Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a method of producing analgesia in a mammal experiencing pain, comprising administering to the mammal a composition comprising a synergistically effective analgesic combination of an opioid analgesic agent and a compound that binds to the SSI or SS2 subunit of a sodium channel in a pharmaceutically suitable vehicle.
• opioid analgesics such as morphine are the most powerful analgesics for treating severe chronic and acute pain.
• An example of chronic pain is the pain experienced bycancer patients.
• An example of acute pain is the pain experienced after operations.
• the pain relieving activity of opioid analgesics includes a depressive effect on the central nervous system.
• the analgesic activity of opioid analgesics such as morphine and deltorphin II can be mediated via different opioid receptors, for example via ⁇ -opioid and ⁇ -opioid receptors.
• Opioid analgesics are invaluable for the treatment of severe acute or chronic pain as, for example, may occur in bone degenerative diseases and cancer conditions.
• opioids are easy to administer and they provide effective pain relief in most patients. Due to the excellent overall tolerability of opioids, the doses of morphine and other strong opioids can be increased to relatively high levels.
• the opioids used for treating such pain are indeed highly effective but have a number of unpleasant and/or undesirable side effects (e.g. a short duration of activity, respiratory depression, nausea, constipation, diuresis and euphoria and they are also addictive). In some patients, particularly in the chronically ill, the opioid side effects make it impossible to continuously administer sufficiently high dosages to adequately control pain over the needed period of time. There are also some pain conditions that do not sufficiently respond to opioid pain treatment alone.
• sodium channel blocking compounds that bind to the SSI or SS2 subunit of a sodium channel, particularly tetrodotoxin and saxitoxin, are found to possess a potent analgesic property (US Patent Application No. 09/695,053).
• Tetrodotoxin is effective on all severe chronic pains. Tetrodotoxin is capable of providing analgesia in a mammal experiencing acute or chronic pain.
• tetrodotoxin was found to be about 3,000 times more analgesically potent than morphine. Moreover, TTX does not produce addiction. Furthermore, trials in humans indicate that TTX also provides a duration of action much longer than morphine. TTX provides significant analgesia for pain from chemical stimulation. However, a larger dose appears to be necessary for suppressing pain induced by heat. In studies of use of TTX to treat addiction, experiments suggest a steep dose-toxicity curve for TTX. Therefore, there is a need to improve safety by reducing the TTX dose needed for efficient pain relief.
• Fairbanks (US Patent No. 6,204,271) introduced co-administration of an opioid analgesic agent and moxonidine as a non-opioid agent for producing synergistic analgesia in mammals, hoping to provide a reduced propensity for causing undesirable side effects.
• Moxonidine is known to be an imidazoline/ a 2 -adrenergic (I ⁇ / ⁇ 2 -AR) receptor agonist and is clinically used in antihypertensive medications.
• Monoxidine is reported to have analgesic activity, but is not comparable to TTX, which is potent and provides long duration of relief in cancer patients.
• TTX is also non-addictive as shown through studies in a variety of animals .
• the present invention is related to producing analgesia in mammals, in particular in humans, by co-administering synergistically effective amounts of (1) a sodium channel blocking compound that specifically binds to the SS 1 or SS2 subunit of a sodium channel, such as tetrodotoxin or saxitoxin or analogs thereof; and (2) an opioid analgesic agent.
• a sodium channel blocking compound that specifically binds to the SS 1 or SS2 subunit of a sodium channel, such as tetrodotoxin or saxitoxin or analogs thereof
• an opioid analgesic agent such as tetrodotoxin or saxitoxin or analogs thereof.
• the present invention further pertains to analgesic pharmaceutical compositions comprising synergistically effective amounts of a sodium channel blocking compound that specifically binds to the SSI or SS2 subunit of a sodium channel and an opioid analgesic agent.
• An object of this invention to provide a potent analgesic composition containing a long-acting analgesic sodium channel blocking compound that binds to the SSI or SS2 subunit of a sodium channel, and an opioid analgesic agent, with a reduced propensity for causing undesirable adverse effects. It is also an object of the invention to provide a non-addictive sodium channel blocker with analgesic activity showing synergy with the analgesic activity of the opioid, and to provide analgesic compositions comprising an opioid analgesic agent, such as morphine and its derivatives, and such a synergistically effective non-addictive sodium channel blocker which allows reducing the amount of the opioid necessary to achieve effective pain treatment.
• an opioid analgesic agent such as morphine and its derivatives
• Figure 1 shows the analgesia effect of co-administered TTX and morphine observed in the formalin-induced inflammatory pain test in rats.
• Figure 2 shows the actual and the theoretical predictive analgesia effect of TTX at 0.19 ⁇ g/kg co-administered with morphine observed in the formalin-induced inflammatory pain test in rats.
• Figure 3 shows the actual and the theoretical predictive analgesia effect of TTX at 0.39 ⁇ g/kg co-administered with morphine observed in the formalin test in rats.
• Figure 4 shows the actual and the theoretical predictive analgesia effect of TTX at 0.39 ⁇ g/kg co-administered with morphine observed in the tail-flick test in mice.
• Figure 5 shows the actual and the theoretical predictive analgesia effect of TTX at 0.79 ⁇ g/kg co-administered with morphine observed in the tail-flick test in mice.
• the present invention is related to producing analgesia in mammals, in particular in humans, by co-administering synergistically effective amounts of (1) a sodium channel blocking compound that specifically binds to the SS 1 or SS2 subunit of a sodium channel; and (2) an opioid analgesic agent.
• a sodium channel blocking compound that specifically binds to the SS 1 or SS2 subunit of a sodium channel
• an opioid analgesic agent can be administered in a low-analgesic dose, or even in a per se sub-analgesic dose.
• the composition may contain both, a sodium channel blocking compound that specifically binds to the SS 1 or SS2 subunit of a sodium channel and the opioid agent, together in one dosage form or each in a separate dosage form
• Tetrodotoxin and saxitoxin are known to be sodium channel blocking compounds that specifically bind to the SSI or SS2 subunit of a sodium channel.
• Tetrodotoxin and its pharmacologically acceptable salts are species of octahy&o-12-(hydroxymethyl)-2-imino-5,9:7, 1 Oa-dimethano- 10aH-[l ,3]dioxocino [6,5-d]pyrimidine-4, 7, 10, 11, 12-pentol derivatives that may be used in accordance with the invention.
• TTX compounds can be manufactured in a known manner essentially in accordance with the processes described in the US Patent Application 09/695,711, 09/818,775, and 09/818,863 or in a manner similar to these processes.
• Saxitoxin (STX) and its pharmacologically acceptable salts are species of 2,6- diamino -4-((aminocarbonyl)oxy) methyl-3a,4,8,9 -tetrahydro-lH, 10H- pyrrolo(l,2 ⁇ c) purine -10,10-diol (3aS-(3a-a-a-4-a,10aR*)) derivatives which may be used in accordance with the invention..
• tetrodotoxin synergizes with the analgesic activity of opioids, in particular opioids such as morphine, when tetrodotoxin and such an opioid analgesic are co-administered for the treatment of pain.
• opioids in particular opioids such as morphine
• TTX and STX possess similar modes of action and toxicity. Therefore, the inventors suggest that STX is also synergistic with the analgesic activity of opioids at similar dosage ranges.
• Opioid or opiate is a general term for natural or synthetic substances that bind to specific receptors ( "opioid receptors" ) in the central nervous system, producing an agonist action.
• opioid receptors ⁇ - and ⁇
• Opioid analgesics are extremely useful in managing severe acute pain, postoperative pain and chronic pain including cancer pain.
• Typical opioid analgesics are morphine, codeine, methadone and fentanyl. These analgesics can be used in the invention.
• Opioid agonists with opioid receptor activity like morphine and compounds structurally related to morphine, or compounds functionally related to morphine such as deltorphin II, or pharmaceutically acceptable derivatives or salts thereof, can be used in the invention.
• Fentanyl, remifentanil and etc. are further examples of opioid analgesics used in clinical treatment that can be employed.
• Morphine is most preferably used as the opioid.
• Suitable pharmaceutically acceptable salts of opioids include hydrochlorides, hydrobromides, hydroiodides, sulphates, bisulphates, phosphates, acetates, nitrates, citrates, tartrates, bitartrates, terephthalates, succinates, malates, maleates, fumarates, pectinates and pamoates.
• the pharmaceutically acceptable salt of morphine is a hydrochloride, a sulphate or a tartrate.
• Nociception is a processing reaction by the central nervous system to the transmission of stimulation of nociceptors. Noxious stimuli can cause depolarization in the primary perceptive nerve endings so as to excite the receptors.
• the nociceptors indeed are the nerve endings of neurons that have their cell bodies outside the spinal column in the dorsal root ganglion.
• the true nociception neurons are the myelinated fibers (A ⁇ ) and unmyelinated fibers (C-fibers).JNociception acts also like an alarm to induce escape or defense reactions against noxious stimuli.
• Tetrodotoxin has long been considered interesting for its action of altering the pain caused by nociception.
• tetrodotoxin inhibits the ectopic discharges originating at related dorsal root ganglia (DRG) and dorsal horn (DH) of the spinal cord and hyperexcitability of neurons, and increases the reaction threshold of pain receptors.
• DRG dorsal root ganglia
• DH dorsal horn
• the TTX-S sodium channel that is sensitive to tetrodotoxin and manifests rapid inward ionic currents
• the TTX-R channel that is resistant to tetrodotoxin and manifests slower inward ionic currents
• TTX Perihperal application of TTX blocked the fast excitatory postsynaptic potentials (EPSP) evoked by electrical stimulation but failed to block the electrically evoked slow EPSPs (Srdija Jeftinija). This finding provides an explanation of the result that TTX produced only 71.7% inhibition even at a dose of 2.5 ⁇ g/kg in the formalin test model in rats.
• Morphine as a classic analgesic produces pain inhibition primarily via ⁇ receptors (Besse, D. et al).
• a recent study shows that morphine can block the excitatory amino acid mediated membrane current in ambignal motoneurons of the rat, produce hyperpolarization in the membrane potential, and cause EPSPs to disappear (Zhang, M. et al.).
• the inventors believe the synergistic analgesic effect of co-administering a trace amount of TTX and a small mo ⁇ hine dose, occurs by tetrodotoxin inhibiting the transmission of noxious stimulation to the spinal column, while mo ⁇ hine produces a central blockade of sodium currents.
• the inventors studied the synergistic analgesic action in two animal pain models. According to the invention, by co-administering an opioid with a trace amount of tetrodotoxin, equal pain relieving effects may be achieved with dosages that are substantially reduced as compared to the dosages needed when the opioid is administered alone.
• tetrodotoxin and mo ⁇ hine will either produce positive synergistic analgesic action, or at least produce equal analgesic effect at lower dose levels for both, establishing the feasibility of the present invention.
• Tetrodotoxin produces pharmacological effects on the cardiovascular system, analgesia and local anesthesia. In particular, it provides significant alleviation of various dull pains and stinging pains without causing addiction. Based upon the findings of the present invention, the safety and efficacy of TTX can be improved by lowering the dose necessary for treating pain through synergistic action.
• Opioid analgesic agents such as mo ⁇ hine, are of limited use because they readily induce tolerance, dependence and addiction.
• the proportions of sodium channel blocker and opiate for co- administration will be preferably from 1:100 to 1:30,000, more preferably from 1:200 to 1:5,000, still more preferably from 1:500 to 1:2000.
• preferred combinations of the sodium channel blocker and opiate are TTX or STX combined with mo ⁇ hine or codeine or fentanyl.
• Tetrodotoxin powder purity 95%, Nanning Maple Leaf Pharmaceutical Co., LTD., batch no. 0324C. Before use, the powder was dissolved into an acetic acid solution at the required concentrations and stored at 4°C in a refrigerator.
• Formaldehyde (formalin), batch no. 9401002, Beijing No. 3 Chemical Plant. Prepared to the required concentrations before use.
• the rats were dosed intramuscularly with a normal saline solution (control), mo ⁇ hine hydrochloride or TTX at 0.39 ⁇ g/kg or 0.19 ⁇ g/kg; or by co-administering intramuscularly TTX at 0.39 ⁇ g/kg +. mo ⁇ hine, or TTX at 0.19 ⁇ g/kg + mo ⁇ hine on either side of a rat.
• the injection volume was 0.1 mL/100 gram body weight.
• each rat was given subcutaneously 0.06 mL of 2.5% formalin in the plantar surface of the right paw. Then the animal was put into a l2 cm x l2 cm x l2 cm polymethyl methacrylate box to observe.
• the pain response scores of the TTX groups were compared with those of the control groups, and the following formula was used to calculate the inhibition rate of TTX on pain responses:
• Inhibition rate (%) (the average of the pain response scores of the control group - that of the TTX group) / the average of the pain response scores of the control group x 100%
• the medium inhibition dose, ⁇ D 50 was calculated by the Logit method. 1.4 Results
• the half inhibition dose (ID 50 ) of mo ⁇ hine in the model of formalin-induced pain in rats was 2.30 mg/kg body weight.
• a trace amount of TTX, 0.19 ⁇ g/kg or 1/100 of LD 50 produced an inhibition rate of 11.6% when used alone, but effected significant analgesia when co-administered with a small dose of mo ⁇ hine, e.g. increasing the inhibition rate to 63.7% in combination with 0.30 mg/kg of mo ⁇ hine.Mo ⁇ hine used alone at 0.30 mg/kg only produced 10.2% inhibition.
• TTX at 0.19 ⁇ g/kg with mo ⁇ hine at 2.50 mg/kg increased the inhibition rate to 86.7% from 34.9% where the latter was used alone.
• TTX at a dose of 0.39 ⁇ g/kg (1/50 of LD 50 ) produced an inhibition rate of 32.9% when used alone and 66.2% in combination of 0.15 mg/kg of mo ⁇ hine, whereas the latter only produced an inhibition rate of 7.2% when used alone.
• Analgesia effect increased with the mo ⁇ hine doses in other groups but not significantly.
• Test article and reagents Tetrodotoxin powder, purity 95%, Nanning Maple Leaf Pharmaceutical Co.,
• Mo ⁇ hine hydrochloride powder batch no. 960802, Qinghai Pharmaceutical Plant. Formaldehyde, batch no. 9401002, Beijing No. 3 Chemical Plant. Prepared to the required concentrations before use.
• TTX and mo ⁇ hine were given intramuscularly on either side of an animal.
• mice 320 screened mice, half male and half female, were randomly divided into 16 groups. They were not given food, only water 12 hours prior to dosing. Rats were dosed with a saline solution as a control, mo ⁇ hine hydrochloride, TTX X2 at 0.79 ⁇ g/kg (1/25 LD S0 ) and 0.39 ⁇ g/kg (1/50 LD 50 ), and 12 co-administering groups of TTX at 0.79 ⁇ g/kg in combination of mo ⁇ hine and TTX at 0.39 ⁇ g/kg in combination with mo ⁇ hine, respectively.
• the heat tail flick analgesia meter includes a heat source consisting of a 12 V, 50 watt, 8.75 mm projector lamp. The light beam from the heat source was focused and directed to a point on the tail of a mouse being tested, having a distance of 1-2 mm plus 1/3 of the tail length to the tail end.
• test drugs were given intramuscularly.
• TTX mo ⁇ hine or a mixture of the two was injected into the gluteal muscle on either side of the animal in a volume of 0.1 mL/10 g body weight.
• the tail-flick latencies were measured and recorded at 15, 30, 45, 60, 90, 120, 150, 180 min after dosing. For each measurement, three readings were made consecutively one minute apart, and their average was recorded as the latency. The testing on one animal would be terminated when tail-flick was not observed within 20 seconds, and the latency would be recorded as 20 seconds.
• the pain inhibition rate was calculated according to the following formula for the pu ⁇ ose of assessing the analgesia potency:
• Inhibition rate (%) [(observed latency - latency of control)/light-deactivation time] x 100 1.4 Statistics:
• ED 50 for mo ⁇ hine used alone was 0.41 mg/kg at 45 min after dosing, providing the criterion of one fold increase in latency for the heat- induced tail flick test in mice.
• Co-administered with TTX at a dose of 1/25 LD 50 (0.79 ⁇ g/kg) the ED 50 of mo ⁇ hine decreased to 0.07 mg/kg.
• TTX at a dose of 1/50 LD 50 (0.39 ⁇ g/kg
• ID 50 for mo ⁇ hine used alone was 0.33 mg/kg at 45 min after dosing.
• the LD 50 of mo ⁇ hine decreased respectively to 0.08 mg kg and 0.15 mg/kg, or only 1/4 and 1/2 of the LD 50 for mo ⁇ hine used alone.
• Morphine Hydrochloride 0.073 10 50 (0.06-0.10) (0.10-0.22) 0.330 20 100
• test protocols are designed for this pu ⁇ ose as shown in Example 3-6.
• Example 3 Toxicity of TTX and morphine co-administeredby intramuscular injection in rats This test is intended to measure the toxicity interaction of TTX and mo ⁇ hine through determining and comparing the half death doses (LD 50 ) of mo ⁇ hine, and co- administered TTX and mo ⁇ hine.
• the LD 50 of TTX is known from US Patent Application No. 09/695,053. The method will follow the test for determining acute toxicity. Toxicity of the combination of TTX and mo ⁇ hine will be examined in two proportions to obtain the LD 50 values, respectively.
• Wistar rats having a body weight between 200-220 grams each, will be randomly divided into 12-15 groups of 10, half male and half female; and each test drug or combination will use 4-5 groups of animals. They will be allowed no food, only water ad-libitum during the 12 hours before dosing.
• TTX or mo ⁇ hine individually, each animal will receive one administration of the test drug.
• TTX and mo ⁇ hine For co-administration of TTX and mo ⁇ hine, each animal will be given TTX and mo ⁇ hine on either side (in separate dosage forms) or one administration of TTX and mo ⁇ hine in a singular dosage form. After dosing, the animals will be monitored with respect to toxic reactions and death for seven consecutive days.
• LD 50 values will be determined by the Bliss method. If the LD 50 increases significantly by comparison with the theoretical additive, the toxicity of co-administeration is lower than that of TTX or mo ⁇ hine individually used, indicating improved safety in light of the synergistic analgesic action between TTX and mo ⁇ hine. Even if the LD 50 remains unchanged, the combined use of TTX and mo ⁇ hine can still be desirable.
• Example 4 Isobolographic profile for the interaction between TTX and morphine by the pain model of formalin-induced inflammation in rats
• the isobologram is a commonly used technique to establish superadditive, subadditive, or merely additive effects resulting from the administration of two compounds.
• the design of this test follows Tallarida' s method, which was also adopted in US Patent No. 5,468,744.
• the pu ⁇ ose is to elicit the optimal analgesic proportions in the combination or composition of TTX and mo ⁇ hine, in light of the findings of toxicity interactions in Example 3.
• the pain model of formalin test in rats will be used to assess the analgesic effects of the test drug or combinations, particularly, determine the half inhibition doses (ID 50 ). For determining ID 50 of TTX or mo ⁇ hine individually, each animal will receive one administration of the test drug.
• TTX and mo ⁇ hine For co-administration of TTX and mo ⁇ hine, each animal will be given TTX and mo ⁇ hine on either side (in separate dosage forms) or one administration of TTX and mo ⁇ hine in a single dosage form.
• the proportions of TTX and mo ⁇ hine in terms of weight for co-administration will be between 1 :200 to 1 :5,000.
• the number of particular proportions/animal groups will be determined based upon these proportion ranges so that sound and sufficient data can be made available for one person in the art with ordinary skills to draw and inte ⁇ ret isobolograms thereupon.
• STX saxitoxin
• STX and mo ⁇ hine through determining and comparing the half death doses (LD 50 ) of STX, mo ⁇ hine, and co-administered STX and mo ⁇ hine. Toxicity of the combination of STX and mo ⁇ hine will be examined in two proportions to obtain the LD 50 values, respectively.
• Wistar rats, half male and half female, having a body weight between 200-220 grams each, will be randomly divided into 16-20 groups of 10, and each test drug or combination will use 4-5 groups of animals.
• the test method and procedure will follow Example 3, as will the analysis of the toxicity interaction between STX and mo ⁇ hine and the feasibility of their combination use.
• Example 6 Isobologram profile for the interaction between STX and morphine by the pain model of formalin-induced inflammation in mice The method will follow Example 4, replacing TTX with STX.
• the proportions of STX and mo ⁇ hine for co-administration will be preferably between 1:200 to 1:5,000.

Landscapes

• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pain & Pain Management (AREA)
• Emergency Medicine (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (1)

Family

ID=4662967

Family Applications (1)

Country Status (9)

Cited By (3)

Families Citing this family (9)

Citations (5)

Family Cites Families (13)

• 2001
  • 2001-05-18 CN CNB011180986A patent/CN1269482C/zh not_active Expired - Fee Related
• 2002
  • 2002-02-05 US US10/062,483 patent/US6780866B2/en not_active Expired - Fee Related
  • 2002-05-20 DE DE60236077T patent/DE60236077D1/de not_active Expired - Lifetime
  • 2002-05-20 WO PCT/CN2002/000339 patent/WO2002094272A1/en not_active Ceased
  • 2002-05-20 ES ES02734980T patent/ES2344631T3/es not_active Expired - Lifetime
  • 2002-05-20 CA CA002485337A patent/CA2485337C/en not_active Expired - Fee Related
  • 2002-05-20 EP EP02734980A patent/EP1387685B1/en not_active Expired - Lifetime
  • 2002-05-20 AT AT02734980T patent/ATE464903T1/de not_active IP Right Cessation
  • 2002-05-20 JP JP2002590989A patent/JP2004529959A/ja active Pending
• 2004
  • 2004-05-20 US US10/849,240 patent/US20040214842A1/en not_active Abandoned

Patent Citations (5)

Non-Patent Citations (10)

Also Published As

Similar Documents

Legal Events