text:
Combinations of superoxide dismutase mimetics and opioids
Combinations of synthetic low molecular weight catalysts for the dismutation of superoxide and opioids are potent analgesics that are effective in elevating the pain threshold in hyperalgesic conditions.
Salvemini, Daniela (Chesterfield, MO, US)
MetaPhore Pharmaceuticals, Inc.
Pharmacia Corporation
424/94.4
A61K31/555; C07F13/00; (IPC1-7): A61K38/44; A61K31/485; A61K31/555
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OLSON, ERIC
DENTONS US LLP (CHICAGO, IL, US)
1. A combination comprising: (a) at least one opioid; and (b) at least one synthetic superoxide dismutase catalyst.
2. A combination according to claim 1, wherein the combination is capable of treating, preventing, reversing or inhibiting pain or inflammation when administered to a patient in need thereof.
3. A combination according to claim 2, wherein the combination is capable of producing an additive or synergistic antihyperalgesia or antinociception effect in the patient after administering the combination.
4. A combination according to claim 3, wherein the opioid of the combination comprises at least about 50% less than the same opioid administered alone to achieve the antihyperalgesia or antinociception effect.
7. A combination according to claim 6, wherein the opioid of the combination comprises at least about 1% less than the same opioid administered alone to achieve the antihyperalgesia or antinociception effect.
8. A combination according to claim 2, wherein the opioid and the synthetic superoxide dismutase catalyst are combined prior to administration to the patient.
9. A combination according to claim 2, wherein the opioid and the synthetic superoxide dismutase catalyst are combined upon administration to the patient.
10. A combination according to claim 1, wherein the opioid is selected from the group consisting of morphine, oxycontin, oxycodone, codeine, fentanyl and any combination thereof.
11. A combination according to claim 1, wherein the synthetic superoxide dismutase catalyst is represented by the formula: 25 wherein (a) R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7 R′7, R8, R′8, R9, and R′9 independently are selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals; and (b) optionally, R1 or R′1 and R2 or R′2, R3 or R′3 and R4 or R′4, R5 or R′5 and R6 or R′6, R7 or R′7 and R8 or R′8, or R9 or R′9 and R or R′ together with the carbon atoms to which they are attached independently form a substituted or unsubstituted, saturated, partially saturated or unsaturated cyclic or heterocyclic having 3 to 20 carbon atoms; and (c) optionally, R or R′ and R1 or R′1, R2 or R′2 and R3 or R′3, R4 or R′4 and R5 or R′5, R6 or R′6 and R7 or R′7, or R8 or R′8 and R9 or R′9 together with the carbon atoms to which they are attached independently form a substituted or unsubstituted nitrogen containing heterocycle having 2 to 20 carbon atoms, which may be an aromatic heterocycle wherein the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; and (d) optionally, R and R′, R1 and R′1, R2 and R′2, R3 and R′3, R4 and R′4, R5 and R′5, R6 and R′6, R7 and R′7, R8 and R′8, and R9 and R′9, together with the carbon atom to which they are attached independently form a substituted or unsubstituted, saturated, partially saturated, or unsaturated cyclic or heterocyclic having 3 to 20 carbon atoms; and (e) optionally, one of R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9 together with a different one of R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9, attached to a different carbon atom in the macrocycle are bound to form a strap represented by the formula: —(CH2)x—M—(CH2)w—L—(CH2)z—J—(CH2)y— wherein w, x, y and z independently are integers from 0 to 10 and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof; and (f) combinations of any of (a) through (e) above; and wherein M is selected from the group consisting of copper, manganese and zinc; X, Y and Z are pharmaceutically acceptable counter ions, or together are a pharmaceutically acceptable polydentate ligand; and n is an integer from 0 to 3.
12. A combination according to claim 11, wherein the synthetic superoxide dismutase catalyst is represented by the formula: 26
15. A compound of the formula An-Qm, wherein A is a superoxide dismutase catalyst moiety, Q is an opioid moiety, and n and m are independently integers from 1 to 3.
16. A compound according to claim 15, wherein the opioid moiety is selected from the group consisting of morphine, oxycontin, oxycodone, codeine, fentanyl and any combination thereof.
17. A compound according to claim 15, wherein the synthetic superoxide dismutase catalyst moiety is represented by the formula: 29 wherein (a) R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9 independently are selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals; and (b) optionally, R1 or R′1, and R2 or R′2, R3 or R′3 and R4 or R′4, R5 or R′5 and R6 or R′6, R7 or R′ 7 and R8 or R′8, or R9 or R′9 and R or R′ together with the carbon atoms to which they are attached independently form a substituted or unsubstituted, saturated, partially saturated or unsaturated cyclic or heterocyclic having 3 to 20 carbon atoms; and (c) optionally, R or R′ and R1 or R′1, R2 or R′2 and R3 or R′3, R4 or R′4 and R5 or R′5, R6 or R′6 and R7 or R′7, or R8 or R′8 and R9 or R′9 together with the carbon atoms to which they are attached independently form a substituted or unsubstituted nitrogen containing heterocycle having 2 to 20 carbon atoms, which may be an aromatic heterocycle wherein the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; and (d) optionally, R and R′, R1 and R′1, R2 and R′2, R3 and R′3, R4 and R′4, R5 and R′5, R6 and R′6, R7 and R′7, R8 and R′8, and R9 and R′9, together with the carbon atom to which they are attached independently form a substituted or unsubstituted, saturated, partially saturated, or unsaturated cyclic or heterocyclic having 3 to 20 carbon atoms; and (e) optionally, one of R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9 together with a different one of R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9 attached to a different carbon atom in the macrocycle are bound to form a strap represented by the formula: —(CH2)x—M—(CH2)w—L—(CH2)z—J—(CH2)y— wherein w, x, y and z independently are integers from 0 to 10 and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof; and (f) combinations of any of (a) through (e) above; and wherein M is selected from the group consisting of copper, manganese and zinc; X, Y and Z are pharmaceutically acceptable counter ions, or together are a pharmaceutically acceptable polydentate ligand; and n is an integer from 0 to 3.
18. A compound according to claim 17, wherein the synthetic superoxide dismutase catalyst is represented by the formula: 30
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending U.S. application Ser. No. 09/997,974 filed Nov. 30, 2001 which is a continuation-in-part of U.S. application Ser. No. 09/634,152 filed Aug. 9, 2000, now U.S. Pat. No. 6,395,725, which is a divisional of U.S. application Ser. No. 09/057,831 filed April 9,1998, now U.S. Pat. No. 6,180,620, which claimed the benefit of U.S. Provisional Application No. 60/050,402 filed Jun. 20, 1997. Each patent and patent application above is incorporated herein by reference in its entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable.
REFERENCE TO A SEQUENCE LISTING
[0005] The present invention relates to the treatment of humans and lower animals in pain management: to prevent or relieve pain, to prevent or reverse tolerance to opioid analgesics and hyperalgesia associated with prolonged opioid treatment, and to prevent or reduce symptoms of opioid withdrawal and related withdrawal syndromes.
[0006] 2. Description of the Related Art
[0007] Numerous analgesics are known to medical science. Many analgesics fall into one of two large categories—nonsteroidal analgesic/anti-inflammatory drugs (NSAIDs) and opioids. NSAIDs operate by inhibiting cyclooxygenase enzymes (including cyclooxygenase-1 and cyclooxygenase-2, also known as COX-1 and COX-2 respectively) and thereby the synthesis of prostaglandins. Prostaglandins sensitize pain receptors, lowering the pain threshold and making normal stimuli, such as touch and stretch sensations, painful. NSAIDs can be quite effective at returning the lowered pain threshold to normal but do not elevate the pain threshold. Common NSAIDs available over-the-counter include: ibuprofen (Advil®), naproxen (Aleve® or Naprosyn®)), and aspirin (Bayer®). Prescription NSAIDs include: celecoxib—Celebrex(®, diclofenac—Voltaren®, etodolac—Lodine®, fenoprofen—Nalfon®, indomethacin—Indocin®, ketoprofen—Orudis®, Oruvail®, ketoralac—Toradol®, oxaprozin—Daypro®, nabumetone—Relafen®, sulindac—Clinoril®, tolmetin—Tolectin®, and rofecoxib—Vioxx®).
[0008] A second class of pain relievers, opioids, operate by mimicking natural peptides such as enkephalins and endorphins to stimulate one or more of the μ-, δ- and κ-receptor systems in the nervous system. Opioids elevate the pain threshold so that normally painful stimuli are perceived as less painful or even euphoric. Opioids are commonly used in the clinical management of severe pain, including chronic severe pain of the kind experienced by cancer patients. Common opioids include morphine, oxycontin, oxycodone, codeine and fentanyl.
[0009] Capsaicin and its derivatives operate by depleting local stores of substance P, a neuropeptide involved in the transmission of pain impulses and are used in several OTC analgesic products.
[0010] Each of these classes of compounds has inherent problems and limitations. The opioid analgesics are antagonized by analogous N-allyl compounds such as naloxone; the NSAID analgesics are not. NSAIDs that are nonselective for the cyclooxygenase-2 produced in inflammation (COX-2) also inhibit constitutive cyclooxygenase-1 (COX-1), causing undesirable damage to the gastric mucosa. They have limited effectiveness as analgesics in lowering an elevated threshold to normal and are generally used for mild to moderate pain. They are also ineffective drugs for elevation of the pain threshold above normal levels, which prevents their use in pain such as surgical pain where an underlying pathological condition has not elevated the pain threshold.
[0011] Opioids have problems with tolerance and dependency, so that over a course of therapy increasing dosages of compound are required to achieve the same level of analgesia, and cessation of opioid administration when analgesia is no longer needed elicits a withdrawal syndrome with unpleasant and potentially serious symptoms. The dependency and withdrawal syndrome both make it difficult for the clinician to discontinue opioid therapy even when the opioids are no longer effective in relieving pain because of the development of tolerance. Narcotic induced hyperalgesia (NIH) can also develop in association with tolerance to the opioids. All of these factors limit the usefulness of opioids in the management of chronic severe pain, despite their potency.
[0012] No adequate strategy has been devised to overcome the development of opioid tolerance and provide an ongoing approach to the management of chronic severe pain. Mechanisms of tolerance are not well understood but are known to involve the NMDA receptor, since the NMDA receptor antagonist MK-801 has been shown in rats to prevent morphine tolerance. NMDA stimulates nitric oxide synthase (NOS) and NOS has been observed histochemically in tissues that contain opioid receptors and are important in the pain response, such as the amygdala, cortical gray matter, and the substantia gelatinosa of the spinal cord. Non-selective NOS inhibitors such as NG-nitroarginine prevent and reverse morphine tolerance. However, nonselective inhibition of NOS is associated with a vast array of undesirable side effects, including hypertension, increased platelet and white blood cell reactivity, decreased cerebral blood flow, and gastrointestinal and renal toxicity.
[0013] Capsaicin and some of its derivatives, in addition to producing analgesia, also elicit a burning sensation. This effect is responsible for the pungency of hot peppers (Capscum spp.) and limits the applicability of many members of this series of compounds.
[0014] For these and other reasons, a continuing need exists for new high potency analgesics which do not result in the drawbacks listed above. A need also exists for methods for reversing tolerance to opioid analgesics so that patients who require these drugs for pain over extended periods can do so without loss of potency and efficacy.
BRIEF SUMMARY OF THE INVENTION
[0015] Accordingly, it is an object of the invention to overcome these and other problems associated with the related art. These and other objects, features and technical advantages are achieved by providing combinations of opioids and synthetic superoxide dismutase catalysts for treating, preventing, reversing or inhibiting pain or inflammation when administered to a patient in need thereof.
[0016] This invention provides a combination of compositions comprising (a) at least one opioid; and (b) at least one synthetic superoxide dismutase catalyst. In one aspect, the combination is capable of treating, preventing, reversing or inhibiting pain or inflammation when administered to a patient in need thereof. In one embodiment, the combination is capable of producing an additive or synergistic antihyperalgesia or antinociception effect in the patient after administering the combination.
[0017] Preferably, the opioid of the combination comprises at least about 50% less than the same opioid administered alone to achieve the antihyperalgesia or antinociception effect. More preferably, the opioid of the combination comprises at least about 25% less than the same opioid administered alone to achieve the antihyperalgesia or antinociception effect. Still more preferably, the opioid of the combination comprises at least about 10% less than the same opioid administered alone to achieve the antihyperalgesia or antinociception effect. And still more preferably, the opioid of the combination comprises at least about 1% less than the same opioid administered alone to achieve the antihyperalgesia or antinociception effect.
[0018] In accordance with one aspect of the invention, the opioid and the synthetic superoxide dismutase catalyst are combined prior to administration to the patient. In another aspect, the opioid and the synthetic superoxide dismutase catalyst are combined upon administration to the patient.
[0019] Preferably, the opioid is selected from the group consisting of morphine, oxycontin, oxycodone, codeine, fentanyl and any combination thereof. In accordance with another aspect of the invention, the synthetic superoxide dismutase catalyst is represented by the formula: 1
[0020] wherein (a) R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9 independently are selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals; and (b) optionally, R1 or R′1 and R2 or R′2, R3 or R′3 and R4 or R′4, R5 or R′5 and R6 or R′6, R7 or R′7, and R8, or R′8, or R9 or R′9 and R or R′ together with the carbon atoms to which they are attached independently form a substituted or unsubstituted, saturated, partially saturated or unsaturated cyclic or heterocyclic having 3 to 20 carbon atoms; and (c) optionally, R or R′ and R1 or R′1, R2 or R′2 and R3 or R′3, R4 or R′4 and R5 or R′5, R6 or R′6 and R7 or R′7, or R8 or R′8 and R9 or R′9 together with the carbon atoms to which they are attached independently form a substituted or unsubstituted nitrogen containing heterocycle having 2 to 20 carbon atoms, which may be an aromatic heterocycle wherein the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; and (d) optionally, R and R′, R1 and R′1, R2 and R′2, R3 and R′3, R4 and R′4, R5 and R′5, R6 and R′6, R7, and R′7, R8, and R′8, and R9 and R′9, together with the carbon atom to which they are attached independently form a substituted or unsubstituted, saturated, partially saturated, or unsaturated cyclic or heterocyclic having 3 to 20 carbon atoms; and (e) optionally, one of R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R7, R8, R′8, R9, and R′9 together with a different one of R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9attached to a different carbon atom in the macrocycle are bound to form a strap represented by the formula:
—(CH2)x—M—(CH2)w—L—(CH2)z—J—(CH2)y—
[0021] wherein w, x, y and z independently are integers from 0 to 10 and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof; and (f) combinations of any of (a) through (e) above; and wherein M is selected from the group consisting of copper, manganese and zinc; X, Y and Z are pharmaceutically acceptable counter ions, or together are a pharmaceutically acceptable polydentate ligand; and n is an integer from 0 to 3.
[0022] Preferably, the synthetic superoxide dismutase catalyst is represented by the formula: 2
[0023] This invention provides a compound of the formula An-Qm, wherein A is a superoxide dismutase catalyst moiety, Q is an opioid moiety, and n and m are independently integers from 1 to 3. Preferably, the opioid is selected from the group consisting of morphine, oxycontin, oxycodone, codeine, fentanyl and any combination thereof. In accordance with one aspect of the invention, the synthetic superoxide dismutase catalyst moiety is represented by the formula: 3
[0024] wherein (a) R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9, independently are selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals; and (b) optionally, R1 or R′1 and R2 or R′2, R3 or R′3 and R4 or R′4, R5 or R′5 and R6 or R′6, R7 or R′7 and R8 or R′8, or R9 or R′9 and R or R′ together with the carbon atoms to which they are attached independently form a substituted or unsubstituted, saturated, partially saturated or unsaturated cyclic or heterocyclic having 3 to 20 carbon atoms; and (c) optionally, R or R′and R1 or R′1, R2 or R′2 and R3 or R′3, R4 or R′4 and R5 or R′5, R6 or R′6 and R7 or R′7, or R8 or R′8 and R9 or R′9 together with the carbon atoms to which they are attached independently form a substituted or unsubstituted nitrogen containing heterocycle having 2 to 20 carbon atoms, which may be an aromatic heterocycle wherein the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and the R groups attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; and (d) optionally, R and R′, R1 and R′1, R2 and R′2, R3 and R′3, R4 and R′4, R5 and R′5, R6 and R′6, R7, R8 and R′8, and R9 and R′9, together with the carbon atom to which they are attached independently form a substituted or unsubstituted, saturated, partially saturated, or unsaturated cyclic or heterocyclic having 3 to 20 carbon atoms; and (e) optionally, one of R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9 together with a different one of R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7R8, R′8, R9, and R′9 attached to a different carbon atom in the macrocycle are bound to form a strap represented by the formula:
[0027] These and other features, aspects and advantages of the present invention will become better understood with reference to the following description, examples and appended claims.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0028] FIG. 1 is a graph depicting the results of a study on the inhibition of carrageenan-induced hyperalgesia by intravenously injected SC-72325. The drug was given at 3 hours post carrageenan injection.
[0029] FIGS. 2 and 3 are graphs depicting the results of a study on inhibition of carrageenan-induced hyperalgesia by intramuscular injection of either SOD mimic compound SC-72325 (Example 157) or the nonsteroidal anti-inflammatory drug ketorolac.
[0030] FIG. 4 is a graph depicting the results of a study comparing the effects of SC-72325 versus ketorolac on carrageenan-induced increase of PGE-2 in cerebrospinal fluid.
[0031] FIG. 5 is a graph depicting the results of a study comparing the effects of SC-72325 versus ketorolac on carrageenan-induced release of PGE-2 in paw exudate.
[0032] FIG. 6 is a graph depicting the results of a study on inhibition of formalin-induced nociception by subcutaneous injection of SC-72325A.
[0033] FIG. 7 is a graph depicting the results of a study on inhibition of carrageenan-induced hyperalgesia by subcutaneous injection of SC-72325A. The drug was given at three (3) hours post carrageenan.
[0034] FIG. 8 is a graph depicting the results of a study on inhibition of carrageenan-induced hyperalgesia by subcutaneous injection of SC-72325A and morphine-SC-72325A synergistic effect.
[0035] FIG. 9 is a graph depicting the results of a study on carrageenan-induced hyperalgesia by SC-72325A and ketorolac. Drugs given by subcutaneous injection at three (3) hours post carrageenan.
[0036] FIG. 10 is a graph depicting the results of a study on the time-related and dose-dependent antihyperalgesia effect of SC-72325A over the dose range of 0.3 to 30 mg/kg in the SNL (L5/L6) model. Drugs administered via subcutaneous injection.
[0037] FIG. 11 is a graph depicting the results of a study on the time-related and dose-dependent attenuation of cold allodynia of SC-72325A over the dose range of 1 to 10 mg/kg.
[0038] This invention is based upon surprising discoveries involving certain organometallic complexes designed as synthetic catalysts for use in the body. These catalysts have been designed as synthetic replacements for or adjuncts to the naturally occurring enzyme superoxide dismutase (SOD).
[0039] Naturally occurring SOD scavenges and eliminates the toxicity of free superoxide radicals (O2•−) liberated by certain metabolic reactions. Although these free radicals play a major (and deleterious) role in the inflammatory response and other toxic reactions to injury, neither superoxide nor SOD has been known to be directly involved in pain perception. In addition, SOD has a very short biological half-life, on the order of seconds or minutes rather than hours, so it would be considered unsuitable for treatment of conditions in which increased dismutation of superoxide radicals would be desirable over periods of from minutes to days.
[0040] Dismutation of superoxide radicals is catalyzed by a coordinated transition metal ion. In the natural SOD enzyme, the metal is manganese, copper or zinc and the coordination complex is a conventional protein structure. Synthetic SOD catalysts also use transition metals, complexed with low molecular weight organic ligands, generally polydentate N-containing macrocycles. These molecules have been designed to be highly efficient and to overcome the pharmacokinetic disadvantages of natural SOD enzyme. The kcat of some of these compounds is as high as about 109 (see Example 165), indicating extraordinary catalytic efficiency, as effective as the natural enzyme and approaching the theoretical rate at which diffusion can deliver free radical substrate to the catalyst under biological conditions. They also have oil:water partition coefficients (log P) that provide excellent bioavailability, and stability in the body on the order of hours to days. Their small size and low molecular weight makes it possible for the synthetic catalysts to cross membrane barriers that restrict movement of natural SOD, and their non-protein structure reduces the risk of allergic reactions that have been a problem with the administration of protein-based recombinant SOD. Finally, natural SOD produces hydrogen peroxide in the process of dismutating superoxide, yet hydrogen peroxide inhibits natural SOD, effectively self-limiting the efficacy of the natural compound. In contrast, synthetic small-molecule SOD catalysts are not susceptible to the action of hydrogen peroxide and thus retain their effectiveness.
[0041] Synthetic SOD catalysts have been proposed in the past for the treatment and prevention of inflammation, ischemia-reperfusion injury, and similar conditions where tissue damage is mediated by levels of free superoxide radicals that overwhelm natural SOD, but they have not been proposed for use as analgesics in the treatment of pain.
[0042] It has now been discovered that synthetic SOD catalysts are highly effective as analgesics to prevent or provide relief from pain in conditions in which the pain threshold is elevated. It has also been discovered that these same compounds are effective in preventing or reversing tolerance to opioid analgesics, that are used to elevate the pain threshold above normal levels.
[0043] No known mechanism accounts for the analgesic properties of these compounds. However, the data shown in the examples illustrate that these compounds can be as effective as morphine in preventing and relieving certain kinds of pain. Y. Lin et al., Int. J. Maxillofac. Surg. 23:428429 (1994) reported the use of intra-articular injections of human Cu/Zn superoxide dismutase as a nonsteroidal anti-inflammatory in the treatment of temporomandibular joint dysfunction. Positive response in terms of mandibular movement and pain was observed in 83% of patients. The authors note that the results "are remarkable because SOD has been studied and shown to exert no peripheral or central analgesic effect." They attribute the reduction in pain to the reduction in tissue injury and inflammation associated with TMJ dysfunction.
[0044] Similarly, no known mechanism accounts for the ability of these compounds to prevent or reverse tolerance to opioids. G. I. Elmer et al., Euro. J. Pharmacol. 283 (1995) 227-232, reported that transgenic mice expressing the human Cu/Zn superoxide dismutase gene had an increase in μ-opioid receptor concentration in dopaminergic related tissues and the central grey area of the CNS, which was associated with a dose-related increased sensitivity to μ-receptor agonists such as morphine. At the same time the authors also observed conflicting effects of transgenic SOD on δ-receptor agonists (mice heterozygous for the transgene were more sensitive than homozygotes, which were more sensitive than untransformed mice) and observed no effect of transgenic SOD on κ-receptor agonists.
[0045] Superoxide dismutase activity is known to play a critical role in regulating the redox state of the cell, as reported by J. L. Cadet, Int. J. Neurosci. 40, 13 (1988). This in turn is reported by Marzullo and Hine, Science 208,1171 (1980) to significantly affect in vitro μ-and δ-opioid binding.
[0046] In particular, this invention provides a method of producing analgesia in a human or lower mammal patient, comprising administering to the patient an analgesic amount of a functional synthetic catalyst for the dismutation of superoxide radicals. Based on the data obtained, it is reasonable to expect that any superoxide dismutase catalyst will be effective in the practice of this invention. A preferred synthetic catalyst is a coordination complex of transition metal with an organic ligand. Preferred transition metals are copper, manganese and zinc. Manganese is most preferred. In general, the organic ligand is a N-containing macrocycle, and most preferred ligands are selected from the group consisting of compounds of the formula 5
[0047] wherein R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R′5, R6, R′6, R7, R′7, R8, R′8, R9 and R′9 independently are selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, alkylcycloalkyl, cycloalkenylalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals, or R or R′ and R1 or R′1, R2 or R′2 and R3 or R′3, R4 or R′4 and R5 or R′5, R6 or R′6 and R7 or R′7, and R8 or R′8 and R9 or R′9, together with the carbon atoms to which they are attached independently form a substituted or unsubstituted saturated, partially saturated or unsaturated cyclic ring structure having 3 to 20 carbon atoms; or R or R′, R1 or R′1, and R2 or R′2, R3 or R′3 and R4 or R′4, R5 or R′5 and R6 or R′6, R7 or R′7, and R8 or R′8, and R9 or R′9, together with the carbon atoms to which they are attached independently form a substituted or unsubstituted nitrogen-containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle that does not have a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent; R and R′, R1 and R′1, R2 and R′2, R3 and R′3, R4 and R′4, R5 and R′5, R6 and R′6, R7 and R′7, R8 and R′8 and R′8 and R9 and R′9, together with the carbon atom to which they are attached independently form a substituted or unsubstituted saturated, partially saturated or unsaturated ring structure having 3 to 20 carbon atoms; or two of R, R′, R1, R′1, R2, R′2, R3, R′3, R4, R′4, R5, R′5, R6, R′6, R7, R′7, R8, R′8, R9, and R′9 attached to different carbon atoms of the macrocycle are bound to form a strap structure of the formula
[0048] wherein w, x, y and z independently are integers from 0 to 10 and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkaryl, alkheteroaryl, aza, amido, ammonium, thio, sulfonyl, sulfinyl, sulfonamido, phosphonyl, phosphinyl, phosphino, phosphonium, keto, ester, carbamyl, ureido, thiocarbonyl, borate, borane, boraza, silyl, siloxy and silaza radicals, and combinations thereof; wherein X, Y and Z are pharmaceutically acceptable counterions or together are a pharmaceutically acceptable polydentate ligand, or are independently attached to one or more of the R groups and n is an integer from 0 to 3.
[0049] Specific examples of the above general formula are provided in the many examples below. While these specific examples provide are provided, one of skill in the art will be able to determine other variants within the scope of the above description. In addition, one of skill in the art will be able to predict and determine antianalgesic and antinociceptive effects of the other variants using the teaching of the numerous examples below.
[0050] By an "analgesic amount" of the synthetic SOD catalysts herein is meant an amount that significantly prevents or alleviates pain in the human or lower animal being treated. At a certain level stimuli are perceived as painful, while below that level they are not. This level is referred to as the pain threshold. Healthy, normal subjects exhibit a normal pain threshold that can be quantified for a given stimulus. A normal healthy individual perceives a pin prick as painful, but does not perceive the movement of a joint within its normal range of motion as painful. An individual suffering from arthritis has a lowered pain threshold and will perceive such normal movement as painful. An individual suffering from sunburn has a lowered pain threshold and may perceive the touch of a finger to be as painful as a normal individual perceives a pin prick. Because these compounds operate to elevate a lowered pain threshold, they will be effective in the treatment of such pain, and an "analgesic amount" of synthetic SOD catalysts in the treatment methods provided here also means an amount that significantly elevates the pain threshold above its pre-treatment level or prevents the pain threshold from being lowered by a pathological condition. From the standpoint of the pharmacologist and pharmaceutical scientist, this can be measured prospectively using common animal models such as the phenylquinone writhing model, the rat tail flick (radiant heat) model, the carrageenan inflammation model, the Freund's adjuvant model, and other pain models well known to pharmacological science. From the standpoint of the clinician, this can be measured according to the subjective response of each patient to a unit dose of the compound, and subsequent doses can be titrated to achieve the desired level of analgesia within the therapeutic range of the compound employed.
[0051] By an "amount sufficient to prevent or reverse tolerance to opioids" is meant The dual administration of a superoxide dismutase catalyst together with an opioid such as morphine or fentanyl allows lower doses of the morphine or fentanyl to elicit its analgesic effects while limiting its side effects. Moreover, a superoxide dismutase catalyst can reverse opioid tolerance in patients who have already developed tolerance. Thus, the superoxide dismutase catalysts restore the analgesic effect lost during prolonged treatment with an opioid. These catalysts prevent or reverse the tolerance to opioids without many of the side effects of other compounds proposed for this purpose, such as clonidine and buprenorphine. And in contrast to other proposed compounds, such as inhibitors of inducible nitric oxide synthase, the superoxide dismutase catalysts themselves have potent analgesic effects that are useful in hyperalgesic conditions such as burns, arthritis and other inflammatory diseases, migraine, and pain associated with tumor infiltration and cancer therapy.
[0052] The compounds of this invention are also useful as adjuncts in the prevention and treatment of pain with opioid analgesics, nitric oxide donors or nonsteroidal anti-inflammatory compounds. In preferred embodiments, the superoxide dismutase catalyst is administered conjointly with the opioid, NO2 donor or NSAID compound. Administered in conjunction with an opioid, the superoxide dismutase catalyst potentiates the opioid and prevents development of tolerance and hyperalgesia. Administered after opioid tolerance, hyperalgesia and/or dependency have developed, the superoxide dismutase catalyst reverses the tolerance and hyperalgesia and reduces the symptoms of the withdrawal syndrome. Administered in conjunction with an NSAID compound or nitric oxide donor, the superoxide dismutase catalyst potentiates both the analgesia and the inflammatory action of the NSAID or NO2 donor. These drug moieties can also be linked to provide bifunctional compounds of the formula An-Qm, wherein A is a superoxide dismutase catalyst moiety, Q is selected from nonsteroidal anti-inflammatory drug moieties, nitric oxide donor moieties and opioid analgesic drug moieties, and n and m are independently integers from 1 to 3. Depending upon the selection of A and Q, this can easily be done by substituting the NSAID or opioid moiety for one or more of counterion/ligands X, Y and Z in the preferred formula above. A simple approach to providing a combination containing a nitric oxide donor is to attach one or more nitrate or nitrite groups to the superoxide dismutase compound.
[0053] While not intending to be limited by theory, it is believed that the opioid withdrawal syndrome has many symptoms in common with the withdrawal syndromes associated with other addictive compounds and behaviors, including symptoms of withdrawal from cocaine, nicotine, and eating disorders such as anorexia and bulimia, especially the hyperreflexia and hyperalgesia associated with withdrawal. Accordingly, this invention also provides a method of preventing and treating symptoms of addition withdrawal, by administering to a patient in need of such treatment an amount of a superoxide dismutase catalyst that is safe and effective to prevent or reduce such symptoms.
[0054] A safe and effective amount of the compounds used in the practice of this invention is an amount that provides analgesia, thereby alleviating or preventing the pain being treated at a reasonable benefit/risk ratio as is intended with any medical treatment. In using the compounds for the reversal of opioid tolerance or reduction of withdrawal symptoms, these endpoints are used rather than analgesia. Obviously, the amount of catalyst used will vary with such factors as the particular condition that is being treated, the severity of the condition, the duration of the treatment, the physical condition of the patient, the nature of concurrent therapy (if any), the route of administration, the specific formulation and carrier employed, and the solubility and concentration of catalyst therein.
[0055] By "systemic administration" is meant the introduction of the catalyst or composition containing the catalyst into the tissues of the body, other than by topical application. Systemic administration thus includes, without limitation, oral and parenteral administration.
[0056] Depending upon the particular route of administration, and compatibility with the active compound chosen, a variety of pharmaceutically-acceptable carriers, well-known in the art, may be used. These include solid or liquid filler, diluents, hydrotropes, excipients, surface-active agents, and encapsulating substances. The amount of the carrier employed in conjunction with the catalyst is sufficient to provide a practical quantity of material per unit dose.
[0057] Pharmaceutically-acceptable carriers for systemic administration that may be incorporated into the compositions of this invention, include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oil, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water.
[0058] The catalysts can be administered parenterally in combination with a pharmaceutically acceptable carrier such as corn oil, Cremophor EL or sterile, pyrogen-free water and a water-miscible solvent (e.g., ethyl alcohol) at a practical amount of the catalyst per dose. Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition. Parenteral administration can be by subcutaneous, intradermal, intramuscular, intrathecal, intraarticular or intravenous injection. The dosage by these modes of administration is usually in the range of from about 0.1 mg to about 20 mg per day.
[0059] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50% of the catalyst. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from noneffervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents, and flavoring agents. Preferred carriers for oral administration include gelatin, propylene glycol, ethyl oleate, cottonseed oil and sesame oil. Specific examples of pharmaceutically-acceptable carriers and excipients that may be used to formulate oral dosage forms containing the catalysts used in this invention, are described in U.S. Pat. No. 3,903,297, Robert, issued Sep. 2, 1975, incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics, Vol. 7 (Banker and Rhodes, editors), 359-427 (1979), incorporated by reference herein.
[0060] By "pharmaceutically acceptable salts" is meant those salts that are safe for topical or systemic administration. These salts include the sodium, potassium, calcium, magnesium, and ammonium salts.
[0061] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following specific examples are offered by way of illustration and not by way of limiting the remaining disclosure. Where Sprague-Dawley rats are mentioned below, 175-200g Sprague-Dawley rats were used (Harlan Sprague Dawley, Indianapolis, Ind., USA) and housed and cared for under the guidelines of the Institutional Animal Care and Use Committee. They received a subplantar injection of carrageenan (0.1 mL of a 1% suspension in 0.85% saline) into the right hind paw. At three hours post-carrageenan, when hyperalgesia is normally at a maximum, the test compound was administered intravenously at dosages of from 1-6 mg/kg. Hyperalgesia is assessed at thirty minutes to three hours post-administration of test compound.
SODm Effect on Carrageenan Paw Hyperalgesia
[0062] SOD catalyst compounds were evaluated in the carrageenan hyperalgesia model described above. Results were as follows: 1
Compound Result
SC-71354 No effect at tested dosages by intravenous injection*
SC-69604 No effect at tested dosages by intravenous injection
SC-72325 Inhibited hyperalgesia 64% at 30 minutes
*Higher dosage levels and other routes of administration were not tested for any of the compounds.
Reducing Hyperalgesia Using SODm
[0063] Analgesia provided by intravenous SC-72325 was evaluated over time in the carrageenan model. Results are shown in FIG. 1.
Comparison of Carrageenan Paw Hyperalgesia Treatments
[0064] Analgesia provided by intramuscular injection of SC-72325 was evaluated over time in the carrageenan model in comparison to the anti-inflammatory drug ketorolac. Results are shown in FIGS. 2 and 3, respectively.
Baseline for Carrageenan Paw Hyperalgesia Testing
[0065] To determine whether the SOD catalyst compounds provide analgesia by some action on the prostaglandin-leukotriene system, release of prostaglandin PGE-2 was measured in rat paw exudate from the carrageenan model as well as in spinal cord fluid. Saline was used as a non-inflamed control and the anti-inflammatory ketorolac was used as a positive anti-inflammatory control. Results are shown in FIGS. 4 and 5. SC-72325 did not significantly reduce release of PGE-2 compared to the carrageenan-injected but untreated rats. Ketorolac treated rats had levels of PGE-2 release similar to non-carrageenan injected animals.
Morphine Tolerance Testing
[0066] Mice were treated twice a day with either saline (naive) or morphine (s.c., 10 mg/kg) for a period of 4 days to induce tolerance. For comparison, a dose of 10 mg, or less than 0.15 mg/kg every 4 to 10 hours, is a morphine dosage routinely prescribed for the 70 kg. human adult with severe pain. On day 5, all mice received a subcutaneous challenge dose of 3 mg./kg morphine and the level of analgesia was measured 30 minutes later. Results are shown graphically in FIG. 6. Dose response measurements in normal mice have indicated that a challenge dose of 3 mg/kg would elicit 90% analgesia in naive or non-tolerant mice when assessed by the standard hot plate test. In this example, mice that were treated with morphine for 4 days showed a decreased analgesic effect from morphine on day 5 when compared with the naive mice. Tolerance to morphine was eliminated in mice that were treated with the superoxide dismutase catalyst SC-72325 administered intraperitoneally.
Examples 6-167
[0067] The following compounds were made for use as superoxide dismutase catalysts or as ligands for combination with transition metal ions for use as superoxide dismutase catalysts within the scope of the invention. The catalytic rate constant kcat is given for each compound. For kcat values marked with an asterisk, the kcat was measured at a pH of 8.1. For all other compounds the kcat was measured at pH 7.4. Compounds marked NT were made but not tested. The ligands of Examples 11, 101, 123-135 and 138-148 were not expected to have activity without the metal ion and most were not tested. However, as can be seen by comparison of Examples 148 and 149, insertion of the metal ion into the ligand forms a complex with good superoxide dismutase activity. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
[0068] In Examples 168-171 below, male Sprague-Dawley rats were used and all drugs were dissolved in 26 mM NaHCO3 buffer (0.218 g NaHCO3 in 100 ml dH2O; pH=8.1 to 8.3) and injections were given subcutaneously (hereinafter "s.c."). When drug combinations were employed, each drug was injected separately, but concurrently. Drugs employed morphine sulfate and SC-72325A, Example 167 which is an enantiomer of SC-72325 also depicted above. In some studies ketorolac was also used and was given by s.c. injection.
[0069] Thermal hyperalgesia and antinociception were assessed in the testing of SC-72325A for treatment of pain. Thermal hyperalgesia was determined by the method of Hargreaves et al., Pain, 32:77-88 (1988). A radiant heat source was focused onto the plantar surface of the affected paw of nerve-injured or carageenan-injected rats. When the animal withdrew its paw, a motion sensor halted the stimulus and timer. A maximal cut-off of 40 seconds was utilized to prevent tissue damage. Paw withdrawal latencies were thus determined to the nearest 0.1 seconds. Reversal of thermal hyperalgesia was indicated by a return of the paw withdrawal latencies to the pre-tremeant baseline latencies (i.e., 21 seconds). Antinociception was indicated by a significant (p≦0.05) increase in paw withdrawal latency above this baseline. Data were converted to % antihyperalgesia or % antinociception by the formula:
100×(test latency—baseline)/(cut-off baseline)
[0070] where cut-off was 21 seconds for determining antihyperalgesia and 40 seconds for determining antinociception.
[0071] Dose response curves were generated for each drug and drug combination for data obtained at the time of peak effect, which was consistently at the 30 minute time point.
[0072] Studies employing combinations of drugs were analyzed for additive or synergistic interactions by isobolographic analysis as described by Tallarida (Tallarida et al., Life Sciences, 45:947-61, 1987) and employed by other (Ossipov et al., J. Pharmacol. Exp. Ther., 255:1107-1116, 1990; Porreca et al., Euro. J. Pharm., 179: 463-468, 1990) by means of a customized Visual Basic computer program (Ossipov, personal communication). Log dose-response curves for each component administered alone were established and the A50 (95% C.L.) were calculated.
[0073] Using these methods, the amount of synergy of a combination of compositions can be determined. The preferred combinations of the present invention treat pain using a smaller dose of an analgesic, such as an NSAID or opioid, when compared to administering the analgesic alone. In other words, a preferred combination will result, for example, in the same amount of pain relief after administering 50 mg of an NSAID or opioid in combination with 50 mg of a synthetic superoxide dismutase catalyst as would normally result from administering 500 mg of an NSAID or opioid alone or 500 mg of a synthetic superoxide dismutase catalyst alone.
[0074] Conversely, the preferred combinations of the present invention treat pain to a greater extent when compared to treating pain with an analgesic alone or a synthetic superoxide dismutase catalyst alone. In other words, a preferred combination will result, for example, in an equivalent amount of pain relief after administering 500 mg of an NSAID or opioid in combination with 50 mg of a synthetic superoxide dismutase catalyst as would normally result from administering 1,000 mg of the NSAID or opioid or 1,000 mg of a synthetic superoxide dismutase catalyst alone.
[0075] Thus, preferred combinations result in additive or synergistic antihypertensive or antinociceptive effects allowing an NSAID or opioid to be administered in a dosage that is at least 50% less than the same NSAID or opioid administered alone. More preferably, the NSAID or opioid combination may be administered in a dosage that is at least 25% less than the same NSAID or opioid administered alone to achieve said therapeutic effect. Still more preferably, the NSAID or opioid may be administered in a dosage that is at least 10% less than the same NSAID or opioid administered alone to achieve said therapeutic effect. And still more preferably, the NSAID or opioid may be administered in a dosage that is at least 1% less than the same NSAID or opioid administered alone to achieve said therapeutic effect.
[0076] The A50 for the log dose-response curve of a drug mixture at a fixed ratio was calculated in terms of "total dose" administered. For a given drug combination a theoretical A50 exists such that A50 add=A50 drug1×(p1+Rp2) where R is the potency ratio of drug 1 to drug 2, p1 is the proportion of drug 1 in the mixture and p2 is the proportion of drug 2. Variances and 95% C.L. for the theoretical additive A50 are derived from the variances of each drug administered alone. A t-test is employed to compare the theoretical additive A50 and 95% C.L. to that obtained for the mixture. A significantly ((p <0.05); t-test) lower experimental value compared to theoretical value denotes a synergistic interaction. See Table 1 below.
Example 168
SC-72325A Treats Pain
[0077] Analgesic effects provided by subcutaneous injection of SC-72325A was studied by formalin-induced hind paw licking response. Male CD-1 mice (Charles River, 28-35 gm) were allowed to feed ad libitum. Mice were housed 5-7 per cage in a temperature controlled room with a twelve hour light-dark cycle. Determination of antinociception was assessed between 7:00 and 10:00 AM. Groups consisted of 7-14 mice, and each animal was used for one experimental condition. The antinociceptive effects of SC-72325A were tested in the formalin-induced hind paw licking procedure (Hunskaar et al., Pain, 30: 103-114, 1987). Mice were injected with by sub-plantar administration with formalin (20 μg of a 1% stock solution) and the duration of paw licking was monitored in the periods of 5-10 minutes (Phase I) and 15-30 minutes (Phase II) thereafter. SC-72325A (10 mg/kg) was given s.c. 10 minutes prior to formalin.
[0078] At 10 mg/kg, the s.c. injection of SC-72325A had a small inhibitory effect on phase 1 of the response but nearly completely abolished Phase II of the response. See FIG. 6.
Antihyperalgesia and Antinociception Synergy Using SC-72325A and Morphine Combination
[0079] Carrageenan-induced inflammation is a well characterized and commonly employed model of peripheral inflammation. This procedure reliably produces a marked inflammatory response within 3 hours of injection which is indicated by swelling of the hind paw, edema, rubor and hyperalgesia and allodynia (Kocher et al., 1987, Ossipov et al., 1995). Peripheral inflammation was induced in the hind paw of male Sprague-Dawley rats by injecting 0.1 ml of a 2% λ-carrageenan suspension into the subplanar surface of the hind paw of lightly ether-anesthetized rats. All drugs were prepared according to the methods set forth in Example 6, above. Testing was performed 15, 30, 45, 60, 120 and 180 minutes after drug injections. The s.c. injection of SC-72325A produced time-related and dose-dependant antihyperalgesia over the dose range of 0.3 to 30 mg/kg. See FIG. 7. Similarly, morphine also produced time-related and dose-dependent antihyperalgesia and antinociception over the dose range of 0.03 to 10 mg/kg. The 1:1 combination of SC-72325A with morphine produced antihyperalgesia activities at much lower doses than either drug alone. See FIG. 8. Isobolographic analyses revealed that the combination of SC-72325A with morphine resulted in a definitive synergistic interaction against hyperalgesia; the A50 values with confidence intervals are presented in Table 1, below. The antihyperalgesic A50 value for the 1:1 combination of SC-72325A plus morphine was 0.046 mg/kg, s.c., which was significantly (p≦0.05) less than the calculated theoretical A50 value for the combination if the activity was additive. See Table 1. SC-72325A also exhibited a slight antinociceptive effect. 2
Antihyperalgesia A50 (mg/kg, s.c.)
SC-72325A 1.34
Morphine 0.22
Morphine + SC-72325A 0.046
Theoretical Additive Curve 0.380
[0080] FIG. 9 shows that the onset of action SC-72325A was much faster than the one obtained with ketorolac. In fact, when compared to ketorolac, SC-72325A was more potent and more efficacious in this model.
SC-72325A Inhibition of Neuropathic Pain
[0081] Neuropathic pain (L5/L6 SNL) was also utilized to assess the antinociceptive effects of SC-72325A. Nerve ligation injury was performed according to the method described by Kim and Chung (1992). This technique reliably produces signs of clinical neuropathic dysesthesias, including tactile allodynia, thermal hyperalgesia and behavior suggestive of spontaneous pain. Rats were anesthetized with 2% halothane in O2 delivered at 2 liters/minute. The skin over the caudal lumber region was incised and the muscles retracted. The L5 and L6 spinal nerves were exposed, carefully isolated, and tightly ligated with 4-0 silk suture to the dorsal root ganglion. After ensuring homeostatic stability, the wounds were sutured, and the animals allowed to recover in individual cages. Any rats exhibiting signs of motor deficiencies were euthanized. Testing was performed 15, 30, 45, 60 and 90 minutes after drug injections.
[0082] The s.c. injection of SC-72325A produced time-related and dose-dependent antihyperalgesia over the dose range of 1 to 30 mg/kg. See FIG. 10. One of the highest doses tested, 10 mg/kg, produced an antihyperalgesic effect of 91±8.8% MPE and an antinociceptive effect of 39 ±6.4% MPE 30 minutes after injection. SC-72325A also exhibited a slight antinociceptive effect.
SC-72325A Inhibition of Allodynia
[0083] Chronic constriction injury was performed as described by Bennett and Xie (1988). Male Sprague-Dawley rats were lightly anesthetized and the sciatic nerve isolated and exposed. Four chronic gut ligatures (4-0) are loosely placed around the nerve about 1 to 2 mm apart and the wound closed. Signs of hyperalgesia and spontaneous pain, including guarding of the hind paw and spontaneous nocifensive responses are normally present within 4 days of surgery. Any rats exhibiting signs of motor deficiency were euthanized. Cold allodynia was evaluated by placing rats in a shallow pan of ice water (0° C., 3 cm deep). The response latency to withdrawal of the hind paw or escape behavior is measured. Normal or sham-operated rats typically show no response during the 30 second exposure to the ice water. Testing was performed 15, 30, 45 and 60 minutes after drug injections. Drugs were given by s.c. injection.
[0084] The s.c. injection of SC-72325A produced time-related and dose-dependent attenuation of cold allodynia over the dose range of 1 to 10 mg/kg. See FIG. 11.
[0085] Other Embodiments
[0086] The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. However, the invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed herein because these embodiments are intended as illustration of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims.
[0087] References Cited
[0088] All publications, patents, patent applications and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention.
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text:
National Doodle Day paves the way for better support and awareness.
Posted by Gillian King
We all doodle when we are bored; in classrooms, in lecture halls and at office desks. But what if your doodle could help somebody feel a little better as opposed to just appease your boredom?
Well National Doodle Day took your doodles, turned them into cash and then Epilepsy Action channelled them into their website, helplines, forums and UK wide support groups to help those with the condition and raise awareness to those who don't.
A record £14,500 was raised in this year's celebrity auction after nine years of the original fundraiser. Over 200 celebrities took part this year and their pictures went on auction. Celebrities, schools, businesses and individuals were all invited to send in their doodles. The rest of the doodles were put into a competition, which cost £1 to enter, and prizes are still to be announced.
Epilepsy is a very misunderstood condition and can affect anybody at any time. Over 54,000 people in Scotland alone have epilepsy, there are lots of different types, making it very difficult to diagnose. It is a very individual condition which means support sometimes has to be individual too.
Louise Cousins from Epilepsy Action said:
"National Doodle Day is a fun, easy and simple way of supporting people with epilepsy. Anybody can take part in it, you don't have to be able to run a marathon or climb a mountain. The money raised goes towards making the services we offer better as well as enhancing health services – there are not enough specialised nurses."
Debbie Keenan (29) is a support worker from Glasgow and agrees saying, "It sounds accessible and fun, getting celebrities involved is always a good way to raise awareness."
Debbie's job is to assist people to live independently in their own homes and this can include people who have epilepsy. She had to go through training to learn about the different types of seizures and to learn how to administer medication to the people that she works with.
"Honestly, before I did the training I didn't know very much about the condition. My generation are very unaware and the stereotypes we pick up are completely wrong. I learned how to react and help in a situation where somebody was having a seizure and I was surprised at the steps involved – you don't find out about these things until you need to."
She said that it is important that she had the training because of the individual that she works with but it should also be important to include more information in general first aid courses because anybody could have a seizure at any point. She found it surprising how many people live with the condition.
Around 70% of those with epilepsy can have episodes controlled by medication; the other 30% can be cured by brain surgery or by just learning to live with it.
Rachel Hanretty (23) from Glasgow was diagnosed at the age of only 11 and went through neurosurgery at the age of 15 to remove the part of her brain that was causing the seizures.
However, at 21 years old Rachel's epilepsy came back and she now has to learn to deal with the condition all over again. She describes her situation as "unique" but she is not alone.
Although she doesn't have what she describes as "full blown epilepsy," Rachel still believes that it is important that people understand about simple seizures:
"I think National Doodle Day is great because it breaks it down…a lot of people get really tense when you talk about epilepsy, people should be less scared.
I was really unhappy when the epilepsy came back and I was put on medication, the devastation of seeing those men in paramedic outfits after I came to…no not again. Nobody could understand the seizures I was having or describe them. There aren't enough epilepsy nurses out there and the few that there are, are overworked. I felt like my situation wasn't as bad as some and I was told it could be a lot worse; it made me feel guilty for speaking about it."
Rachel has already tried to raise awareness about epilepsy independently and also by working with charities.
She says, "I know that support is available but only because I have kept up with Epilepsy Scotland, I think the helpline is in particular a great idea. However, I have never really used the support available because of my own pride, I don't want to sound defeated by asking for help."
However, only 12 years ago when Rachel was first diagnosed, she was not told about the 'teen' support groups available to her. It was only as she got older that she became aware of what was out there for her.
Charlene Black (34) also lives in Glasgow and was diagnosed with epilepsy 19 years ago:
"I didn't receive very much support at all except from my own parents. My brother was also diagnosed with the condition 6 years ago when he was 31 years old, he found that he wasn't made aware to any support either.
However, my friend's child was also diagnosed around that time and she received more support and guidance. Although it isn't always needed, it is nice to know that it is there."
Epilepsy doesn't have to be misunderstood and people shouldn't have to feel alone when first diagnosed. Sometimes just finding somebody else who is willing to talk about their situation can help.
Not everyone can run a marathon, or do a sponsored swim, but everyone can draw something, even if it isn't a work of art.
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My name is Gillian King and I have been writing for as long as I have been able to. More recently I have been blogging about my experience as a new parent during the Coronavirus pandemic. Have a read, leave feedback, and enjoy.
New Parents in Lockdown: Food, food, food.
New Parents in Lockdown: Phasing Out
New Parents in Lockdown: Routine
New Parents in Lockdown: Child of the internet
New Parents in Lockdown: A new normal
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Kirsteen, squirrelboss on Squirrel Cross: Preparing for my first ever bike race
Vince on MORAY WILL NOT BE LEFT OUT OF TORCH CELEBRATIONS.
cancer on MORAY WILL NOT BE LEFT OUT OF TORCH CELEBRATIONS.
LouisaNacnud on Oh I do wish to be beside the seaside…
Rebecca Tracy on Valentines Day – What is it really all about?

redpajama_set_name: RedPajamaCommonCrawl


text:
package io.cortical.services.api.client.api;

import io.cortical.services.api.client.ApiException;
import io.cortical.services.api.client.model.ExpressionOperation;
import io.cortical.services.api.client.model.Image;
import org.testng.annotations.BeforeClass;
import org.testng.annotations.Test;

import java.io.ByteArrayInputStream;
import java.io.IOException;
import java.util.List;

import static org.testng.Assert.*;

public class ImageApiTest {
    private static final String inputJSON = "{ \"term\" : \"apple\" }";
    private static final String inputJSONarray = "[ { \"term\" : \"apple\" }, { \"term\" : \"banana\" } ]";
    private static final String inputJSONarray3 =
            "[ { \"term\" : \"apple\" }, { \"term\" : \"banana\" }, { \"term\" : \"fruit\" } ]";

    private ImageApi imageApi;

    @BeforeClass
    public void setUp() throws Exception {
        imageApi = new ImageApi(TestConfig.getClient());
    }

    @Test
    public void testImage() throws IOException, ApiException {
        ByteArrayInputStream imageData =
                imageApi.getImageForExpression(new ExpressionOperation(inputJSON), TestConfig.getRetinaName(), null,
                        null, null, null);
        assertNotNull(imageData);
    }

    @Test
    public void testCompare() throws IOException, ApiException {
        ByteArrayInputStream imageData =
                imageApi.getOverlayImage(new ExpressionOperation(inputJSONarray), TestConfig.getRetinaName(), null,
                        null, null);
        assertNotNull(imageData);
    }

    @Test
    public void testBulk() throws IOException, ApiException {
        List<Image> images =
                imageApi.getImageForBulkExpressions(new ExpressionOperation(inputJSONarray3), true,
                        TestConfig.getRetinaName(), null, null, null);
        assertEquals(images.size(), 3);
        for (Image image : images) {
            assertNotNull(image);
            assertNotNull(image.getImage_data());
            assertNotEquals(image.getFingerprint().getPositions(), 0);
        }
    }
}

redpajama_set_name: RedPajamaGithub


Culpeper Foster Parent Information Session – Children's Services of Virginia, Inc.
Please join us for a no obligation Information Session at the Culpeper County Library to learn more about becoming a foster parent. Feel free to e-mail or call our Resource Parent Recruiter at jallen@csv-inc.com or 540-398-7938.


I have to admit that the Concept Art of the Bandersnatch for Tim Burton's Alice in Wonderland is 100 times better than that white ugly beast. The black Bandersnatch is more terrifying and savage.
BTW, thanks to model Adrianne Curry for uploading this Concept Art, she is also a great Alice in Wonderland fan.


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FT. LAUDERDALE, FL – May 9, 2018 – Jamel Gordon has joined Provenance Wealth Advisors as a financial advisor based in the firm's Ft. Lauderdale office. Gordon offers financial planning consulting services to entrepreneurs, business owners and high-net-worth families and individuals. He has specialized experience in financial planning for professional athletes and entertainers.
Gordon most recently worked as a financial advisor for Edward Jones. He is a Certified Financial Planner (CFP®) and holds Series 7, 31, 63 and 66 licenses and a Life, Health and Annuity license. Gordon is a member of the South Florida Sports Lawyers Association. He has a bachelor's degree in Family Financial Planning from Ohio State University.
Provenance Wealth Advisors provides comprehensive financial planning, estate planning and insurance services to entrepreneurs, professionals and business owners.
PWA has offices in Miami, Ft. Lauderdale, Boca Raton, West Palm Beach, Cincinnati and New York City.
Provenance Wealth Advisors is not a registered broker/dealer and is independent of Raymond James Financial Services. Investment advisory services offered through Provenance Wealth Advisors and Raymond James Financial Services Advisors, Inc.
515 E. Las Olas Blvd, Ft. Lauderdale, FL 33301 (954) 712-8888.


exposure to a world full of cultures that has taught me that my culture is not the center of the world.
the ability to remember that clean water, bathtubs, spinach, strawberries and good coffee are a gift.
grace to understand that I'll always have to be learning more.
200 million photos that someday–when I'm 100– I might have time to look at.
Every time I complete a crazy trip like my solo Thanksgiving round-the-world adventure, I sleep for a week, and then when I finally wake up, I make a promise to myself that next time I'll travel slower and try not to go to as many places on one trip.
Inevitably, after a month passes, however, I somehow forget all these promises I've made to myself. Even though I start with planning my next trip simply, I somehow wind up with an itinerary that crosses to the moon and back.
Confession: Some people are addicted to Girl Scout cookies and pizza. I lack complete lack self-control when it comes to national borders.
Here's my logic: If you've already made the effort to fly half way around the world to go to country X, why not also go to country Y if it's not that far away, and maybe also stop in at country Z if you have to fly past it anyway to get home?
I'm not convinced that country hopping is always a bad thing, but I do know one thing for sure: Country hopping makes for very tricky packing. Especially if you are a person, like me, committed to a carry-on only travel style.
This week I'm headed out for my first multi-country 2018 travel adventure, and as you may have guessed, I didn't keep it simple. I'm on my way to a tango festival in Vietnam via a long weekend of hanging out at the Women's Travel Fest in New York City. From Vietnam I'll go onward through South East Asia, visit friends in Cambodia and Thailand, stop for a beach week in the Maldives, and then hit up one final stop in the UAE for a fellow traveler's birthday celebration in the desert before I head back to the US across the Atlantic.
I'm very excited about every single part of my adventure–besides the one thing I have to do to get myself out the door: Pack.
Now, some travelers will recommend that you keep it simple by always packing the same things. For me, always packing the same jeans and black shirt just never seems to work—I like to pack for the occasion.
Not only will I be traveling while working on the road for six weeks, I'll be crisscrossing countries, climates and cultures that all require very different clothing.
New York, for example, is currently under a blizzard warning, while Bangkok is about 100 degrees every day with 100 percent humidity. A Tango festival requires me to bring specific shoes that I literally can't wear anywhere else, and transiting home through the Middle East also means that I need to have something in my bag that is long and modest.
When your trip isn't simple, your wardrobe isn't simple either.
Guys might be able to get away with those zip off khaki travel pants everywhere, but if you're a girl and you want to look decent and be appropriate for whatever culture you might have accidentally added onto your trip, you'll need to kit yourself appropriately.
When I declared on my Instagram story this week that I would pack for six weeks, three cultures, and four climates in one carryon, so many of you said it would be impossible. I will confess it was a challenge, but here's how I did it.
The key to any good multi-climate packing plan is layers. When it is cold you wear all the layers, when it's bloody Asian hot, you wear as few layers as the culture deems appropriate.
A couple of tank tops, long sleeves, tights, basic skirt, and a dress that can double as a tunic go a long way in the mix and match game. Multi-weather fabrics like merino wool are also a secret weapon to keep you warm when it's cold and cool when it's hot (hat tip to Smartwool and Icebreaker).
Also, it helps to keep your layering strategy color coordinated. While I'm definitely not a monochromatic dresser in my day to day (orange and yellow are my favorite) I tend to stick with a color theme for the basics–most commonly blacks and grays with some pops of color. Color coordinating also means that you can get away with fewer pairs of shoes.
I'm definitely not the kind of person who buys new things to take on a trip. When it comes time to pack I'd prefer to dig to the back of my closet to see what is hiding in my Goodwill pile.
I love to pack things that I still like enough to wear for the trip, but am definitely going to be okay with getting rid of along the way. I take old tank tops instead of my new tank tops so I can fit the new tank tops I'm bound to buy in the market in Bangkok. I take my oldest running shoes instead of the newest model because I can leave them at my last stop to make room for whatever souvenir I fancy from my adventure. And I also take the contents of my underwear drawer that really should be thrown out–it's always nice to have extra undies and much easier to get rid of those holey ones when you're on the road.
Disposable clothing are my key for keeping my packing light as I collect things along the way—plus you don't have to worry as much about your things getting lost or stolen if they aren't your absolutely favorite things.
3.Let your bag evolve as you go.
After many years of travel I've finally learned that I don't actually need to purchase ahead and pack everything I need. People who live in other places usually need and want many of the same things that I want. If I need shampoo I can buy it there–why pack it? I can buy new flip flops if I lose mine, or pick up a fancy dress on the occasion that I find a hot date in my next location.
If you start somewhere cold and move on to somewhere warm, take warm layers you don't mind leaving along the way, or organize to leave things with a friend to pick up later.
Last fall when I packed for a beach trip to Mauritius, but decided to fly home via Paris in winter, I was worried I was going to freeze. Instead of skipping Paris, I kitted myself out locally with a new hat from a street vendor and some jeans and a sweater. The bonus–I now have an awesome sweater and I get to say "I picked it up in Paris" when people comment on it.
You don't have to pack to be prepared for everything—just prepare to be prepared and 99% of the time it will all work out (the other 1% will make great stories to tell someday).
So, what's in my Mary Poppins bag?
If you really want to know, here's everything I'm schlepping around the world for the next 6 weeks. Contents are subject to change. In fact, I'm less than 18 hours into the trip and I've already lost my hat!
Boots, Jacket, Dress and shoes for speaking event, jeans, and long sleeves (I'll keep the long sleeves and jeans and leave the rest with a friend in NY to pick up later).
headphones, computer, folded up flip chart paper and sharpies, work papers that I will dispose of as I go.
What will be in the Mary Poppins bag by the end of the trip? Follow along, or wait and see!
I mostly travel alone. Sometimes it is by choice, and sometimes it is simply because I'm not one to let my perpetually single status stop me from doing anything I dream of doing.
To be honest, most times I travel solo, I don't even notice. I'm pretty awesome company (I think), and there are always people to talk to on the road. Plus with modern capabilities to connect from the remotest places, I'm never further than a Facetime away from my mother when I get tired of talking to myself. She always likes to see what I'm seeing.
Yet, even as independent as I can be, there are times that I choose to not go somewhere because I'm solo. And it isn't just about safety. There are lots of reasons that cause the unaccompanied to press pause on their travel plans.
For years I'd wanted to travel to the French Polynesian island of Bora Bora and sleep in an overwater bungalow with tropical fish below me. But I put it off, and I put it off. Pushing pause on my dream time and time again.
You see, the entire tourism structure of Bora Bora is designed to cater to couples—destination weddings, honeymooners, and 25th anniversary celebrators. The airlines might as well sell tickets by the pair. Part of me was waiting for +1 to present to Air Tahiti to validate my worthiness to see this Polynesian paradise.
It wasn't until recently that I said, F*%& it. My +1 is apparently lost in the Bermuda Triangle or undertaking a very extended journey across the Sahara. And so I went to Bora Bora by myself. Honeymoon island, party of one.
In all of my alone time watching the fish swim in the crystal clear lagoon from the perch of my over-the-water bungalow dock I spent some time reflecting on what really stops many of us from solo travel—and why we should do it anyway.
If you're struggling with any of these reasons of why you shouldn't travel alone, here's some real reasons you should ignore them.
Reason not to go #1: It isn't a solo-traveler kind of place.
Like Bora Bora, many of the most beautiful destinations in the world have been turned into "honeymoon hot-spots" and "romantic getaways". Some places are tagged "family destinations". Other places just have reputations for being more difficult to see solo. Most of this is a marketing ploy. At honeymoon resorts, tables are for two–but who cares. You have just as much right to take up space in your dream destination as any one else- and you don't have to share the bread basket.
Lesson: If you want to go somewhere solo do your own research and don't let the reputation of the place stop you from going. There are single people everywhere in the world (therefore there is no destination that isn't solo-appropriate with a little bit of creativity). There are also ways that you can connect up with other solo travelers if you feel more confident being part of a group.
Lesson: When it comes to travel (and, well, a lot of other things) the lesson that I've learned is that it really doesn't matter what other people think about where you want to go and if you want to be there by yourself. Sure, you may have to explain your situation, but why not make it fun and be true to what you want? Most of the travelers I talked to were intrigued about why I was there alone. I used this opportunity to talk to them about a new travel guide I'm writing (stay tuned) and handed out more business cards in Bora Bora than I do at a typical networking event.
Most people assume that safety is the primary concern of solo travelers—and solo female travelers in particular. However, as I've talked to more and more female travelers I've learned that safety isn't often their biggest fear—they are much more afraid of being lonely and not having anyone to share their trip with. While safety isn't always at the top of the list for what holds people back—or at the top of your worries in a pretty peaceful place like Bora Bora staying safe on the road is still important.
Lesson: The thing I've learned from years of solo globetrotting and my own run-ins with danger, is that staying safe on the road is very much like staying safe at home. Know where you're going, be intentional when you're wandering around alone in the dark, stick to areas with people, make local connections and ask if there are places that you should stay away from.
Being alone does not always equal being lonely. By the time I left Bora Bora and Tahiti, I'd made a dozen new and very interesting friends: My over-the-water bungalow neighbor who had patented an inflatable tent and was celebrating his 25th anniversary, an American sailor who'd just finished a 31 day crossing of the Pacific Ocean from Mexico in his 26 foot sailboat, two Belgian grandfathers on a dive trip who wanted to buy me beer and talk about pre-election U.S. politics, and a dozen honeymooning and anniversary-ing couples who were really thrilled to have an unusual person to talk to after a week on an island with only their significant other.
Lesson: Being lonely and being alone are not the same thing (It's worth repeating). The world is full of amazing people and amazing stories and people worth talking to. You don't have to be that chatty person on the airplane who talks for the whole flight to make friends (please, don't be him/her)—just be friendly. Just do you.
Maybe you aren't single, maybe you just wonder what having a solo adventure would be like, or you want to go somewhere that your partner doesn't want to go–but you've never traveled alone before and aren't sure if you'll like it. Well, one thing is for certain, you'll never know unless you try it. When I was preparing to take my first solo backpacking trip around Indonesia I confess I was a little nervous (even though I was already living alone in Thailand) so I faced my fear and took myself on a practice weekend trip to a Thai island all by myself–and I was totally fine!
Lesson: Think about what makes you afraid of traveling solo and figure out a way to practice so you can reassure yourself you'll be okay on the road. Worried about being alone? Get in your car by yourself and go on a weekend road trip. Worried about flying alone? Practice with some domestic flights by yourself.
I'm guessing you're stronger, braver, and more prepared than you believe. I definitely learned that I was.
Bora Bora or Bust: Why aren't you getting on the plane?
For several years I've been helping people learn how to travel for nearly free using points and miles. There's something amazing about encouraging people to dream about a place they've never visited—one that would most likely never be accessible to them if they had to save the money to get there—and then show a few practical tools to make this a reality.
As I challenge people to learn to travel hack by working towards a goal of a dream destination, I've always shared my own dream of sleeping in an over-the-water bungalow in Bora Bora–falling asleep to the sound of the surf, waking up to the fish under my feet, and morning coffee with my toes in the brilliant blue water.
The funny thing was, however, after years of teaching people how to hack their way to Bora Bora, I'd still never actually been there myself.
I had the points, I'd done all the research. If there ever was anyone qualified to hack their way to Bora Bora, I was she. What was I waiting for?
In October I flew to New Zealand. As my plane crossed the Pacific on it's 17 hour journey I watched as we flew directly over Tahiti and the rest of French Polynesia on the inflight entertainment system flight tracker. Then it struck me. Was this the closest I was ever going to get to Bora Bora? A mile above it in the sky?
The wheels in my brain started turning. What was keeping me from going there if it wasn't time or money? Why wasn't I getting on the plane bound for Bora Bora? Was I subconsciously waiting for a significant moment. For my perfect traveling companion. For all the stars in the southern cross to align?
As I watched the sun rise at 37,000 feet, it literally dawned on me that I was waiting for no real reason. I was just putting it off because later felt easier than now. And then I thought some more. What other things was I putting off in my life like Bora Bora with no reason whatsoever?
Why is it that we put off our dreams and desires while waiting for the perfect time or circumstance to magically present itself? Aren't we old enough to know that the magical present is the actual PRESENT? I made a pledge to myself to make it happen. And since I had to fly over Bora Bora again to get home from New Zealand —I decided that I would just do it now.
And as I typed the draft of this post from the deck of my over-the-water bungalow of my dreams, I can ensure you that NOW was the exact right time.
Whether you're putting off a dream trip, calling your long lost family, waiting to pick up your pen to write your best-seller (points finger at self), the lesson is this: The perfect time is now. If you're waiting for a sign, this is it.
I guess next time I teach this lesson I'll be using my own photos and telling my own Bora Bora stories—and perhaps I'll have to find another travel dream to share!
Wonder how I actually hacked my way to Bora Bora? I knew you'd ask. Keep reading the bonus section below if you want to know how to plan this kind of trip.
My first ticket was from Portland (PDX) to Auckland, New Zealand (AKL) on American Airlines with a stop in Los Angeles (LAX) and an intentional one day layover in Sydney, Australia (SYD). This ticket was First Class and cost a total of 72,500 American Airlines points with a dollar value of $11,000! As this ticket was on American and Qantas flights, I was able to search for and book the ticket online at aa.com. I booked this flight 10 months in advance as a one way award. (This ticket was purchased prior to American's devaluation in early 2016- the current ticket cost for this same route one way is 90,000 AA Miles on a First Class saver award). Most of my miles on AA are earned from AA domestic flights and from my Citi AAdvantage credit card.
While the first half of my trip was booked very far in advance, all of the remaining flights were booked at the very last minute since I didn't decide to fly home via Bora Bora until I was already in New Zealand.
Air Tahiti (not to be confused with Air Tahiti Nui) has a monopoly of the French Polynesian skies and is the only way to get to Bora Bora once you've made it as far as Tahiti. I flew PPT to BOB and came back to Tahiti via Moorea—another island that connected to Papaetee by ferry. The only way to hack this leg is with lots of points on a credit card with a "travel eraser" or cash back travel credits like my Chase Sapphire Reserve. The cost of the flight is about $220 each way and doesn't fluctuate much. I booked the flight directly through airtahiti.com to receive travel credits on my credit card. The most important thing to know about this flight is that you want a seat on the left side on the way out and right side on the way back. Catching a view of Bora Bora from the sky is worth the cost of the flight alone.
* Note: if you make it this far, and are hoping to use points to stay at hotels in Tahiti and Bora Bora, you'll want to stock up on Starwood, Hilton or IHG points. These are the chains that operate properties around French Polynesia. I used points from my IHG and SPG Amex Credit cards to cover my hotel nights.
To get from Tahiti back across the Pacific to the US, there are very limited choices of Airlines: Air Tahiti Nui, Air France, and Hawaiian Airlines–and not all of these airlines fly to the island every day. Since I had a stash of Hawaiian airlines miles that I'd never used after signing up for a Hawaiian airlines credit card, I decided to take the once a week Hawaiian flight to Honolulu (HNL) and then connect onward to Kona (KON) for no additional cost. An economy class ticket for the 5 hour overnight flight was 27,500 (at a cash value of $950) and bookable online at Hawaiian Airlines. The same flight was also bookable online via AA.com using American Advantage points, but cost more at 37,500 points.
Since I had to fly through Hawaii anyway, I took the opportunity to explore the big island for a few days before heading the rest of the way home via American Airlines. There were dozens of flights to choose at all times of day from on an assortment of airlines for about $220 or 20,000 miles on American. I went with a paid AA flight so the redemption value was low. Buying the ticket allowed me to earn qualifying miles and a paid flight allowed me to request a complimentary upgrade with my status..
All together, I saved more than $14,010 on flights by using points and miles! But more importantly than getting something of high value for a fraction of the cost. I finally got to see Bora Bora for myself!
My first trip to Italy was in 1993. I was a young and hip backpacker, too cool for the universe—as most teenagers are—and especially too cool for my family. Or so I thought.
Now that I'm much older and a little wiser I've come to realize that this whole time my family is awesome.
My family has deep Italian roots. My father is Italian. His parents were Italian. My great grandparents were Italians straight off the boat. (See above, those were the immigration papers of my Grandmother's mother).
I don't know enough stories about that boat and why the patriarchs and matriarchs of my "Italian-American" family came to the "new" world of their time. Perhaps they were "explorers" rather than "settlers". Maybe this is where my genes of adventure come from. If I am cool now, it is only because it is hereditary.
There is one story that I do remember well about my learning my family history. Sadly, it is both my own story and a story of regret.
In 1993 when I took my very first trip to Europe, my Italian grandparents were alive. They religiously hand wrote me letters nearly every week during the duration of my first study abroad semester in London. I'll never forget my Grammy's perfect cursive penmanship or the way she and Pappy always tucked 20$ bills into their tri-folded drugstore notepad letters.
As the end of my time in the U.K. neared, I prepared for my first backpacking trip through Italy–Rome, Florence, Pisa, and Venice were on the list. I was excited, and in advance of the trip received one of Grammy and Pappy's letters with a 20$ travel bonus! This time, however, the letter wasn't the ordinary update with the regular news of their local Italian choir and spaghetti dinner club they hosted. In preparation for my first trip to Italy, they had carefully created a list of the names and telephone numbers of all of my relatives in the cities I would be visiting so I could connect with my roots. It was a treasure map.
Unfortunately, the thing about teenagers and treasure maps, was that I wasn't smart enough to know the value of this letter at the time. It was just a piece of the same old drug-store notepad paper from my grandparents with the names of people I didn't know on it. I put the 20$ in my wallet, tucked the address list into my Let's Go guide, and hit the road!
One day in Florence, where some of the relatives on the list lived, I pulled out the piece of paper from my guidebook, admired Grammy's perfect cursive, and picked up a hostel payphone. And then I got scared and put the receiver down. I didn't know who these people were. Maybe they were somehow related to my 'old' grandparents, but I didn't know them, I didn't know what to say to them, AND they didn't speak English. Game over.
I never made that call. I put the list back in my book and never looked at it again. I had assumed that I was living my once in a lifetime chance to visit Italy and I didn't want to waste it with cheek pinching strangers who might serve me funny food and not be able to talk to me in 18 year old English. I had no inkling that I'd spend the next 20+ years traveling.
I've been back to Italy at least ten times since, and I've thought about this moment dozens of times. I'd give anything to be able to pick up the phone, dial into the past, and get to know the family on that list. I'd call them all and mumble in my best incoherent Duo-Lingo Italian.
Sadly, I lost that paper, and within a few years after that trip I also lost both of my grandparents who were my connections to these living stories. For some reason, however, I've never lost that memory of putting down the receiver and making that choice not to call.
Sure, it was just a phone call in the past that I didn't make, but moments like these also go by another name. We call them regret, and regret strangely has a way of sticking around—even longer than estranged relatives and cold cheese-less pizza.
Perhaps regret sticks and stings because it so badly doesn't want us to forget the lesson it teaches. She stays with us to remind us to run the other way from our fears and failures. Not to condemn, but to condition us for the better and to prepare us for the future. To make us stronger and more willing to pick up the phone the next time we get the chance.
I'm headed back to Italy next week, making my own mission to chase my roots into the village where my great grandparents came from. I'm not sure what I'll discover, but I know one thing that won't be hanging out there: Regret.
You may never get a rewrite of that moment from your past, but you do get to write the end of your story.
"When are you going to settle down?" As a wander of more than 20 years, this is the question I've learned to field at least once a week. Friends, family, people I date, random acquaintances, and readers of the internet inquire about my ability to "settle" all of the time.
"Settle down?" It's a simple question, and most often curious and well-meaning. Yet, on most occasions whenever these words enter my ears this question triggers my inner world into a mild state of panic.
Part of my brain screams "YES!". Part of my brain screams "NO!". It's paralyzing.
What does settling down even mean for goodness sake? As a traveler who has built much of her existence on the premise of not being long-term geographically committed to one place, this question instantaneously triggers my self doubt to the very core.
For a long time I thought this inner struggle was a sign I must be broken, but eventually I realized that this is a trick question.
You see, there is no right answer to the "When will you settle down?" question, because, my friend, there's a paradox in the very concept of settling.
In the strange universe of the English language, the word "settle" has multiple and very different—perhaps even contradictory–meanings.
If you're a traveler, most people actually don't care, beyond a mild curiosity, where you go or how long you stay there. The asker is usually just wondering "Are you going to stick around for awhile?" This usually isn't a question that comes from a place of judgment, rather people want to know where they fit into your life.
Can you be settled without settling?
I've lived a very non-traditional life for most of the last 20+ years. Although it seems to some on the outside that I've been wandering aimlessly, I have been very "settled" into a global community and cause. I have been at home in my purpose-driven wandering. I have been settled without settling for years.
Three years ago I chose to move to a place where I could build a more sustainable geographically-based home and community. While I've unpacked and settled into Portland for now, I'm less about "settling down" and more about extraordinary living from a fixed address. It's less settling and more striving for the new things that I want–making decisions for important things that are bigger than me—community, home, relationships, roots, etc.
A permanent address or our drive to be location interdependent doesn't determine a settled or un-settled life.
Perhaps you've lived in the same home for 20 years, yet have given up on your dreams to be a painter or a writer or a supreme court justice (I hear there's a job vacancy). If where you live makes you happy, great, but perhaps it's time to choose to change something if life circumstances have driven you to settle for something less than what you were born to be.
We only have one chance in this life after all.
Stop settling. Start living your dreams.