Prescription & OTC Drugs – Richard A. Smith, Avanir Pharmaceuticals Inc
Abstract for “To treat dermatitis, use dextromethorphan or an oxidase inhibitor”
“This invention relates to a method of treating human patients with severe dermatitis. These patients can be treated with dextromethorphan, an antitussive agent that is commonly found in cough syrup. An antioxidant drug, such as quinidine, can be given to patients who are deemed excessive metabolizers. This will inhibit the DM-degrading activities of debrisoquin hydroxylase which is an enzyme that converts DM quickly into its metabolite dextrorphan. This combination has shown great success in severe dermatitis treatment. Most patients experience no adverse effects.
Background for “To treat dermatitis, use dextromethorphan or an oxidase inhibitor”
“This invention is related to pharmacology and the use dextromethorphan with a second drug that inhibits enzyme oxidation of dextromethorphan.”
“Dextromethorphan (frequently abbreviated as DM) is the common name for (+)-3-methoxy-N-methylmorphinan. It is a non-addictive opioid that includes a dextrorotatory antiomer (mirror images) of the morphinan rings structure, which makes up the molecular core for most opiates. DM is used in many over-the-counter cough syrup formulations as an antitussive (i.e. as a cough suppressant). It is being studied as a treatment for excitotoxic brain injury caused by hypoxia (inadequate oxygen flow) or ischemia (low bloodflow). These are conditions that can be caused by stroke, cardiac arrest, asphyxia, and other events. The anti-excitotoxic properties of the drug are discussed in Choi 1987 (full references to articles are provided below), Wong and al 1988, Steinberg and al 1988, as well as U.S. Pat. No. 4,806,543 (Choi 1989).”
“The antitussive properties of DM are believed to be due to its activity at a group of neuronal receptors called sigma receptors. These receptors are inhibitory. This means that activation suppresses certain kinds of nerve signals. Although sigma receptors are sometimes called sigma opiate orphan receptors, there are some questions about whether these receptors are actually opiate receptors. Many researchers simply refer to them as sigma receptors. Researchers refer to “high-affinity Dextromethorphan Receptors”; this group may include, but not necessarily exclude, sigma receptors.
“The anti-excitotoxic properties of DM may be due to its activity on another class of receptors known N-methyl-Daspartate receptors (NMDA), which are one type excitatory amino acid receptor (EAA). DM is an antagonist at NMDA, meaning that it suppresses nerve impulses mediated through NMDA. Since NMDA are excitatory receptors and DM is an antagonist, certain nerve signals can be suppressed.
“Because it acts as an NMDA antagonist, which may be able block excitotoxic damage neurons, DM could also be of interest as a treatment for neurodegenerative disorders, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis, also known as Lou Gehrigs disease. All of these diseases are thought to contain an excitotoxic component of their etiology. Walker and Hunt 1989, Albers and colleagues 1991, and Applebaum and associates 1991 are some examples of reports in this area of research.
“Dextromethorphan also has been shown to inhibit neural activity via neuronal calcium channels (Carpenter and al 1988).
It is difficult to attribute the suppressive effects of DM on nerve impulses to a single type because DM activity appears to involve at least three types of neuronal receptors. Despite this, the chemistry and structure DM are well-known. The pharmacology of DM is also described in standard texts like Goodman and Gilman?s Pharmacological Basis for Therapeutics and Rodd 1960.
“Dextromethorphan Metabolism”
“DM is being investigated as a potential treatment for neurodegenerative conditions such as Parkinson’s, Alzheimer’s, and ALS. The Applicant is a neurologist who specializes in treating ALS patients. He conducted a study on DM to see if it could slow down the progression of ALS.
“Unfortunately, DM was unable to slow down the gradual loss of strength, slurring speech and other muscular symptoms that these patients were experiencing.” Nevertheless, important findings were made during that study. They are discussed below.
“Before his study started, the Applicant knew that DM disappears quite quickly from the bloodstream in most people (see, e.g. Vetticaden et. al 1989 and Ramachander et. al 1977). DM is converted by the liver into two metabolites, dextrorphan or 3-methoxymorphinan. This is done by an enzymatic process known as O-demethylation. In this process, one pendant methyl group is replaced with hydrogen. The resulting metabolite can be called 5-hydroxymorphinan if the second methyl is removed. Dextrorphan or 5-hydroxymorphinan can be covalently bonded with other compounds in the liver, primarily glucuronic acids or sulfur-containing compounds like glutathione, to form glucuronide conjugates. These are quickly eliminated from the body via the urine. FIG. 1.”
“During his initial studies the Applicant confirmed the normal processes for rapid oxidation/elimination occur in most ALS patients.” ALS patients had no difference in their metabolism of dextromethorphan compared to healthy adults.
It is difficult to compare DM amounts administered to patients with DM levels in their bloodstreams due to DM’s rapid metabolism. The Applicant was interested in stabilizing blood levels of DM to increase the reliability and significance of any results for patients with ALS. He conducted a literature search to find out the metabolic pathways that lead to DM disappearing from the bloodstream. This search quickly revealed a specific enzyme that is responsible for DM oxidation. This enzyme, commonly referred to in most articles as debrisoquin-hydroxylase, was first discovered to perform a hydroxylation reaction of debrisoquin some years back. This enzyme is also known as P450-2D6 or P450DB. It appears to be identical to the enzyme sparteine monooxygenase which has been shown to metabolize sparteine since years ago. Scientists discovered that one isozyme was responsible for both oxidizing debrisoquin, sparteine, and dextromethorphan as well as various substrates.
“Debrisoquin-hydroxylase is part of a group of enzymes called cytochrome P450 enzymes or cytochrome oxygenase enzymes. These enzymes can be found in high levels in liver cells, particularly microsomes which are organelles within the liver cells. They are also found in lower concentrations in other organs and tissues, such as the lungs. See, for example, Fonne-Pfister and Niznik et. al 1987. Cytochrome oxidase enzymes aid in the elimination of compounds that could otherwise be toxic or accumulate at unfavorable levels. The body can make lipophilic compounds more easily soluble in water. This helps eliminate them from the urine and aerosols in the lungs.
The Applicant did a follow-up literature search and found that many compounds inhibit the activity debrisoquin monooxygenase (sparteine hydroxylase). See Inaba et. al 1985. Quinidine is the most potent inhibitor. It is a stereoisomer dextrorotatory quinine that is commonly used to treat arrhythmias. Inaba et. al 1986 and Nielsen et. al 1990 discuss quinidine’s ability to inhibit oxidation of sparteine using in vivo animal testing. Brosen et. al 1987 and Broly et. al 1989 discuss quinidine’s ability to inhibit DM metabolism of liver cell preparations.
The Applicant studied the 1985 Inaba et al article which rated quinidine the most potent inhibitor for the sparteine monoxygenase enzymatic enzyme. He also recognized that it was the same enzyme referred elsewhere as debrisoquin hydroxylase. When he tried that hypothesis with quinidine and DM (both orally administered), he found that quinidine has a pronounced effect on increasing and stabilizing the amount of DM in blood. This discovery is described in U.S. Pat. No. No. 5,166,207 was also invented and used by the Applicant. The teachings of this patent are included by reference.”
“The Applicant also found that DM, when combined with quinidine, had a remarkable side effect: It was extremely effective in reducing symptoms of emotional lability”. This condition is also known as emotional incontinence. Emotional lability refers to a complex condition in which patients with neurological damage, such as a stroke or head injury, or ALS, become unable or unwilling to control their emotional outbursts. U.S. Patent. No. No. 5,206,248, also invented by Applicant. The contents of that patent can be incorporated by reference. Patients who have been treated with the combination DM/antioxidant regimen have also reported that it is extremely effective and very beneficial since the application was filed.
Patients who were treated with DM alone did not experience an unexpected benefit in emotional lability. To ensure that they would not be adversely affected, all patients who participated in the study received DM and/or quenidine only. After a patient had established a tolerance or dosage range for one of the drugs, they were given coadministered. Patients who started taking both drugs together did not realize the benefits of each drug in suppressing their emotional lability.
“The Applicant found an unexpected benefit from giving DM along with quinidine to another ALS sufferer who was a prolific metabolizer. Her severe skin condition, lichen planus, had plagued her for more than ten years. The condition was marked by severe itching and discolored lesions on her legs and abdomen. Skin specialists had prescribed many medications to her, including steroids to reduce swelling and various analgesics to relieve pain and itching. None of these had given any significant relief. She experienced significant relief from her itching and pain within two months of starting a quinidine/DM regimen. Within two months, the lesions had almost disappeared without any visible scarring.
The Applicant discovered this unexpected result and shared it with a dermatologist who is currently performing preliminary tests on patients suffering from severe or persistent dermatitis. Although preliminary results have shown that a combination of DM and an antioxidant that inhibits oxidation of DM is effective in treating severe dermatitis in extensive metabolizers has not been conclusive.
“The Prior Art re Anti-Oxidants.”
“The Applicant was surprised to discover that a combination DM/quinidine could reduce ALS patients’ emotional lability. He therefore focused his attention on the prior art, which covered both DM/antioxidant drugs. During a review of the prior art, a question arose repeatedly to the Applicant: Since quinidine and other antioxidant drugs have been proven to suppress the metabolism DM, why hasn’t anyone ever given quinidine or any other antioxidants to patients receiving DM?
“The answer to this question was found when several previously unrelated facts were correlating:
“1. “1.
“2. Doctors and pharmacologists refer to patients who lack the proper functioning debrisoquin hydroxylase enzyme as “poor metabolizers” (this term is used by Kupfer et al. 1984 and Guttendorf et al. 1988). These patients are considered high-risk and require special attention. They are more sensitive to drugs than people with the complete set of cytochrome P450 enzymes.
“3. Quinidine is likely to inhibit other cytochrome P450 enzymes, including the debrisoquin-hydroxylase inhibitor, which is extremely potent and easily demonstrated. It also has varying levels in binding affinity. The cytochrome P450 enzymes are not specific. A single isozyme may react with many substrates with very different chemical structures. Moreover, multiple isozymes have been known to overlap activity on one substrate. This is consistent with their role as lipophilic toxins eliminators. It is shown by the ability to dextromethorphan, debrisoquin and sparteine metabolize many different substrates (which all have very different structures). Quinidine has a significant effect on debrisoquin, but it can also suppress other cytochrome P450 enzymes, thus causing a greater loss of normal and desirable metabolic activity.
“4. DM is a safe drug that can be given without a prescription. It is frequently used in clinical tests to determine if a patient is a good or poor metabolizer. These tests can help identify patients who are a poor metabolizer and protect them against drugs that they cannot properly metabolize.
Guttendorf et al 1988 and Kupfer et al 1985, which both discuss poor metabolizers, provide some information. Other points can be gleaned from articles like Koppel et al 1986, which discusses the general characteristics of cytochrome P450 enzymes.
Broly et. al. 1989 reports that quinidine inhibits DM oxidation of liver cell preparations in liver cells are warnings that patients who take quinidine must be protected from the risks and dangers that can affect poor metabolizers. These articles also warn doctors that quinidine can cause poor metabolizers. The diagnostic test used to identify them should not be used if the patient is using quinidine.
“The Applicant also discovered another important factor in his literature analysis. Dextromethorphan’s primary oxidized metabolic product is dextrorphan. This is widely believed by neurologists to be the same as dextromethorphan. Both drugs are sigma agonists and NMDA antagonists. Neurologists and others were not motivated to try to increase DM levels in blood because the metabolite is believed to have the exact same neuronal activities.
“As evidence that there is no interest among neurologists to use cytochrome P450 inhibits to increase the dextromethorphan levels in the bloodstream of patients receiving DM,” Walker and Hunt 1989, Albers et Al 1991, Applebaum et Al 1991, Askmark et Al 1993. These researchers recognized the problems caused by DM metabolism and reported on them. However, they did not mention or show any interest in quinidine or any other oxidation inhibitor to slow down the enzymatic degrading of DM.
“Despite all the facts and prevailing beliefs in the field of research, the Applicant’s work has shown that quinidine can be administered in combination with DM to provide at least two therapeutic benefits, including the suppression of emotional lability and treatment of dermatitis. These effects were evident in patients who were treated with quinidine in combination with DM, but were not observed in patients receiving dextromethorphan.
“Accordingly, the invention discloses that DM can be given in combination with quinidine (a second compound such as quinidine) to treat severe or difficult dermatitis in patients who are extensive metabolizers”.
“Another object in this invention is to disclose that any one of the compounds known to inhibit DM-degrading oxidative activation of debrisoquin hydroxylase can also be tested to determine if they are suitable for use in a patient with severe dermatitis. Routine tests can identify a specific antioxidant compound that has minimal adverse effects for a patient in need of treatment. Once a patient has been identified, the optimal dose of anti-oxidant medication can be determined. This will ensure that the patient receives the highest blood levels of DM. To treat the dermatitis, the chosen compound can be administered in combination with a suitable dose of DM at the appropriate dosage.
“Another object in this invention is to disclose that DM appears to be able, on its own, to treat dermatitis in patients who have been classified as poor metabolizers”. This refers to patients without a functioning debrisoquin hydroxylase. These patients don’t have a functioning debrisoquin hydroxylase enzyme, so they won’t require any anti-oxidant drug to prevent DM oxidation or elimination. DM should be administered alone in patients with “poor metabolizer” because it will produce the same effect as a DM/antioxidant combo in patients with “extensive metabolizer”.
These and other objects will be apparent from the following description.
“It should also be noted that the copending application Ser. No. No. These conditions include (1) emotional lability as discussed above: (2) the itching and pain that accompany severe dermatitis; and, (3) at least one other other medically significant, otherwise-intractable condition that has been identified and treated with excellent results using a DM/antioxidant combination (this method of treatment is the subject of another patent application that is pending before the U.S. Patent and Trademark Office). The co-pending application Ser. No. 07/896.053, now abandoned. It disclosed and claimed a method for treating unwanted nerve impulses”. This was done using a DM/antioxidant combination therapy. These claims were not examined and will be the subject of a divisional patent application. They are also mentioned in the co-pending Ser. No. No.
“This invention relates to a method of treating human patients with severe dermatitis. These patients can be treated with dextromethorphan, an antitussive agent that is commonly found in cough syrup. An antioxidant drug, such as quinidine, can be given to patients who are deemed excessive metabolizers. This will inhibit the DM-degrading activities of debrisoquin hydroxylase which is an enzyme that converts DM quickly into its metabolite dextrorphan. This combination has shown great success in severe dermatitis treatment. Most patients experience no adverse effects.
Summary for “To treat dermatitis, use dextromethorphan or an oxidase inhibitor”
“This invention is related to pharmacology and the use dextromethorphan with a second drug that inhibits enzyme oxidation of dextromethorphan.”
“Dextromethorphan (frequently abbreviated as DM) is the common name for (+)-3-methoxy-N-methylmorphinan. It is a non-addictive opioid that includes a dextrorotatory antiomer (mirror images) of the morphinan rings structure, which makes up the molecular core for most opiates. DM is used in many over-the-counter cough syrup formulations as an antitussive (i.e. as a cough suppressant). It is being studied as a treatment for excitotoxic brain injury caused by hypoxia (inadequate oxygen flow) or ischemia (low bloodflow). These are conditions that can be caused by stroke, cardiac arrest, asphyxia, and other events. The anti-excitotoxic properties of the drug are discussed in Choi 1987 (full references to articles are provided below), Wong and al 1988, Steinberg and al 1988, as well as U.S. Pat. No. 4,806,543 (Choi 1989).”
“The antitussive properties of DM are believed to be due to its activity at a group of neuronal receptors called sigma receptors. These receptors are inhibitory. This means that activation suppresses certain kinds of nerve signals. Although sigma receptors are sometimes called sigma opiate orphan receptors, there are some questions about whether these receptors are actually opiate receptors. Many researchers simply refer to them as sigma receptors. Researchers refer to “high-affinity Dextromethorphan Receptors”; this group may include, but not necessarily exclude, sigma receptors.
“The anti-excitotoxic properties of DM may be due to its activity on another class of receptors known N-methyl-Daspartate receptors (NMDA), which are one type excitatory amino acid receptor (EAA). DM is an antagonist at NMDA, meaning that it suppresses nerve impulses mediated through NMDA. Since NMDA are excitatory receptors and DM is an antagonist, certain nerve signals can be suppressed.
“Because it acts as an NMDA antagonist, which may be able block excitotoxic damage neurons, DM could also be of interest as a treatment for neurodegenerative disorders, including Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis, also known as Lou Gehrigs disease. All of these diseases are thought to contain an excitotoxic component of their etiology. Walker and Hunt 1989, Albers and colleagues 1991, and Applebaum and associates 1991 are some examples of reports in this area of research.
“Dextromethorphan also has been shown to inhibit neural activity via neuronal calcium channels (Carpenter and al 1988).
It is difficult to attribute the suppressive effects of DM on nerve impulses to a single type because DM activity appears to involve at least three types of neuronal receptors. Despite this, the chemistry and structure DM are well-known. The pharmacology of DM is also described in standard texts like Goodman and Gilman?s Pharmacological Basis for Therapeutics and Rodd 1960.
“Dextromethorphan Metabolism”
“DM is being investigated as a potential treatment for neurodegenerative conditions such as Parkinson’s, Alzheimer’s, and ALS. The Applicant is a neurologist who specializes in treating ALS patients. He conducted a study on DM to see if it could slow down the progression of ALS.
“Unfortunately, DM was unable to slow down the gradual loss of strength, slurring speech and other muscular symptoms that these patients were experiencing.” Nevertheless, important findings were made during that study. They are discussed below.
“Before his study started, the Applicant knew that DM disappears quite quickly from the bloodstream in most people (see, e.g. Vetticaden et. al 1989 and Ramachander et. al 1977). DM is converted by the liver into two metabolites, dextrorphan or 3-methoxymorphinan. This is done by an enzymatic process known as O-demethylation. In this process, one pendant methyl group is replaced with hydrogen. The resulting metabolite can be called 5-hydroxymorphinan if the second methyl is removed. Dextrorphan or 5-hydroxymorphinan can be covalently bonded with other compounds in the liver, primarily glucuronic acids or sulfur-containing compounds like glutathione, to form glucuronide conjugates. These are quickly eliminated from the body via the urine. FIG. 1.”
“During his initial studies the Applicant confirmed the normal processes for rapid oxidation/elimination occur in most ALS patients.” ALS patients had no difference in their metabolism of dextromethorphan compared to healthy adults.
It is difficult to compare DM amounts administered to patients with DM levels in their bloodstreams due to DM’s rapid metabolism. The Applicant was interested in stabilizing blood levels of DM to increase the reliability and significance of any results for patients with ALS. He conducted a literature search to find out the metabolic pathways that lead to DM disappearing from the bloodstream. This search quickly revealed a specific enzyme that is responsible for DM oxidation. This enzyme, commonly referred to in most articles as debrisoquin-hydroxylase, was first discovered to perform a hydroxylation reaction of debrisoquin some years back. This enzyme is also known as P450-2D6 or P450DB. It appears to be identical to the enzyme sparteine monooxygenase which has been shown to metabolize sparteine since years ago. Scientists discovered that one isozyme was responsible for both oxidizing debrisoquin, sparteine, and dextromethorphan as well as various substrates.
“Debrisoquin-hydroxylase is part of a group of enzymes called cytochrome P450 enzymes or cytochrome oxygenase enzymes. These enzymes can be found in high levels in liver cells, particularly microsomes which are organelles within the liver cells. They are also found in lower concentrations in other organs and tissues, such as the lungs. See, for example, Fonne-Pfister and Niznik et. al 1987. Cytochrome oxidase enzymes aid in the elimination of compounds that could otherwise be toxic or accumulate at unfavorable levels. The body can make lipophilic compounds more easily soluble in water. This helps eliminate them from the urine and aerosols in the lungs.
The Applicant did a follow-up literature search and found that many compounds inhibit the activity debrisoquin monooxygenase (sparteine hydroxylase). See Inaba et. al 1985. Quinidine is the most potent inhibitor. It is a stereoisomer dextrorotatory quinine that is commonly used to treat arrhythmias. Inaba et. al 1986 and Nielsen et. al 1990 discuss quinidine’s ability to inhibit oxidation of sparteine using in vivo animal testing. Brosen et. al 1987 and Broly et. al 1989 discuss quinidine’s ability to inhibit DM metabolism of liver cell preparations.
The Applicant studied the 1985 Inaba et al article which rated quinidine the most potent inhibitor for the sparteine monoxygenase enzymatic enzyme. He also recognized that it was the same enzyme referred elsewhere as debrisoquin hydroxylase. When he tried that hypothesis with quinidine and DM (both orally administered), he found that quinidine has a pronounced effect on increasing and stabilizing the amount of DM in blood. This discovery is described in U.S. Pat. No. No. 5,166,207 was also invented and used by the Applicant. The teachings of this patent are included by reference.”
“The Applicant also found that DM, when combined with quinidine, had a remarkable side effect: It was extremely effective in reducing symptoms of emotional lability”. This condition is also known as emotional incontinence. Emotional lability refers to a complex condition in which patients with neurological damage, such as a stroke or head injury, or ALS, become unable or unwilling to control their emotional outbursts. U.S. Patent. No. No. 5,206,248, also invented by Applicant. The contents of that patent can be incorporated by reference. Patients who have been treated with the combination DM/antioxidant regimen have also reported that it is extremely effective and very beneficial since the application was filed.
Patients who were treated with DM alone did not experience an unexpected benefit in emotional lability. To ensure that they would not be adversely affected, all patients who participated in the study received DM and/or quenidine only. After a patient had established a tolerance or dosage range for one of the drugs, they were given coadministered. Patients who started taking both drugs together did not realize the benefits of each drug in suppressing their emotional lability.
“The Applicant found an unexpected benefit from giving DM along with quinidine to another ALS sufferer who was a prolific metabolizer. Her severe skin condition, lichen planus, had plagued her for more than ten years. The condition was marked by severe itching and discolored lesions on her legs and abdomen. Skin specialists had prescribed many medications to her, including steroids to reduce swelling and various analgesics to relieve pain and itching. None of these had given any significant relief. She experienced significant relief from her itching and pain within two months of starting a quinidine/DM regimen. Within two months, the lesions had almost disappeared without any visible scarring.
The Applicant discovered this unexpected result and shared it with a dermatologist who is currently performing preliminary tests on patients suffering from severe or persistent dermatitis. Although preliminary results have shown that a combination of DM and an antioxidant that inhibits oxidation of DM is effective in treating severe dermatitis in extensive metabolizers has not been conclusive.
“The Prior Art re Anti-Oxidants.”
“The Applicant was surprised to discover that a combination DM/quinidine could reduce ALS patients’ emotional lability. He therefore focused his attention on the prior art, which covered both DM/antioxidant drugs. During a review of the prior art, a question arose repeatedly to the Applicant: Since quinidine and other antioxidant drugs have been proven to suppress the metabolism DM, why hasn’t anyone ever given quinidine or any other antioxidants to patients receiving DM?
“The answer to this question was found when several previously unrelated facts were correlating:
“1. “1.
“2. Doctors and pharmacologists refer to patients who lack the proper functioning debrisoquin hydroxylase enzyme as “poor metabolizers” (this term is used by Kupfer et al. 1984 and Guttendorf et al. 1988). These patients are considered high-risk and require special attention. They are more sensitive to drugs than people with the complete set of cytochrome P450 enzymes.
“3. Quinidine is likely to inhibit other cytochrome P450 enzymes, including the debrisoquin-hydroxylase inhibitor, which is extremely potent and easily demonstrated. It also has varying levels in binding affinity. The cytochrome P450 enzymes are not specific. A single isozyme may react with many substrates with very different chemical structures. Moreover, multiple isozymes have been known to overlap activity on one substrate. This is consistent with their role as lipophilic toxins eliminators. It is shown by the ability to dextromethorphan, debrisoquin and sparteine metabolize many different substrates (which all have very different structures). Quinidine has a significant effect on debrisoquin, but it can also suppress other cytochrome P450 enzymes, thus causing a greater loss of normal and desirable metabolic activity.
“4. DM is a safe drug that can be given without a prescription. It is frequently used in clinical tests to determine if a patient is a good or poor metabolizer. These tests can help identify patients who are a poor metabolizer and protect them against drugs that they cannot properly metabolize.
Guttendorf et al 1988 and Kupfer et al 1985, which both discuss poor metabolizers, provide some information. Other points can be gleaned from articles like Koppel et al 1986, which discusses the general characteristics of cytochrome P450 enzymes.
Broly et. al. 1989 reports that quinidine inhibits DM oxidation of liver cell preparations in liver cells are warnings that patients who take quinidine must be protected from the risks and dangers that can affect poor metabolizers. These articles also warn doctors that quinidine can cause poor metabolizers. The diagnostic test used to identify them should not be used if the patient is using quinidine.
“The Applicant also discovered another important factor in his literature analysis. Dextromethorphan’s primary oxidized metabolic product is dextrorphan. This is widely believed by neurologists to be the same as dextromethorphan. Both drugs are sigma agonists and NMDA antagonists. Neurologists and others were not motivated to try to increase DM levels in blood because the metabolite is believed to have the exact same neuronal activities.
“As evidence that there is no interest among neurologists to use cytochrome P450 inhibits to increase the dextromethorphan levels in the bloodstream of patients receiving DM,” Walker and Hunt 1989, Albers et Al 1991, Applebaum et Al 1991, Askmark et Al 1993. These researchers recognized the problems caused by DM metabolism and reported on them. However, they did not mention or show any interest in quinidine or any other oxidation inhibitor to slow down the enzymatic degrading of DM.
“Despite all the facts and prevailing beliefs in the field of research, the Applicant’s work has shown that quinidine can be administered in combination with DM to provide at least two therapeutic benefits, including the suppression of emotional lability and treatment of dermatitis. These effects were evident in patients who were treated with quinidine in combination with DM, but were not observed in patients receiving dextromethorphan.
“Accordingly, the invention discloses that DM can be given in combination with quinidine (a second compound such as quinidine) to treat severe or difficult dermatitis in patients who are extensive metabolizers”.
“Another object in this invention is to disclose that any one of the compounds known to inhibit DM-degrading oxidative activation of debrisoquin hydroxylase can also be tested to determine if they are suitable for use in a patient with severe dermatitis. Routine tests can identify a specific antioxidant compound that has minimal adverse effects for a patient in need of treatment. Once a patient has been identified, the optimal dose of anti-oxidant medication can be determined. This will ensure that the patient receives the highest blood levels of DM. To treat the dermatitis, the chosen compound can be administered in combination with a suitable dose of DM at the appropriate dosage.
“Another object in this invention is to disclose that DM appears to be able, on its own, to treat dermatitis in patients who have been classified as poor metabolizers”. This refers to patients without a functioning debrisoquin hydroxylase. These patients don’t have a functioning debrisoquin hydroxylase enzyme, so they won’t require any anti-oxidant drug to prevent DM oxidation or elimination. DM should be administered alone in patients with “poor metabolizer” because it will produce the same effect as a DM/antioxidant combo in patients with “extensive metabolizer”.
These and other objects will be apparent from the following description.
“It should also be noted that the copending application Ser. No. No. These conditions include (1) emotional lability as discussed above: (2) the itching and pain that accompany severe dermatitis; and, (3) at least one other other medically significant, otherwise-intractable condition that has been identified and treated with excellent results using a DM/antioxidant combination (this method of treatment is the subject of another patent application that is pending before the U.S. Patent and Trademark Office). The co-pending application Ser. No. 07/896.053, now abandoned. It disclosed and claimed a method for treating unwanted nerve impulses”. This was done using a DM/antioxidant combination therapy. These claims were not examined and will be the subject of a divisional patent application. They are also mentioned in the co-pending Ser. No. No.
“This invention relates to a method of treating human patients with severe dermatitis. These patients can be treated with dextromethorphan, an antitussive agent that is commonly found in cough syrup. An antioxidant drug, such as quinidine, can be given to patients who are deemed excessive metabolizers. This will inhibit the DM-degrading activities of debrisoquin hydroxylase which is an enzyme that converts DM quickly into its metabolite dextrorphan. This combination has shown great success in severe dermatitis treatment. Most patients experience no adverse effects.
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