Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-17
2002-07-09
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S220000, C514S264110, C514S317000, C514S376000, C514S392000, C514S401000, C514S561000, C514S567000, C514S617000, C514S618000, C514S634000, C514S654000
Reexamination Certificate
active
06417184
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the treatment and prevention of acute or chronic pain syndromes.
2. Description of the Related Art/Background Information
Pain sensation is complex and variable. Experiences considered painful by one subject may not be equally painful to another and may vary in the same subject depending on the circumstances presented. In addition, subjective experiences, i.e. “phantom limb pain” make it clear that there is a strong psychological component to pain. Wingard et al.,
Human Pharmacology: Molecular to Clinical
, Mosby-Year Book, Inc., 1991, p. 383.
Several groups of compounds are used to relieve pain, depending on the severity and duration of the pain sensation, and on the nature of the painful stimulus. Drugs used to relieve mild, moderate or severe pain without causing unconsciousness are generally called analgesics. Mild analgesics that are termed non-narcotic agents include aspirin, acetaminophen and non-steroidal anti-inflammatory drugs. Should non-narcotic based agents prove ineffective, narcotic/opioid analgesic agents such as morphine, codeine, meperidine, and the like are used to treat more severe acute or chronic forms of pain. Ibid., pp. 383, 391-92.
Generally, there are two different types of nociceptive (noxious) stimuli, which are intense enough to be perceived as pain within the human body and can be alleviated by narcotic and non-narcotic analgesic agents. One type, somatic pain, consists of an intense, localized, sharp or stinging sensation. Somatic pain is believed to be mediated by fast-conducting lightly myelinated A-delta fibers that have a high threshold (i.e. require a strong mechanical stimulus to sense pain) and enter into the spinal cord through the dorsal horn of the central nervous system where they terminate mostly in lamina I of the spinal cord. Ibid., p. 383.
The second type of pain, sometimes referred to as visceral pain, is characterized as a diffuse, dull, aching or burning sensation. Visceral pain is believed to be mediated largely by unmyelinated, slower-conducting C-fibers that are polymodal (i.e., mediate mechanical, thermal, or chemical stimuli). C-fibers also enter the spinal cord through the dorsal horn of the central nervous system where they terminate mostly in the outer layer of lamina II of the spinal cord. Ibid., p. 383. Both somatic and visceral pain can be sensed centrally and peripherally within the human body.
Central sensitization, i.e. central pain, takes place within the dorsal horn of the spinal cord, the brain stem, and brain. Amplification of nociceptive input in the spinal cord produces secondary hyperalgesia around the site of injury once central sensitization has begun. Central sensitization is believed to be evoked by A-beta low-threshold mechanoreceptors. Often, central sensitization is initiated by slow synaptic potentials through A-delta and C fibers within the dorsal horn of the central nervous system. The long duration of these slow potentials permit summation of potentials during repetitive nociceptor input and generates progressively greater and longer-lasting depolarization in dorsal horn neurons. Several seconds of C fiber input results in several minutes of postsynaptic depolarization.
This depolarization is believed to result from the activation of N-methyl-D-aspartic acid (NMDA) receptors like glutamate, and activation of the NK-1 tachykinin receptor by substance P and neurokinin A. Activation of these receptors allows an inrush of calcium through ligand and voltage-gated ion channels and activation of guanosine triphosphate (GTP) binding proteins. “Pain and Memory”,
Pain Clinical Updates
, Vol. VII, Iss. 1, Spring 1999, p. 2. These second messengers in turn simulate protein kinase C activity, which enhances the function of ion channels and intracellular enzymes by phosphorylating proteins. Ibid., p. 3.
Another mechanism of central sensitization involves the production of intracellular nitric oxide. It has been proposed that activation of the NMDA receptor leads to an influx of calcium ion, which activates a central enzyme nitric oxide synthetase. Intracellular nitric oxide release stimulates transduction of protein kinase C, increases the effects of glutamate, and may interfere with the release of inhibitory neurotransmitters from inhibitory neurons within the central nervous system, causing increases in pain in both the acute and chronic syndromes. Nitric oxide antagonism is therefore another strategy to prevent central sensitization. Ibid., p. 3.
Peripheral sensitization, i.e. peripheral pain, is generally caused by activating A-delta and C nociceptors. Peripheral sensitization is induced by neurohumoral alterations at the site of injury to the human body and surrounding tissue area. Biochemicals released by tissue injury, such as potassium, prostaglandins, bradykinin, and the like excite nociceptors or increase their sensitivity at the injured site (primary hyperalgesia). Substance P, released by an axon reflex, induces vasodilation and mast cell degranulation, resulting in the release of histamine and serotonin which aid in pro-inflammatory reactions, which in turn sensitize adjacent A-delta and C nociceptors further causing pain stimulation. Increased transduction produces continuous nociceptive input that can induce allodynia, primary hyperalgesia, and secondary hyperalgesia. Ibid., p. 2.
Also within the central nervous system are endogenous pain control systems, which descend the spinal cord through the dorsolateral funiculus to the spinal dorsal horn where they inhibit neurons that are activated by binociceptive stimuli. The higher brain centers connected to these descending systems include the pariaqueductal gray region and various subregions of the medulla within the brain. The neurotransmitters for these systems include substance P, somatostatin, vasoactive intestinal polypeptide, cholecystokinin, calcitonin gene-related peptide, norepinephrine, serotonin and opioid peptides. Ibid., pp. 383-84.
The spinal cord itself also contains opioid receptors, which are mainly localized within laminae-I to III of the dorsal horn within the tract of Lissauer. Of these, the highest density of opioid receptors is generally localized in the inner segment of lamina II. Ibid., p. 384. There are multiple types of opioid receptors within the central nervous system designated as mu, kappa, sigma, and delta receptors, with additional subclasses for each of these receptor types. Activation of these receptors in the brain is believed to be responsible with production of analgesic effects. For example, it is believed that kappa receptors, which exist in the brain's spinal cord, produce analgesia at the spinal level. The majority of the psychotomimetic effects of opioid drugs, i.e. dysphoria and hallucinations are believed to be mediated by sigma receptors. Delta receptors have a different distribution in the brain, and are thought to be the primary receptor for endogenous opioid pentapeptides, such as enkephalins. Ibid., p. 385.
These types of receptors are located on the membranes of neurons and interaction of agonists, such as narcotic analgesics, with these receptors generally leads to a reduction in excitability and firing rate within the neuron causing a decrease in pain sensation. Agonists of mu receptors, for example, increase the outward flux of potassium ions, which may make the neuron less excitable, causing a decrease in pain. Agonists of kappa receptors more directly inhibit the entry of calcium into a neuron through voltage-dependent calcium channels, again causing a decrease in pain in this manner. Agonists of mu and delta receptors are believed to decrease neuronal cAMP synthesis to decrease pain sensation. Ibid., p. 387.
Thus, the use of opioids, NSAIDS, and many other analgesics within the prior art reduce both central and peripheral sensitization through interaction with the various pain-based receptors within the human body. For example, morphine and most other opioid analgesics elicit an inhibitory neuronal eff
Jarvis William R. A.
Price Heneveld Cooper DeWitt & Litton
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