Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-25
2002-06-18
Henley, Jr., Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S257000, C514S267000, C514S282000
Reexamination Certificate
active
06407088
ABSTRACT:
FIELD OF THE INVENTION
This invention presents a method of alleviating pain, such as central pain, pain arising from cancer and phantom limb pain, by systemic administration of sodium channel blocking compounds, including tetrodotoxin and saxitoxin.
BACKGROUND OF THE INVENTION
Pain is a sensation that hurts. It may cause discomfort or distress or agony. It may be steady or throbbing. It may be stabbing, aching, or pinching. However pain is felt, only the person experiencing pain can describe it or define it. Because pain is so individual, pain cannot be truly evaluated by any third person.
The World Health Organization (WHO) recognizes a “Three-step Analgesic Ladder” for pharmacologic management of pain. The ladder begins with relatively low doses of low-potency analgesics and progresses to higher doses of more potent compounds. The three steps involve use of:
Nonopioid analgesics with or without coanalgesics, such as Nonsteroid Anti-inflammatory Drugs (NSAIDs);
Lower-potency opioids with or without coanalgesics as pain persists or increases to moderate levels;
High-potency opioids with or without nonopioid coanalgesics as pain persists or increases to severe levels.
Use of opioid analgesics, even for treatment of severe pain, is controversial in the medical community, due to the possibility of addiction. See, e.g. S. E. Weitz et al., New Jersey Medicine, Vol. 97: 63-67 (2000).
Tetrodotoxin is a nonprotein neurotoxin that is found in multiple diverse animal species, including puffer fish, goby fish, newt, frogs and the blue-ringed octopus.
Tetrodotoxin can be obtained from the ovaries and eggs of several species of pufferfish of the suborder Gymnodontes. Tetrodotoxin is the agent for poisoning occurring from the consumption of ill-prepared fugu fish in sushi bars. Tetrodotoxin can also be obtained from California newts of the genus taricha.
One biological activity of tetrodotoxin is binding of the alpha subunit of neuronal sodium channels. Tetrodotoxin has a chemical formula of C
11
H
17
N
3
O
8
, and has a molecular weight of 319.28. The Merck Index, 10
th
Ed. (1983), states tetrodotoxin is the generic name for the compound octahydro-12-(hydroxymethyl)-2-imino-5,9:7,10a-dimethano-10aH-(1,3)dioxocino(6,5-d)-pyrimidine-4,7,10,11,12-pentol, which has the following structure:
The Merck Index, 10
th
Ed. (1983), states tetrodotoxin is also referred to as maculotoxin, spheroidine, tarichatoxin, tetrodontoxin, fugu poison and TTX.
According to U.S. Pat. No. 6,030,974, “tetrodotoxin” or “TTX” refers to the amino perhydroquinazoline compounds having the molecular formula C
11
H
17
N
3
O
8
and to derivatives thereof, including but not limited to anhydrotetrodotoxin, tetrodaminotoxin, methoxytetrodotoxin, ethoxytetrodotoxin, deoxytetrodotoxin and tetrodonic acid (Kao). Examples of TTX analogs include novel TTX analogs isolated from various organisms, as well as those that are partially or totally chemically synthesized. See e.g., Yotsu, M. et al. Agric. Biol. Chem., 53(3):893-895 (1989). Such analogs bind to the same site on the alpha subunit of sodium channels as does TTX.
Adams, et al., U.S. Pat. Nos. 4.022,899 and 4,029,793 pertain to a local anesthetic composition comprising a mixture in a pharmaceutically acceptable carrier of a particular toxin, namely tetrodotoxin or desoxytetrodotoxin, and another compound, generally a conventional local anesthetic compound or a similar compound having nerve-blocking properties. The conventional local anesthetic can be an aminoacylanilide such as lidocaine, an aminoalkylbenzoate such as procaine, cocaine, an amino carbamate such as diperodon, a N-phenylamidine such as phenacine, a N-aminoalkyl amide such as dibucaine, an aminoketone such as falicain, or an aminoether such as pramoxine.
According to U.S. Pat. No. 6,030,974, “saxitoxin” or “STX” refers to a compound comprising a tetrahydropurine moiety composed of two guanidine units fused together in a stable azaketal linkage, having a molecular formula C
10
H
17
N
7
O
4
, (mol. wt. 299.30) and to derivatives thereof, including but not limited to hydroxysaxitoxins and neosaxitoxin. See Bower et al., Nonprotein Neurotoxins, Clin. Toxicol. 18(7):813-863 (1981).
Tetrodotoxin and its significance in the study of excitation phenomena has been reviewed by C. Y. Kao, Pharmacological Reviews, Vol. 18, No. 2, 997-1049 (1966). Kao notes that one of the most prominent actions of tetrodotoxin in the whole animal is a rapidly progressive and marked weakening of all voluntary muscles, including the respiratory muscles (Kao at 1016). However, Kao notes that specific action of tetrodotoxin on the central nervous system is debatable (Kao at 1022, line 3).
Pan et al., U.S. Pat. No. 5,846,975, discloses the use of amino hydrogenated quinazoline compounds, such as tetrodotoxin, for treating drug dependence in humans. Tetrodotoxin was shown to be effective against withdrawal symptoms from opium, heroin, morphine, cocaine, amphetamine, dolandin, dihydroetorphine and methadone. Amounts effective for relieving withdrawal symptoms are described in this patent.
Tetrodotoxin can be used as a local anesthetic and is ten thousand times more powerful than commonly used local non-narcotics, as is discussed by C. Y. Kao and F. A. Fuhrman, J. Pharmacol., 140, 31-40 (1963). Tetrodotoxin preparations in combination with other widely used anesthetics have been noted in U.S. Pat. Nos. 4,022,899 and 4,029,793.
U.S. Pat. No. 6,030,974 describes a method of producing local anesthesia in a mammal experiencing pain in an epithelial tissue region. The method includes topically administering to the region, in a suitable pharmaceutical vehicle, an effective dose of a long-acting sodium channel blocking compound. The sodium channel blocking compound of U.S. Pat. No. 6,030,974 can be a formulation of tetrodotoxin or saxitoxin at a concentration of between 0.001-10 mM.
Zapata et al., Pain 72:41-49 (1997) discusses the utilization of tetrodotoxin for the inhibition of neuropathic ectopic activity in neuromas, dorsal root ganglia and dorsal horn neurons. The neuronal activity arises from neuroma caused by mechanical, chemical or ischemic injury. The effect of intravenously administered TTX on the neuronal induction by sciatic nerves in male rats was researched. However, the dosages and effects studied by Zapata et al. were applied to animals under anesthesia and artificial ventilation, thus these doses are above the maximal tolerated dose and the administration was under conditions that are not applicable to the presently intended clinical use of tetrodotoxin.
Although there has been extensive research into the effectiveness of TTX and its derivatives as a sodium channel blocker and local anesthetic, systemic administration of pure TTX as an analgesic has never been disclosed. The potential for TTX to alleviate pain arising from the activity in the central nervous system, rather from the stimulation of peripheral nerves does not seem to have been described.
The alleviation of chronic severe pain, such as that arising from cancer and “phantom limb pain” is an important topic in modern medicine. Cancer is highly pervasive in the human population.
A person suffering from cancer frequently experiences severe pain. This pain can also be known as central pain or chronic pain. However, a patient need not be suffering from cancer to experience central pain or chronic pain. A related type of pain is phantom limb pain. These types of pain have been treated by opiates such as morphine. A drawback of the opiate analgesia is the addictive nature of the opiates.
Acute local pain can arise, for example, from toothaches, eye irritation, inflammation in a nervous tissue region, canker sores, genital ulcers, and pain in epithelial tissues caused by burns, surgery or soreness.
Perception of pain can also be divided into three areas; acute nociceptive processing, facilitated pain arising from persistent afferent input (as after tissue injury) and neuropathic pain that arises from altered processing after nerve injury.
Some sodium channel blocking compounds, e.
Dong Qingbin
Shum Frank Hay Kong
Birch & Stewart Kolasch & Birch, LLP
Henley, Jr. Raymond
Wex Medical Instrumentation Co., Ltd.
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