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(12) Patent Application Publication (10) Pub. No.: US 2015/0258111A1 Maillet Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0258111A1 Maillet Et Al US 20150258111A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0258111A1 Maillet et al. (43) Pub. Date: Sep. 17, 2015 (54) METHODS AND COMPOSITIONS FOR Publication Classification REDUCING TOLERANCE TO OPOD ANALGESCSUSING BOGAINE AND (51) Int. Cl. DERVATIVES THEREOF A613 L/55 (2006.01) (52) U.S. Cl. (71) Applicant: DemeRx, Inc., Fort Lauderdale, FL (US) CPC ...................................... A6 IK3I/55 (2013.01) (72) Inventors: Emeline Maillet, Miami, FL (US); Lawrence Friedhoff, River Vale, NJ (57) ABSTRACT (US) (21) Appl. No.: 14/635,871 A method for modulating tolerance to an opioid analgesic in (22) Filed: Mar. 2, 2015 a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with Related U.S. Application Data said opioid analgesic therapy an amount of ibogaine, ibogaine (63) Continuation of application No. 61/952,743, filed on derivative, or pharmaceutically acceptable salt and/or Solvate Mar. 13, 2014. thereof. US 2015/025811 1 A1 Sep. 17, 2015 METHODS AND COMPOSITIONS FOR resensitization. In one aspect, the resensitized patient obtains REDUCING TOLERANCE TO OPOD improved therapeutic effect from the same dose of the opioid ANALGESCSUSING IBOGAINE AND analgesic compared to before resensitization. DERVATIVES THEREOF 0008. The use of ibogaine for the modulation of tolerance to opioid analgesic agents is limited due to potentially adverse CROSS-REFERENCE TO RELATED side effects. For example, ibogaine exhibits undesirable APPLICATIONS stimulant and hallucinogenic properties, and in addition, can 0001. This application claims benefit from U.S. Provi induce tremors. At conventional doses, ibogaine causes sional Application No. 61/952,743, filed Mar. 13, 2014, adverse side effects in a majority of patients receiving treat which is hereby incorporated by reference in its entirety. ment. Thus, the use of ibogaine to modulate opioid tolerance is generally not favored due to the adverse side effects that can FIELD OF THE INVENTION result from receiving a therapeutic dose according to conven tional known methods. 0002 This invention is directed to methods for reducing 0009. It has been discovered that the use of ibogaine, tolerance to opioids in a patient undergoing opioid analgesic ibogaine derivative, or pharmaceutically acceptable salt and/ treatment for pain comprising treating the patient with or Solvate thereof imparts a dose dependent prolongation of ibogaine, an ibogaine derivative, or a pharmaceutically the treated patient’s QT interval, rendering higher dosing of acceptable salt and/or solvate thereof (hereinafter referred to ibogaine unacceptable. A prolonged QT interval is a marker as “ibogaine') at a therapeutic dosage. of potential Torsades de Pointes, a serious arrhythmia that can result in death. For reasons that are not apparent, this prolon STATE OF THE ART gation increases in opioid addicted patients as compared to 0003. Addictive opioid analgesic agents such as morphine healthy individuals. Heretofore, it was unclear whether a are well-known and exceptionally potent analgesics. Such therapeutic dose of ibogaine could be found that resulted in opioids operate as mu receptor agonists. Upon administra QT interval prolongation within an acceptable range. It is tion, opioids initiate a cascade of biological events including expected that other compounds that share ibogaine's core increased serotonin and dopamine expression. As is well structure will have a similar prolongation effect on QT inter known, continued use of many Such opioids (especially at val. See, U.S. Provisional Patent Application No. 61/945,746 high doses) carries a significant risk of dependency/addiction. filed Feb. 27, 2014 entitled METHOD FOR ACUTE AND Indeed, potential addiction to such opioids is a serious issue LONG-TERM TREATMENT OF DRUG ADDICTION, that limits the therapeutic use of addictive opioids as analge which application is incorporated by reference in its entirety. sic agents. For example, the use of morphine as an analgesic 0010. The current invention is predicated on the surprising is common among end stage patients suffering from serious discovery that treatment with a narrow dosage range of pain where addiction is no longer a concern. ibogaine, ibogaine derivative, orpharmaceutically acceptable 0004 Drug tolerance to opioid analgesics is common, and salt and/or solvate thereof, between greater than about 1 may be psychological and/or physiological. A patient who mg/kg body weight and about 8 mg/kg body weight, provides has developed tolerance to the opioid analgesic is not neces atherapeutic modulation of intolerance to opioid analgesics. sarily addicted to or misusing the analgesic. Drug tolerance Preferably, the dose range that provide both therapeutic occurs when the patient’s reaction to the drug is reduced, results and an acceptable QT interval prolongation of less requiring an increase in dose to achieve the same desired than 50 milliseconds is between about 1.3 mg per kg body effect. There are several potential methods for how tolerance weight and no more than about 4 mg per kg body weight and, develops, including receptor desensitization, receptor phos more preferably between about 1.3 mg per kg body weight phorylation, receptor internalization or down-regulation, and and no more than about 3 mg per kg body weight, or any up-regulation of inhibitory pathways. Subrange or Subvalue within the aforementioned ranges. 0005 Drug tolerance requires that the dosage of analgesic 0011. In a preferred embodiment, the narrow therapeutic be increased in order to provide Sustained analgesic effect. doses of ibogaine, ibogaine derivative, or pharmaceutically However, high doses of opioids may lead to serious compli acceptable salt and/or Solvate described above do not prolong cations and side effects, including physical dependence, the QT interval to unacceptable levels in human patients. In addiction, respiratory depression, nausea, sedation, euphoria Some embodiments, patients will be administered therapeutic or dysphoria, decreased gastrointestinal motility, and itching. doses of ibogaine, ibogaine derivative, or pharmaceutically 0006. It would be beneficial to provide a method for modu acceptable salt and/or Solvate thereof in a clinical setting with lating opioid analgesic tolerance in a patient taking one or cardiac monitoring. In some embodiments, the patient will be more opioid analgesics for the treatment of pain. pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre SUMMARY existing cardiac conditions which would disqualify them 0007. This invention is directed, in part, to the use of from treatment with ibogaine. ibogaine to modulate tolerance to addictive opioid analgesic 0012. In one embodiment, ibogaine, ibogaine derivative, agents in a patient who has developed or is at risk of devel or pharmaceutically acceptable salt and/or Solvate thereof is oping a tolerance for the analgesic. In such methods, effective administered concurrently with the opioid analgesic. In one analgesia can be achieved in a patient while resensitizing the embodiment, ibogaine, ibogaine derivative, or pharmaceuti patient to the addictive opioid analgesic. The term “resensi cally acceptable salt and/or solvate thereof is administered tizing the patient' is used herein to refer to reducing, reliev after administration of the analgesic, for example one, two, ing, attenuating, and/or reversing tolerance to the analgesic. three, four, eight, ten, twelve, 24 hours or more after admin In one aspect, the resensitized patient obtains therapeutic istration of the analgesic. In one embodiment, one dose of effect from a lower dose of the opioid analgesic than before ibogaine, ibogaine derivative, orpharmaceutically acceptable US 2015/025811 1 A1 Sep. 17, 2015 salt and/or solvate thereof is administered. In one embodi course, vary. It is also to be understood that the terminology ment, two or more doses of ibogaine, ibogaine derivative, or used herein is for the purpose of describing particular pharmaceutically acceptable salt and/or Solvate thereof are embodiments only, and is not intended to be limiting, since administered. In one embodiment, the opioid analgesic is the scope of this invention will be limited only by the interrupted for a period of time while ibogaine, ibogaine appended claims. derivative, orpharmaceutically acceptable salt and/or Solvate 0017. The detailed description of the invention is divided thereof is administered. In one embodiment, a non-opioid into various sections only for the reader's convenience and analgesic is administered while the opioid analgesic is inter disclosure found in any section may be combined with that in rupted. In one embodiment, ibogaine, ibogaine derivative, or another section. Unless defined otherwise, all technical and pharmaceutically acceptable Salt and/or Solvate thereofacts Scientific terms used herein have the same meaning as com as an analgesic. In one embodiment, the opioid analgesic is monly understood by one of ordinary skill in the art to which not interrupted during ibogaine treatment. this invention belongs. 0013. In some embodiments, the therapeutic dose of 0018. It must be noted that as used herein and in the ibogaine, ibogaine derivative, orpharmaceutically acceptable appended claims, the singular forms “a”, “an', and “the salt and/or solvate thereof administered to the patient is suf include plural referents unless the context clearly dictates
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