Abstract:
An alkaloid composition for an inhaler contains a solvent and at least about 25 wt. % anatabine based on the total alkaloid weight of the composition. The alkaloid composition may be contained in a refilling cartridge for an inhaler, or in a container as part of a kit for refilling an inhaler. The alkaloid compositions disclosed herein feature a balanced form of alkaloids to provide an attractive alternative to smoking tobacco, in which nicotine makes up about 90 wt. % of the total alkaloid content. The alkaloid compositions are characterized by a significant quantity of anatabine, which has lower toxicity than other alkaloids such as nicotine. The alkaloid compositions enable individuals to experience the pleasure-enhancing attributes of conventional cigarette smoking, while avoiding exposure to combusted materials and other potentially hazardous components present in tobacco.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a continuation-in-part of U.S. application Ser. No. 13/493,132, filed Jun. 11, 2012, which claims benefit under 35 U.S.C. §119(e) to U.S. Application No. 61/500,237, filed Jun. 23, 2011, the disclosure of each of which is hereby incorporated by reference in its entirety. 
     
    
     BACKGROUND 
       [0002]    Combustion of organic materials such as tobacco is known to produce tar and other potentially harmful materials. Inhalers have been used as one non-combustion type of device for delivering nicotine for inhalation. Some types of inhalers use a highly pressurized chamber for delivering a powdered medium for inhalation. See, e.g., U.S. Pat. No. 7,461,649 to Gamard et al. Other varieties of inhalers employ a tube in which the active component is volatized into vapor form for inhalation. See, e.g., U.S. Pat. No. 6,769,436 to Horian. Current inhalers of this type generally use nicotine, a toxic and addictive substance, as the sole active component. 
         [0003]    The art has recognized a need for non-nicotine or reduced-nicotine alternatives to tobacco and tobacco replacement products. See D. K. Hatsukami et al., “ Nicotine reduction revisited: science and future directions ,” Tobacco Control 19: e1-e10 (2010). It would be especially desirable to develop non-nicotine or reduced-nicotine alternatives that more effectively achieve the pleasure-enhancing attributes of traditional cigarette smoking, which in turn may assist smokers in quitting traditional cigarette smoking. 
       SUMMARY 
       [0004]    Embodiments of the present invention are directed to inhalers, alkaloid compositions for inhalers, and refilling cartridges for inhalers containing certain alkaloid compositions. In one aspect, a refilling cartridge for an inhaler contains an alkaloid composition comprising at least about 25 wt. % anatabine based on the total alkaloid weight of the composition. 
         [0005]    In another aspect, a kit for refilling an inhaler comprises (i) an alkaloid composition comprising at least about 25 wt. % anatabine based on the total alkaloid weight of the composition, and (ii) instructions for filling the alkaloid composition into a receptacle of an inhaler. 
         [0006]    In another aspect, a method of refilling an inhaler includes the steps of (i) providing an alkaloid composition comprising at least about 25 wt. % anatabine based on the total alkaloid weight of the composition, and (ii) filling the alkaloid composition into a receptacle of an inhaler. 
         [0007]    In yet another aspect, an inhaler comprises a cartridge containing an alkaloid composition comprising at least about 25 wt. % anatabine based on the total alkaloid weight of the composition. The inhaler may be of a single-use or disposable type, or may be refillable with alkaloid compositions to facilitate reuse. 
         [0008]    The alkaloid compositions disclosed herein feature different ranges of alkaloids (e.g., as compared to alkaloid ranges found in tobacco) to provide an attractive alternative to conventional nicotine inhalers, in which nicotine typically makes up about 90 to 100 wt. % of the total alkaloid content. The disclosed alkaloid compositions are particularly characterized by a significant quantity of anatabine, which has lower toxicity and risk of abuse as compared to other alkaloids such as nicotine. The alkaloid compositions described herein enable individuals to experience the pleasure-enhancing attributes of conventional cigarette smoking, while avoiding exposure to combusted materials and other potentially hazardous components present in tobacco. As a result, individuals may be more likely to quit conventional cigarette smoking. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0009]    A more complete understanding of the present invention and certain advantages thereof may be acquired by referring to the following detailed description in consideration with the accompanying drawings, in which: 
           [0010]      FIG. 1  is a schematic illustration of an inhaler in accordance with one embodiment. 
           [0011]      FIG. 2  is a sectional view of the drum of the inhaler shown in  FIG. 1  used to hold the alkaloid composition. 
           [0012]      FIG. 3  is a schematic illustration of an inhaler in accordance with another embodiment. 
           [0013]      FIG. 4  shows that administration of single doses of anatabine dose-dependently decreased nicotine self-administration. 
           [0014]      FIG. 5  shows the nicotine dose-effect curve in monkeys under the same conditions as in  FIG. 4 . 
           [0015]      FIG. 6  shows the effects of anatabine on nicotine self-administration by rats. 
       
    
    
     DETAILED DESCRIPTION 
       [0016]    Tobacco is among the most chemically complex substances known, with tobacco and tobacco smoke containing more than 8,000 compounds. In addition to nicotine, tobacco contains the minor alkaloids nornicotine, anabasine, and anatabine. While nicotine is regarded as the principal addictive component in tobacco, a variety of other factors also are believed to contribute to tobacco addiction. For example, tobacco smoke has been reported to have a monoamine oxidase (MAO) inhibitory effect. MAO is an enzyme involved in the breakdown of dopamine, a pleasure-enhancing neurotransmitter. See J. S. Fowler et al., “Inhibition of Monoamine Oxidase B in the Brain of Smokers,” Nature (Lond), 379(6567):733 736 (1996); J. Stephenson, “Clues Found to Tobacco Addiction,” Journal of the American Medical Association, 275(16): 1217-1218 (1996). See also Williams et al. U.S. Pat. No. 6,350,479. 
         [0017]    Aspects of the present invention are directed to alkaloid compositions for inhalers which are designed to provide different ranges of alkaloids to more effectively achieve the pleasure-enhancing effects that smokers obtain through smoking traditional cigarettes, while avoiding or reducing exposure to nicotine. In one embodiment, the alkaloid composition comprises at least about 25 wt. % anatabine based on the total alkaloid weight. In some examples, anatabine is the sole alkaloid present in the composition, e.g., anatabine comprises 100 wt. % of the total alkaloid weight. In other examples, up to about 75 wt. % of one or more other alkaloids, such as nicotine, nornicotine, and/or anabasine, may be present in addition to anatabine. For example, anatabine and nicotine may be combined in a weight ratio (anatabine-to-nicotine) of about 50:1 to about 1:3, or from about 25:1 to about 1:2, from about 10:1 to about 3:2, or from about 5:1 to about 1:1. 
         [0018]    Unless otherwise clear from context, all percentages referred to herein are expressed as percent by weight based on the total weight of the composition. 
         [0019]    Anatabine may be prepared synthetically, such as via a benzophenoneimine pathway as described in commonly-owned U.S. Pat. No. 8,207,346 B1, the disclosure of which is incorporated herein by reference in its entirety. Anatabine may be present in the form of a racemic mixture or as isolated enantiomer, e.g., R-(+)-anatabine or S-(−)-anatabine, and/or as one or more pharmaceutically acceptable (or food grade) salts of anatabine. Unless otherwise clear from context, “anatabine” as used herein refers to racemic mixtures of anatabine, enantiomers of anatabine, salt and non-salt forms of anatabine, as well as salt and non-salt forms of anatabine enantiomers. Non-limiting examples of possible salts are described in P. H. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002, including salts of 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (−L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (−L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid. 
         [0020]    As an alternative to synthetic preparation, anatabine may be obtained by extraction from tobacco or other plants, such as members of the Solanaceae family, such as datura, mandrake, belladonna, capsicum, potato, tomato, nicotiana, eggplant, and petunia. A tobacco extract may be prepared from cured tobacco stems, lamina, or both. Flue (bright) varieties of tobacco are often used, i.e., Virginia flue. Other tobacco varieties may be used, such as Burley, dark-fired, and/or other commercial tobacco varieties. Two or more tobacco varieties may be combined to form a blend. In the extraction process, cured tobacco material is extracted with a solvent, typically water, ethanol, steam, or carbon dioxide. The resulting solution contains the soluble components of the tobacco, including alkaloids such as anatabine. Anatabine may be purified using known techniques such as liquid chromatography. 
         [0021]    The amount of anatabine present in the composition may vary depending on factors such as the type of inhaler and whether other active components, such as nicotine and/or other alkaloids, are present. By way of example, the amount of anatabine may range from about 0.1 to about 25 mg, from about 0.5 to about 20 mg, or from about 1 to about 10 mg, per total gram of the composition. 
         [0022]    As described in commonly-owned U.S. Pat. No. 8,241,680 B1 to Williams et al., compositions containing anatabine were found to be efficacious for the temporary reduction of tobacco cravings, even without the presence of nicotine. Anatabine and other minor alkaloids also have been reported to bind to nicotinic receptors. See “Receptors for Nicotine in the Central Nervous System: 1 Radioligand Binding Studies,” Group Research &amp; Development Centre, British-American Tobacco Co. Ltd. (1984). 
         [0023]    In addition to anatabine, the composition may contain up to about 75 wt. % of one or more other alkaloids, such as nicotine, nornicotine, and/or anabasine, based on the total alkaloid weight. Such alkaloids may be extracted from tobacco or other plant materials and purified using known techniques, and/or prepared synthetically using known synthesis methods. Anatabine and additional alkaloid(s), such as nicotine, may be combined in a weight ratio (anatabine-to-total other alkaloids) of about 50:1 to about 1:3, or from about 25:1 to about 1:2, from about 10:1 to about 3:2, or from about 5:1 to about 1:1. 
         [0024]    The alkaloid composition most often is provided in a solid, powdered form, although it is contemplated that other forms such as liquids may be used depending on the structure and operation of the particular inhaler used. Micronized dry powder used in inhalers typically is produced with an original particle range of about 1-10 microns. An individual dose may include, for example, from about 5 mg to about 20 mg of powder. The active agent(s) may be combined with one or more excipient carriers, non-limiting examples of which include lactose, trehalose, and mannitol. If desired, one or more flavorants may be added to the composition, non-limiting examples of which include peppermint, menthol, wintergreen, spearmint, propolis, eucalyptus, cinnamon, natural or artificial tobacco flavors, or the like. The total amount of flavorants and/or other additives typically ranges from about 0.5 to about 15 wt. %, often from about 1 to about 10 wt. %, based on the total weight of the composition. 
         [0025]    The inhaler may be of various types of configurations, the details of which form no part of the present invention. In general, inhalers may be of a single-use or disposable type, or may be refillable with alkaloid compositions and/or cartridges containing alkaloid compositions to facilitate reuse. One example of an inhaler is shown in  FIG. 1 . The inhaler  30  of this embodiment has a high pressure chamber  32  coupled to an equalization chamber  34 . The high pressure chamber  32  contains a compressed mixture  52  of helium and oxygen. The chamber  32  has a resealable, refilling opening  31 . The high pressure chamber  32  includes a housing  36  defining a third chamber  38 . The housing  36  includes an opening  40  on a top portion thereof and a gas passage  42  on a side. The third chamber  38  communicates with both the high pressure chamber  32  and the equalization chamber  34 . A consistent volume of gas is produced with the help of a diaphragm plate  56 . 
         [0026]    The equalization chamber  34  includes a housing  58  having a gasket  46  disposed therein. The gasket  46  includes a gas passage  48  on a side thereof for allowing gas disposed in the third chamber  38  to communicate with the second chamber  34 . A piston  44  is slidably mounted within the gasket  46  and within the housing  36 . The piston  44  includes a communication opening  50 . The piston  44  is pushed downwards with a spring  60  located inside chamber  38  to allow gas communication between chambers  32  and  34 . When the canister  32  is separated from the inhaler, the spring  60  is pushing the piston  44  sealing the canister by closing the opening  42 . When the canister is inserted in the inhaler, the tip of the piston  44  will rest on the diaphragm  56 , and pushing the piston  44  up inside chamber  38  just so that high-pressure gas passage  42  is communicating with the communication opening  50 . The communication opening  50  is designed to selectively allow gas  52  stored in high pressure chamber  32  to communicate with gas stored in the equalization chamber  34 . A pressure plate  56  is also disposed within housing  58 . One side of pressure plate  56  is coupled to piston  44 . 
         [0027]    Through the use of high pressure chamber  32  and equalization chamber  34 , inhaler  30  produces a desired gas pressure without requiring an external pump. When the pressure inside the equalization chamber  34  is too low to allow inhaler  30  to be used, high-pressure gas  52  from the high pressure chamber  32  fills into equalization chamber  34 . A spring  60  and pressure plate  56  are designed to facilitate this operation. The piston  44  has a communication opening  50  which selectively allows high pressure chamber  32  to communicate with equalization chamber  34  through gas passages  42  and  48 . 
         [0028]    The gas  52  applies pressure against a small area defined by the top of piston  44 . The net force applied by the high-pressure side of high pressure chamber  32  on the piston  44  works with the biasing force of spring  60  and against the force applied by gas  54  on pressure plate  56 . The spring constant of spring  60  and the surface area of pressure plate  56  are chosen so that when equalization chamber  34  has received sufficient pressure to utilize inhaler  30 , the force applied by the gas on pressure plate  56  will exceed that of the force produced by the gas  52  on piston  44  on the high-pressure side of the device and the force of the spring  60 . At such a time, the force applied by the gas will cause piston  44  to move upward within housings  58  and  36 . As piston  44  moves upwardly, communication opening  50  will move away from gas passage  48 , effectively stopping any additional high-pressure gas  52  from entering equalization chamber  34 . 
         [0029]    Once the gas is dispensed, the pressure exerted by the gas on pressure plate  56  is lower and the high-pressure gas  52  along with the spring  60  will force piston  44  downwardly thereby repeating the cycle described above until equalization chamber  34  once again has a desired pressure of gas therein. 
         [0030]    One alternative to this delivery system employs mechanical actuation by the user. As the high-pressure chamber  32  is depressed, the piston  44  allows the gas to escape from the high-pressure gas passage  42  and be stored into a secondary chamber. The amount of gas released into equilibrium chamber  34  is then defined by the volume of this secondary chamber. The gas is released from this chamber into the equilibration chamber  34  when the high-pressure cylinder  32  is returned to its original position. 
         [0031]    An activating trigger  94  is disposed on a drum section  64 . An inhalation port door  98  coupled to a mouth piece  99  of a spacer  96  closes to inhibit a user from inhaling the gas disposed within spacer  96 . The spacer  96  may also have a scented receptacle  110  near to where a patient&#39;s nose would be. The air in the spacer  96  is purged through a pressure port  100 . 
         [0032]    As the user inhales the dosage, a vacuum begins to form in spacer  96 . At a certain pressure, vacuum/pressure valve  104  opens, allowing ambient air into the spacer  96 . By opening vacuum/pressure valve  104 , the user may continue a steady deep inhalation of ambient air following inhalation of the dosage. 
         [0033]    Upon actuation of the inhaler  30 , the gas is injected into a gas passage  62  of a drum section  64 . The drum section  64  includes a housing  65  that contains a rotating drum which includes a plurality of tubes  68  that are substantially cylindrical and extend longitudinally therethrough. The tubes  68  contain the powdered alkaloid composition  76 . 
         [0034]    As shown in  FIG. 2 , a disposable multi-dose drum  66  may include hollow tubes  70  which have a diameter that is larger than the diameter of tubes  68 . The diameter of each tube  68  is dependent on the volume and weight of dry powder to be delivered. Both tubes  68  and  70  may be packed within the rotating drum  66  so as to maximize the amount of doses available per rotating drum. For each tube  68 , there is a corresponding hollow tube  70 . One arrangement is for the powder-filled tubes  68  and hollow tubes  70  to be arranged in pairs vertical to each other. The drum  66  may be placed on spindle (not illustrated) which is inserted into a bore  72  such that the drum  66  is coaxial with the spindle. A clear sealed plastic overlay  86  may be disposed on the front and rear surfaces of the drum  66  to cover the tubes  68 . 
         [0035]    A diffuser  112  includes an impact ball  114  at a portion that is proximate to the gas passage. The impact ball  114  is used to reduce the initial high velocity of highly turbulent gas and drug that enters diffuser  112 . When gas and the alkaloid composition is injected into the diffuser  112 , a high-energy flow may concentrate in the center of the unit. The impact ball  114  helps avoid this channeling effect. The diffuser  112  is shaped as an expansion cone to slow down the gas-powder mixture. The spacer  96  may be combined with the diffuser  112  so that the large particles can drop out of particle cloud in the spacer  96 . Other details of this type of inhaler and variations thereof are described in U.S. Pat. No. 7,461,649 to Gamard et al., the disclosure of which is hereby incorporated by reference in its entirety. 
         [0036]    Another, non-limiting example of an inhaler that may be used is shown in  FIG. 3 . The inhaler of this embodiment is a one-piece tube  10  of generally uniform wall thickness. The tube  10  may be extruded, molded or fabricated out of flat stock such as a thermoplastic material having suitable gas barrier properties, and then rolled and sealed into a formed tube. The tube should be impermeable to the active agent(s). The tube  10  may have, for example, a wall thickness of about 0.002″ to about 0.020″. The tube  10  may be formed in a circular (as shown) or noncircular cross-section. The extruded tube may be cut into lengths between about 1″ to 5″ to resemble the length of conventional cigarettes. A plurality (e.g., 20) of the cut tubes may be provided in a pack (not illustrated) similar to a conventional cigarette pack. 
         [0037]    Once cut, the tube  10  is loaded with ingredients comprising the volatile delivery system. An absorbent material  12  compatible with the volatile agent(s) may be inserted into the tube  10  for delivery to the user. The absorbent material  12  can be in the form of a plug, strips, or the like. A liquid alkaloid composition (e.g., anatabine in an organic solvent) may be loaded into the tube  10  via spray or direct injection. The alkaloid composition may be loaded into the tube in a gaseous atmosphere, such as nitrogen or other gas, conducive to preserving the alkaloid(s). The tube  10  then may be pinched closed at the two open ends  16  and heat-sealed according to well known techniques. The heat seal affected at the two ends  16  prevents ambient air from entering the tube  10  or the ingredients within the tube from escaping to the atmosphere. Other details of this type of inhaler are shown in U.S. Pat. No. 6,769,436 to Horian, the disclosure of which is hereby incorporated by reference in its entirety. 
         [0038]    By providing a balanced alkaloid composition containing anatabine as a significant alkaloid component, it is possible to prepare inhalers that reduce cravings for traditional tobacco smoking, while minimizing toxicity and other undesirable side effects associated with nicotine and other tobacco components. The inhaler may be used as needed to satisfy cravings, or at intervals such as once daily, twice daily, or three or more times daily, depending on such factors as the concentration of active components and the subject&#39;s physiological conditions. 
       Examples 1-16 
       [0039]    Alkaloid compositions for inhalers may be prepared by combining the components listed in Tables 1 and 2 below. Powdered compositions (Table 1) may be prepared by blending the alkaloid(s), excipient carriers, and flavors. Liquid compositions (Table 2) may be prepared by blending the alkaloid(s), solvents, water, and flavors. Anatabine may be prepared synthetically as described in Examples 1-3 of commonly-owned U.S. Pat. No. 8,207,346 B1. Nicotine, anabasine, and nornicotine may be extracted from tobacco materials and purified using known techniques. 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                   
                 TABLE 1 
               
             
             
               
                   
                   
               
               
                   
                 Example 
               
             
          
           
               
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
               
               
                   
                   
               
             
          
           
               
                 Anatabine (mg) 
                 10 
                 8 
                 4 
                 6 
                 7 
                 12 
                 8 
                 6 
               
               
                 Nicotine (mg) 
                 — 
                 4 
                 8 
                 4 
                 5 
                 6 
                 — 
                 4 
               
               
                 Nornicotine (mg) 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 4 
                 2 
               
               
                 Anabasine (mg) 
                 — 
                 — 
                 — 
                 3 
                 1 
                 1 
                 — 
                 2 
               
               
                 Mannitol (mg) 
                 10 
                 10 
                 10 
                 10 
                 10 
                 10 
                 10 
                 10 
               
               
                 Flavors (g) 
                 1 
                 1.25 
                 1.5 
                 1 
                 1 
                 1.5 
                 0.75 
                 1.25 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                   
                 TABLE 2 
               
             
             
               
                   
                   
               
               
                   
                 Example 
               
             
          
           
               
                   
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
               
               
                   
                   
               
             
          
           
               
                 Anatabine (mg) 
                 10 
                 8 
                 4 
                 6 
                 7 
                 12 
                 8 
                 6 
               
               
                 Nicotine (mg) 
                 — 
                 4 
                 8 
                 4 
                 5 
                 6 
                 — 
                 4 
               
               
                 Nornicotine 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 4 
                 2 
               
               
                 (mg) 
               
               
                 Anabasine 
                 — 
                 — 
                 — 
                 3 
                 1 
                 1 
                 — 
                 2 
               
               
                 (mg) 
               
               
                 Polyethylene 
                 91 
                 90 
                 92 
                 93 
                 92 
                 94 
                 91 
                 90 
               
               
                 Glycol (g) 
               
               
                 Ethyl acetate 
                 0.5 
                 0.5 
                 — 
                 0.5 
                 0.4 
                 0.5 
                 — 
                 0.4 
               
               
                 (g) 
               
               
                 Water (g) 
                 4 
                 4.5 
                 3.5 
                 4 
                 2.5 
                 3.5 
                 5 
                 4.5 
               
               
                 Flavors (g) 
                 1 
                 1.25 
                 1.5 
                 1 
                 1 
                 1.5 
                 0.75 
                 1.25 
               
               
                   
               
             
          
         
       
     
         [0040]    The compositions described in Examples 1-16 may be filled into refilling cartridges for inhalers, or filled into a container that is used as part of a kit for refilling receptacles in inhalers. The compositions alternatively may be filled into a single-use or disposable type of inhaler. 
       Example 17 
       [0041]    This example describes a medication-based treatment of nicotine addiction in a nonhuman primate model of nicotine self-administration. The acute effects of anatabine (0.18-3.2 mg/kg, IM) or saline on nicotine- and food-maintained responding were examined in seven rhesus monkeys. Nicotine (0.01 mg/kg/inj, base) and banana-flavored food pellets (1 g) were available under a second-order schedule (FR 2 [VR 16:S]). Anatabine or saline injections were administered 15 min. before the mid-day food self-administration session began. Saline control treatment was in effect after administration of each anatabine dose. 
         [0042]    Seven adult rhesus monkeys ( Macaca Mulatta ) were trained to self-administer nicotine (0.01 mg/kg/inj [base]) and 1 g banana-flavored food pellets on a second-order schedule of reinforcement (FR 2 [VR 16:S]). Food was available during three 1-hour sessions each day (7 AM, 3 PM and 7 PM). A test session began at 11:00 AM and consisted of a 30 min food session and a 90 min nicotine session. A second nicotine session began immediately following the food session at 3 PM. 
         [0043]    A time-out period during which responding had no scheduled consequences followed each food and nicotine self-administration session. Nicotine injections were not limited during the 90 min test session, but were limited to 20 during the one-hour session. Food pellets were limited to 25 per session or 100 per day. The sequence of food and nicotine sessions is shown in the diagram. At the time of these studies, monkeys were nicotine-experienced and had at least five months of nicotine exposure. 
         [0044]    During test sessions, a single dose of anatabine (0.18-3.2 mg/kg, IM) or saline control treatment was given 15 min before the mid-day food self-administration session began. Following each dose of anatabine or saline, monkeys returned to stable baseline levels of nicotine- and food-maintained responding before the next treatment dose was administered. This control is essential to avoid confounding effects of the previous medication dose and to establish that catheter malfunction did not account for any decreases in nicotine self-administration. 
         [0045]    Systematic assessments to monitor any changes in behavior (e.g., sedation or agitation) were conducted after each saline or anatabine test session (Kato and Yanagita, 1981). Nicotine and anatabine solutions were prepared in sterile saline or cyclodextrin and filter-sterilized using a 0.22 μm Millipore filter. Nicotine hydrogen tartrate was buffered with NaOH to achieve a pH of 6-7. Nicotine doses are expressed as the base. 
         [0046]    During saline control treatment monkeys earned an average of 20.37±2.45 nicotine injections (0.01 mg/kg/inj) and 25 food pellets during the nicotine and food test sessions conducted at midday. Administration of single doses of anatabine (0.18-3.2 mg/kg, IM) dose-dependently decreased nicotine self-administration at the training dose (0.01 mg/kg/inj [base]) ( FIG. 4 ). Decreases in nicotine-maintained responding were significantly different from baseline at anatabine doses of 1.8 and 3.2 mg/kg, IM (P&lt;0.005-0.02). Food-maintained responding also decreased as a function of increasing doses of anatabine but these changes were not statistically significant. 
         [0047]    Subsequently, the nicotine dose-effect curve (0.001-0.1 mg/kg/inj) was determined under the same conditions in 7 monkeys ( FIG. 5 ). The peak of the dose effect curve was at 0.0032 mg/kg/inj. Increasing doses of nicotine did not change food-maintained responding. Data for two monkeys suggest that a moderate dose of anatabine (0.32 mg/kg) shifts the peak of the dose-effect curve to the right. A higher dose of anatabine (1.0 mg/kg) flattened the dose-effect curve. Food-maintained responding also decreased at the peak reinforcing doses of nicotine (0.0032 and 0.01 mg/kg/inj) and there was considerable variability across animals. 
         [0048]    Anatabine was found to dose-dependently reduced nicotine self-administration (P&lt;0.005-0.02) with no significant effects on food-maintained responding. Systematic behavioral assessments following each treatment session revealed no evidence of sedation or agitation that could disrupt operant responding. Each monkey returned to baseline levels of nicotine self-administration before administration of the next dose of anatabine, so catheter malfunction could not account for the significant decreases in nicotine self-administration observed. These findings in rhesus monkey are consistent with anatabine&#39;s effects on nicotine self-administration in rats (Caine et al., 2013). Anatabine (1.8-5.6 mg/kg) significantly reduced nicotine-maintained responding at doses of 0.003 and 0.01 mg/kg/inj (P&lt;0.5-0.001) and flattened the nicotine dose-effect curve. 
         [0049]      FIG. 6  shows similar effects of anatabine on nicotine self-administration by rats. Anatabine (1.8 and 3.2 mg/kg, IP) significantly reduced nicotine-maintained responding at peak reinforcing doses of 0.003 and 0.01 mg/kg/inj (P&lt;0.05-0.001). 
       Example 17 
       [0050]    This example describes a study conducted on anatabine along with other common nicotinic alkaloids in rat frontal and hippocampal homogenates. Table 3 shows binding data of anatabine relative to nicotine. 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                 TABLE 3 
               
               
                   
                   
               
               
                   
                   
                 Nicotine Binding 
                 Relative Binding 
               
               
                   
                 Site 
                 Constant 
                 Constants for Anatabine 
               
               
                   
                   
               
             
             
               
                   
                 Frontal cortex 
                 1.0 
                 4.55 (lower potency) 
               
               
                   
                 Hippocampus 
                 1.0 
                 2.67 (lower potency) 
               
               
                   
                   
               
             
          
         
       
     
         [0051]    A study was conducted to evaluate the in vitro effects of anatabine on three cloned human nicotinic acetylcholine receptor (nAChR) channels expressed in mammalian cells using a Fluo-8 calcium kit and a Fluorescence Imaging Plate Reader (FLIPRTETRA™) instrument. In this study, the ability of anatabine racemate to act as an agonist, positive allosteric modulator (PAM), or antagonist of the α3/β4, α4/β2 and α7 nAChR channels was tested. Nicotine (−) isomer was included as a comparator, and the endogenous neurotransmitter acetylcholine was included as a positive control. 
         [0052]    The results showed that anatabine functioned as an agonist at all three nAChR channels tested, but showed no antagonist or PAM effects at any of the receptor subtypes. In the agonist assay, the maximum level of stimulation for the α4β2 receptor was similar for anatabine and nicotine, indicating that anatabine acted as a full agonist at this receptor. However, the EC50 for anatabine&#39;s agonist effects at the nAChR α4β2 receptor was approximately 200-fold less potent than nicotine (282 μM and 1.302 μM for anatabine and nicotine, respectively). For the α3β4 channel, the EC50 of nicotine was determined to be 9.37 μM and that of anatabine was 14.58 μM. The maximal response of the channel to nicotine approached that of ACh indicating that nicotine is a full agonist of the α3β4 receptor, as expected. However, the maximal response to anatabine was about 5-fold lower than that of ACh indicating that anatabine is a partial agonist of this receptor. For the α7 assay, nicotine and anatabine were both potent agonists, and the EC50&#39;s were calculated to be approximately 0.008 μM for each compound. The maximum level of activation for both nicotine and activation was also similar (and similar to ACh), suggesting that anatabine and nicotine are full, potent agonists of the α7 nAChR. 
         [0053]    To summarize, the results of this study showed that anatabine is an agonist of all three nAChR channels tested, but with different characteristics at each subtype, and with some significant differences relative to nicotine. Although anatabine was a full agonist at the α4β2 receptor, it was much less potent than nicotine or ACh. Anatabine showed partial agonist activity towards the α3β4 receptor, and was only slightly less potent than nicotine. Finally, anatabine showed full agonist activity at the α7 nAChR channel, with similar potency as nicotine. 
         [0054]    These data indicate that anatabine may activate α4β2 receptors, but very high concentrations beyond any recommended or tolerated doses are likely needed to produce significant agonist effects. This suggestion is supported by behavioral data which showed that rodents trained to self-administer nicotine do not find anatabine to be rewarding, and that anatabine administration does not reverse precipitated nicotine withdrawal. Nicotine is the prototypic full α4β2 agonist, and its higher potency at this receptor is likely at least partially responsible for the reinforcing and dependence-producing effects of tobacco products. Conversely, anatabine was shown to be a full and highly potent agonist at the α7 receptor, suggesting that this may be one mechanism by which anatabine exerts anti-inflammatory effects such as those that have been observed in both in vitro and in vivo studies. Although it is not selective for the α7 receptor, the findings from this study suggest that anatabine&#39;s activity toward this particular nAChR subtype is similar to nicotine, and provide evidence that this may be one pathway through which anatabine&#39;s immuno-modulatory effects are mediated. 
         [0055]    While the invention has been described with respect to specific examples, those skilled in the art will appreciate that there are numerous variations and permutations of the above described systems and techniques that fall within the spirit and scope of the invention as set forth in the appended claims.