxetine (sold by Eli Lilly and Co. under the trade name Prozac) is also effective in increasing DM concentrations in the blood of some people.
Any of the drugs listed above with low K. values for debrisoquin hydroxylase are good candidates for screening tests to determine whether they will increase the effectiveness of DM
for treating intractable coughing or dermatitis in specific patients. It is impossible to predict which particular antioxidants will work most effectively in specific patients, since people vary in their cytochrome oxidase enzymes; however, predictability is not necessary, because there are simple and straightforward ways to screen candidate antioxidants in any patient and to identify and select one or more antioxidants that are effective in that particular person.
A preferred screening approach is to prescribe, for a patient with an intractable cough (or dermatitis), DM in conjunction with a series of several different antioxidants.
Each antioxidant is tested for a period of time such as one or two weeks. During that time, no other antioxidants are taken.
If desired, an antioxidant can be administered by itself for several days, with no dextromethorphan, to make sure the patient can tolerate the antioxidant by itself. If the results of the tolerance test are positive, the patient will begin taking both DM and the antioxidant, preferably at a relatively low dosage initially, which can be increased after a few days if the initial dosage is not adequately effective. During the test period, the patient will keep track of the effectiveness of the combined drugs against the coughing or dermatitis, and will record any side effects that are noticed. When a DM-antioxidant combination that works well in a specific patient is identified, the screening process can stop, and that combination of drugs can be continued until the coughing or dermatitis has been resolved. If desired, additional testing can also be carried out to optimize the dosages of both the DM
and the antioxidant.
If desired, such testing can be supplemented by laboratory analysis of urine or blood to quantitatively evaluate the effectiveness of each antioxidant in inhibiting DM oxidation in a specific patient. Such tests can be carried out as described in Example 4 and in Zhang et al 1992.
The results of preliminary tests on various antioxidants (described in Example 4) illustrate the variability of responses in different people to different antioxidants. In these tests, DM was administered at a constant dosage to various individuals (all were healthy volunteers who were not suffering from severe coughing). 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.
The results indicated substantial variations between individuals. While quinine (which is structurally quite similar to quinidine) was shown to be highly effective in increasing DM/DRP ratios in both of the people tested, other drugs did not show the same level of consistency. For example, one person showed an increase in the DM/DRP ratio after taking fluoxetine, while a different person showed a drop in the DM/DRP ratio after taking the same compound. Similarly, one person showed an increase in DM/DRP after taking propranolol, while another person showed a decrease.
As noted above, the variability of these results between different patients was not surprising, since people have different oxidative profiles. These differences are reflected by the fact that some people are classified by doctors as "extensive" metabolizers while others are classified as "poor"
metabolizers. Similarly, it is well known that different people have differing abilities to tolerate and metabolize alcohol, tobacco smoke, various environmental contaminants, certain prescription drugs, and various illegal intoxicants. This is a routine aspect of medicine and metabolism; it's no different from observing that some people (but not all) are allergic to bee stings, or to certain foods. As noted above, routine screening tests can be used by the treating physician to determine the best antioxidant drug for use in combination with DM by any specific patient suffering from intractable coughing.
It should also be noted that a number of antioxidants have their own pharmaceutical effects, which vary widely. For example, haloperidol (HaldolTM) is a tranquilizer, yohimbine (AphrodyneTM) is a stimulant, and fluoxetine (ProzacTM) is an anti-depressant. A treating physician should consider such additional effects, which are not related to DM, when selecting an antioxidant for a specific patient, since the patient might benefit from a well-chosen antioxidant or suffer unwanted side effects from a poorly selected antioxidant.

Salts, Analogs, and Routes of Administration 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 addition salts of free acids or free bases. Acids that may be employed to form acid addition salts include inorganic acids (e.g., to form 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 may be prepared by conventional means. Various salts of the compounds described herein which are currently in widespread pharmaceutical use are listed in sources 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 in a targeted and controlled manner to replace one or more components 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 activity of the referent molecule.
Administration of the drugs described herein can be by any method capable of introducing the compounds into the bloodstream. Although oral administration is the simplest and therefore the preferred route of administration, parenteral or subcutaneous injection can be used if desired. Although evaluation of topical or inhalant formulations has not yet commenced, it is possible that the drugs described herein can be administered effectively in either (1) topical formulations such as lotions or ointments to treat dermatitis, or (2) inhalable aerosols to treat coughing. An injectable, topical, or inhalant formulation can comprise a mixture of active compounds with pharmaceutically acceptable carriers or diluents.

EXAMPLES
Since the research that led to this invention was done by a neurologist who was initially interested in finding out whether DM might be able to retard the progress of amyotrophic lateral sclerosis (ALS, also called Lou Gehrig's disease), the studies described in Examples 1-3 were done on patients suffering from ALS, most of whom are adults more than 50 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 beta-glucuronidase in 1 mL of acetate buffer (0.1 M, pH 5.0). The mixture was incubated for 18 hours at 37 C and then extracted by adding 1 mL of phosphate buffer (pH 12, 0.10 M) 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 0.01 N 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 KHPO4, 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 5.0 with 0.1 M acetate buffer (usually about 1.0 ml), and beta-glucuronidase was added (2000 units/ml urine). The mixture was incubated and shaken at 370 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 C, oven 70 C to 260 C at 20 C per minute, and source temperature 180 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.

URINARY 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 Followup 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 5 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.

Effects of 150 mg/day quinidine on plasma dextromethorphan levels DEXTROMETHORPHAN DEXTROMETHORPHAN QUINIDINE
PATIENT DOSE PLASMA LEVEL DOSE (MG/DAY) 2 120 MG/DAY 9.3 NG/ML 0 60 MG ONCE 29.7 NG/ML 150 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 the quantity of DM orally administered to a patient 10 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, including the activity of DM an antitussive (cough suppressing) agent.

EXAMPLE 4: PILOT STUDIES ON 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. These tests, which were pilot studies on a small number of individuals rather than large-scale tests on large population samples, were carried out at the Applicant's request in the labs of Dr. Robert Straka (St. Paul, Minnesota).
Twelve volunteers were studied. None were suffering from severe coughing. 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 nortryptiline. 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 ratio increased from 0.02 (pre-quinine baseline) to 0.09; in the other subject, the DM/DRP ratio 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 the other.
These levels of variability were not surprising, since it has been known for decades that different people have important variations in their oxidative enzymes. It should be emphasized that these were just pilot studies on small numbers of people.
EXAMPLE 5: TESTS ON PATIENTS WITH INTRACTABLE COUGHING
The Applicant, who specializes as a neurologist, contacted a physician (Dr. Malcolm Edwards of Charleston, South Carolina) whom he knew to be working with patients suffering from intractable cough. At the Applicant's request, Dr. Edwards agreed to test several such patients. The initial tests on three patients with intractable coughing indicated highly effective results, with virtually no side effects.
Patient ER, 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 albuterol (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, 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 but with two sons who had 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%. 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 no reported side effects. The results clearly confirm the effectiveness and utility of the invention.

EXAMPLE 6: TREATMENT OF SEVERE DERMATITIS
During an initial examination, the Applicant 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 relatively small purplish patches ("polygonal papules"). Her condition had recently been diagnosed as lichen planus. The etiology is unknown, although a variety of drugs reportedly can aggravate this condition. 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, the Applicant 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 almost completely healed with no apparent evidence of scar tissue.
After seeing this result, the Applicant disclosed his finding to a dermatologic specialist at a nearby university and suggested that additional tests be done. The first such test by the specialist involved a male Caucasian who suffered from severe but intermittent dermatitis. The patient was treated during a relapse (i.e., during an outbreak of dermatitis), and 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.
Thus, there has been shown and described a new and useful method for treating coughing and dermatitis, particularly for treating severe and intractable coughing and dermatitis that will not respond to other forms of treatment. Although this invention has been exemplified for purposes of illustration and description by reference to certain specific embodiments, it will be apparent to those skilled in the art that various modifications and alterations of the illustrated examples are possible without departing from the spirit and scope of these teachings. Such changes are deemed to be covered by this invention.

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Claims (10)

1. Use of a combination of dextromethorphan or a pharmaceutically acceptable hydrobromide salt thereof and a second compound selected from the group consisting of quinidine, quinine, and a pharmaceutically acceptable sulfate salt thereof at a therapeutically effective dosage which, in the body of a person, is pharmaceutically acceptable and causes a significant inhibition of enzymatic oxidation of dextromethorphan by debrisoquin hydroxylase, for treating emotional lability by reducing intermittent spasmodic outbursts of emotion in a patient in need thereof.

2. The use of claim 1, wherein the emotional lability is associated with Alzheimer's disease.

3. The use of claim 1, wherein the emotional lability is associated with bilateral neurological damage.

4. The use of claim 1, wherein the emotional lability is associated with amyotrophic lateral sclerosis.

5. The use of claim 1, wherein the emotional lability is associated with a neurodegenerative disease.

6. A therapeutic formulation comprising a combination of:

dextromethorphan or a pharmaceutically acceptable hydrobromide salt thereof; and, a second compound selected from the group consisting of quinidine, quinine, and a pharmaceutically acceptable sulfate salt thereof;

for use in treating emotional lability by reducing intermittent spasmodic outbursts of emotion in a patient in need thereof at a therapeutically effective dosage which, in the body of a person, is pharmaceutically acceptable and causes a significant inhibition of enzymatic oxidation of dextromethorphan by debrisoquin hydroxylase.

7. The therapeutic formulation of claim 6, wherein the emotional lability is associated with Alzheimer's disease.

8. The therapeutic formulation of claim 6, wherein the emotional lability is associated with bilateral neurological damage.

9. The therapeutic formulation of claim 6, wherein the emotional lability is associated with amyotrophic lateral sclerosis.

10. The therapeutic formulation of claim 6, wherein the emotional lability is associated with a neurodegenerative disease.