Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-14
2004-03-30
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06713488
ABSTRACT:
BACKGROUND OF THE INVENTION
Endogenous opiate receptors were discovered in the 1970s, and have been intensely studied in seeking the mechanisms by which particular drugs lead to addiction. However, such mechanisms have remained elusive. See, for example,
J. Neurosci.,
12(7): 2349-2450 (1992).
A number of different opioid receptor types have been identified. Known receptor types include, for example, the mu &mgr; (MOR), delta &dgr; (DOR), and &kgr; kappa receptors. Narcotic analgesics act at the opioid &mgr; receptor to produce analgesia. The &mgr; receptor mediates analgesia, respiratory depression, and inhibition of gastrointestinal transit. As such, narcotic analgesics act at the &mgr; receptor to produce analgesia. However, continued use of narcotic analgesics typically leads to habit or addiction, and use of one leads to cross-tolerance/dependence for the others. Despite their therapeutic uses, undesirable side effects such as physical dependence and drug craving can develop.
Opiates, are a class of centrally acting compounds and are frequently used agents for pain control. Opiates are narcotic agonistic analgesics and are drugs derived from opium, such as morphine, codeine, and many synthetic congeners of morphine, with morphine being the most widely used derivative. Opioids are natural; and synthetic drugs with morphine-like actions and include the opiates. Opioids are narcotic agonistic analgesics which produce drug dependence of the morphine type and are subject to control under federal narcotics law because of their addicting properties. The chemical classes of opioids with morphine-like activity are the purified alkaloids of opium consisting of phenanthrenes and benzylisoquinolines, semi-synthetic derivatives of morphine, phenylpiperidine derivatives, morphinan derivatives, benzomorphan derivatives, diphenyl-heptane derivatives, and propionanilide derivatives.
Physical dependence or drug addiction to narcotic drugs, for example, opioids, has been traditionally treated by drug withdrawal through administering an opioid antagonistic drug such as naltrexone or naloxone, withholding the opioid from the drug-dependent individual, gradually decreasing the amount of opioid taken by the individual over time, or substituting another drug, such as methadone, buprenorphine, or methadyl acetate, for the opioid to ameliorate the physical need for the opioid. When an opioid is discontinued, withdrawal symptoms appear, the character and severity of which are dependent upon such factors as the particular opioid being withdrawn, the daily dose of the opioid that is being withdrawn, the duration of use of the opioid, and the health of the drug dependent individual. The pain associated with withdrawal symptoms can be quite severe.
For example, the withdrawal of morphine, heroin, or other opioid agonists with similar durations of action from an individual dependent upon the opioid gives rise to lacrimation, rhinorrhea, yawning, and sweating 8 to 12 hours after the last dose of the opioid. As withdrawal progresses, the individual will be subject to dilated pupils, anorexia, gooseflesh, restlessness, irritability, and tremor. At the peak intensity of withdrawal, which is 48 to 72 hours for morphine and heroin, the individual suffers from increasing irritability, insomnia, marked anorexia, violent yawning, severe sneezing, lacrimation, coryza, weakness, depression, increased blood pressure and heart rate, nausea, vomiting, intestinal spasm, and diarrhea. The individual commonly experiences chills alternating with hot flushes and sweating, as well as abdominal cramps, muscle spasms and kicking movements, and pains in the bones and muscles of the back and extremities, and exhibits leukocytosis and an exaggerated respiratory response to carbon dioxide. Typically the individual does not eat or drink which, when combined with the vomiting, sweating, and diarrhea, results in weight loss, dehydration, and ketosis. The withdrawal symptoms from morphine and heroin usually disappear in 7 to 10 days, but the drug dependent individual suffers greatly during the withdrawal period.
Alternatively, if an opioid antagonistic drug is administered to the individual, such as naloxone or naltrexone, withdrawal symptoms develop within a few minutes after parenteral administration and reach peak intensity within 30 minutes, with a more severe withdrawal than from withholding the opioid. For example, naloxone is the current treatment of choice in cases of overdose. It is immediately effective but is encumbered by intense withdrawal syndrome. Naltrexone can be used, for example, in maintenance therapy, but is quite aversive, which impedes wide acceptance and efficacy. Since addiction to cocaine and alcohol have been reported to also be mediated by specific opioid-sensitive brain cell networks (See, Gardner et al.,
Substance Abuse
2
nd
Ed
., pp. 70-99 (1992)) the use of opioid antagonists can be suitable for use in the treatment of alcohol and cocaine dependency. Thus, the opioid receptors can play a role in the dependency of multiple drug substances.
The use of opioid analgesics for the treatment of pain and during and/or after anesthesia can also lead to unwanted side effects, for example, respiratory depression. It is frequently necessary to titrate back or adjust the degree of analgesic/anesthesia in an individual receiving opioid pain management, for example, undergoing or recovering from a surgical procedure, due to complications associated with too high of a dose. The use of naltrexone and naloxone present undesirable side effects such as exacerbation respiratory depression when used to titrate back. Further, use of opioid analgesics for chronic pain can often be associated with constipation which can be a significant and limiting problem. There is currently no known treatment strategy to reduce the constipating effects of the opioid analgesics without blocking the analgesic effect and/or causing additional side effects (e.g., diarrhea and hyperalgesia).
Therefore, a need exists for agents which can be used in the treatment of drug dependency or in pain management to, for example, modify the anesthesia/analgesia of an opioid drug or its unwanted side effects but which have reduced aversive properties and can result in reduced withdrawal symptoms.
SUMMARY OF THE INVENTION
The invention relates to the use of naltrexone and naloxone analogs, which are neutral antagonists at the &mgr; opioid receptor, for the treatment of drug dependency in a drug-dependent individual. Surprisingly, it has been found that administration of a therapeutically effective amount of the naloxone or naltrexone analogs described herein for the treatment of a drug dependency, can result in reduction of undesirable side effects resulting from current treatments using naloxone and naltrexone. For example, the treatment described herein can result in a reduction in the withdrawal symptoms and aversion encountered in the use of naloxone and naltrexone in the treatment of drug dependency. In addition, the naltrexone and naloxone analogs of the invention can be used for modulating the treatment of pain or anesthesia in an individual in need thereof by decreasing or reversing the effects of high doses of the narcotic analgesic, for example, respiratory depression, or decreasing side effects such as constipation without blocking analgesia.
U.S. Pat. No. 6,007,986, teaches that the &mgr; opioid receptor has a constitutively active state that may be represented as &mgr;*. The &mgr; opioid receptor is the main mediator of narcotic analgesia and addiction and can be classified as a G protein coupled receptor (GPCR). This feature of basal level signalling activity is emerging as a recognized feature of a number of GPCRs, for example, the dopamine receptors, D1, D2 and D3, the adenosine receptor, the &bgr;2-adrenergic receptor, the serotonin receptor (5HT-2A) and the &dgr;-opioid receptors. In the naive state (no prior drug exposure), the activity of the &mgr;* state is minimal, and most receptors are drug sensitive. Recent findings, indicate th
Sadee Wolfgang
Wang Danxin
Mueller and Smith LPA
Reamer James H
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