Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.
Reexamination Certificate
1999-06-18
2003-04-15
Lukton, David (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Tripeptides, e.g., tripeptide thyroliberin , etc.
C514S018700, C514S019300, C562S445000
Reexamination Certificate
active
06548637
ABSTRACT:
BACKGROUND OF THE INVENTION
Millions of people suffer from chronic or intractable pain. Persistent pain varies in etiology and presentation. In some cases, symptoms and signs may be evident within a few weeks to a few months after the occurrence of an injury or the onset of disease, e.g. cancer or AIDS. Like many illnesses that at one time were not well understood, pain and its many manifestations may be poorly treated and seriously underestimated. Inappropriately treated pain seriously compromises the patient's quality of life, causing emotional suffering and increasing the risk of lost livelihood and disrupted social integration. Severe chronic pain affects both the pediatric and adult population, and often leads to mood disorders, including depression and, in rare cases, suicide.
In the last several years, health policy-makers, health professionals, regulators, and the public have become increasingly interested in the provision of better pain therapies. This interest is evidenced, in part, by the U.S. Department of Health and Human Services' dissemination of Clinical Practice Guidelines for the management of acute pain and cancer pain. These publications state that opioids are an essential part of a pain management plan. There is currently no nationally accepted consensus for the treatment of chronic pain not due to cancer, yet the economic and social costs of chronic pain are substantial, with estimates ranging in the tens of billions of dollars annually.
Opioids are the major class of analgesics used in the management of moderate to severe pain because of their effectiveness, ease of titration, and favorable risk-to-benefit ratio. Opioids produce analgesia by binding to specific receptors both within and outside the CNS. Opioid analgesics are classified as full agonists, partial agonists, or mixed agonist-antagonists, depending on the specific receptors to which they bind and their intrinsic activity at that receptor.
Three subclasses of opioid receptor have been identified in humans, namely the &dgr;-, &kgr;-, and &mgr;-opioid receptors. Analgesia is thought to involve activation of both &mgr; and &kgr; receptors. Notwithstanding their low selectivity for &mgr; over &kgr; receptors, it is likely that morphine and morphine-like opioid agonists produce analgesia primarily through interaction with &mgr; receptors; selective agonists of &kgr; receptors in humans produce analgesia, but rather than the euphoria associated with morphine and congeners, these compounds produce dysphoria and psychotomimetic effects. The consequences of activating &dgr; receptors in humans remain unclear.
Commonly used full agonists include morphine, hydromorphone, meperidine, methadone, levorphanol, and fentanyl. These opioids are classified as full agonists because there is not a ceiling to their analgesic efficacy, nor will they reverse or antagonize the effects of other opioids within this class when given simultaneously. Side effects include constipation, nausea, urinary retention, confusion, sedation, and respiratory depression. Morphine is the most commonly used opioid for moderate to severe pain because of its availability in a wide variety of dosage forms, its well-characterized pharmacokinetics and pharmacodynamics, and its relatively low cost. Meperidine may be useful for brief courses (e.g., a few days) to treat acute pain and to manage rigors (shivering) induced by medication, but it generally should be avoided in patients with cancer because of its short duration of action (2.5 to 3.5 hours) and its toxic metabolite, normeperidine. This metabolite accumulates, particularly when renal function is impaired, and causes CNS stimulation, which may lead to dysphoria, agitation, and seizures; meperidine, therefore, should not be used if continued opioid use is anticipated.
Buprenorphine is an example of a partial agonist. Buprenorphine has a relatively low intrinsic efficacy at the opioid receptor in comparison to full opioid agonists, and it displays a ceiling effect to analgesia. Clinical studies found buprenorphine to be effective in the treatment of heroin addiction and to have some advantages over methadone in terms of relative safety. Buprenorphine also reduces cocaine abuse in individuals who are dependent on both heroin and cocaine. The dual effects of buprenorphine provide new insight into the mechanisms of cocaine and heroin dependence; these observations suggest, furthermore, that the underlying mechanisms of these dependencies may be similar.
Mixed agonist-antagonists in clinical use include pentazocine, butorphanol tartrate, and nalbuphine hydrochloride. These drugs have an analgesic ceiling. In contrast to full agonists, these drugs block opioid analgesia at one type of opioid receptor (&mgr;) or are neutral at the &mgr; receptor while simultaneously activating a different opioid receptor (&kgr;). Patients receiving full opioid agonists should not be given a mixed agonist-antagonist because doing so may precipitate a withdrawal syndrome and increase pain.
The development of physical dependence with repeated use is a characteristic feature of the opioid drugs, and the possibility of developing drug dependence is one of the major limitations of their clinical use. Almost all opioid users rapidly develop drug dependency which can lead to apathy, weight loss, loss of sex drive, anxiety, insomnia, and drug cravings.
Historically, the development of analgesic tolerance was believed to limit the ability to use opioids efficaciously on a long-term basis for pain management. Tolerance, or decreasing pain relief with the same dosage over time, has not proven to be a prevalent limitation to long-term opioid use. Experience with treating cancer pain has shown that what initially appears to be tolerance is usually progression of the disease. Furthermore, for most opioids, there does not appear to be an arbitrary upper dosage limit, as was once thought.
Cessation of opioid administration may result in withdrawal. Symptoms of withdrawal are often the opposite of the effects achieved by the drug; withdrawal from morphine, however, results in complex symptoms that may seem unrelated to its effects. Misunderstanding of addiction and mislabeling of patients as addicts result in unnecessary withholding of opioid medications. Addiction is a compulsive disorder in which an individual becomes preoccupied with obtaining and using a substance, the continued use of which results in a decreased quality of life. Studies indicate that the de novo development of addiction is low when opioids are used for the relief of pain. Furthermore, even opioid addicts can benefit from the carefully supervised, judicious use of opioids for the treatment of pain due to cancer, surgery, or recurrent painful illnesses such as sickle cell disease.
Zadina et al. recently reported the isolation and characterization of endomorphins 1 (1) and 2 (2) (Nature 1997, 386, 499-502). The endomorphins are tetrapeptides, isolated from bovine frontal cortex, that selectively bind in vitro to the &mgr;-opioid receptor; 1 (Seq. ID No.1) and 2 (Seq. ID No.2) select for &mgr; over &dgr; receptors by factors of 4,183 and 13,381, respectively; and 1 (Seq. ID No.1) and 2 (Seq. ID No.2) select for &mgr; over &kgr; receptors by factors of 15,077 and 7,594, respectively. Additionally, 1 (Seq. ID No.1) and 2 (Seq. I.D. No.2) are potent analgesics in vivo; intracerebroventricular injections to mice of 1 (Seq. ID No.1) and 2 (Seq. ID No.2) established ED
50
values of 8.4 &mgr;g and 2.9 &mgr;g, respectively. Finally, the analgesic effects of the endomorphins were antagonized by naloxone and &bgr;-funaltrexamine.
Oligopeptides do not easily cross the GI/blood and blood/brain barriers. This problem cannot be attributed solely to a lack of metabolic stability. Crossing both the GI/blood and blood/brain barriers are key steps when considering using a peptide as a drug. While several peptides have been successfully stabilized against degradation, their bioavailability, namely their ability to cross the blood/brain barrier remained problematic.
Hauske James R.
Hussoin Roushan A.
Persons Paul E.
Foley Hoag & Eliot LLP
Gordon Dana M.
Lukton David
Sepracor Inc.
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