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US006503950B1

12 United States Patent 10 Patent N0.: US 6 9 503 9 950 B1 Ockert (45) Date of Patent: Jan. 7, 2003

(54) TRIPLE DRUG THERAPY FOR THE 5,855,908 A 1/1999 Stanley et a1...... 424/440 TREATMENT OF NARCOTIC AND ALCOHOL WITHDRAWAL SYMPTOMS OTHER PUBLICATIONS Stedman’s Medical Dictionary. 25* Ed., 1990, pp. 745, (76) Inventor: David M. Ockert, 145 E. 32nd St., 851* Sixth F100r> New York NY (Us) 10016 Mondavio et al. As A Preventative Treatment Of * _ _ _ _ _ Alcohol Withdrawal, Nov. 1, 1989, Minerva Medica, vol. ( ) Notice: SubJect to any disclaimer, the term of this 80, pp 1233_1235_* Patent 15 extended or adlusted under 35 Guthrie S. K., The treatment of alcohol Withdrawal, Phar U-S-C- 154(b) by 0 days- macotherapy, 1989, 9th Ed., vol. 3, pp. 131—143. AN 1989—36764.* (21) Appl- NO-I 09/634,555 Riley et al., Drug Facts and Comparisions, 1999, pp. 232f . _ and 261g.* (22) Flled' Aug' 8’ 2000 Schmidt et al., antihypertensive agents, Harper’s Handbook - - f Thera eutic Pharmacolo 1981 . 227* Related US. Application Data 0 p _ _ gy’ ’ p _ (60) Provisional application NO‘ 60/150,249’ ?led on Aug‘ 23’ Laffont F., Clmrcal assessment of moda?ml, Drugs Today, 1999 1996, vol. 32, pp. 35—44. AN 1997:75024.* (51) Int. Cl.7 ...... A61K 31/165; A61K 31/5513; * Cited by examiner A61K 31/4168; A61K 31/155; A61K 31/195; . . A61K 31/192; A61K 31/438; A61K 31/495; ' 3722mm A61K 31/522; A61K 31/4458; A61K 31/137; . g y . 1d A61K 31/421 l()74‘)vAttgcrify, Agent, or Fzrm—Pr1ce, Heneve , Cooper, It It (52) US. Cl...... 514/618; 514/221; 514/401; 6 1 1 on 514/617; 514/567; 514/811; 514/634; 514/278; (57) ABSTRACT 514/225.04; 514/263; 514/317; 514/654; _ _ _ _ _ 514/376; 514/377; 514/653 A triple drug, pharmaceutical kit, composition, and method (58) Field of Search 514/618 392 of treatment containing a combination of effective amounts 514 401’ 617’ of at least one anXiolytic agent, at least one centrally acting 567 634 27’8 22’5 04’ 263’ 317’ 376’ 377’ alpha antiadrenergic agent, and at least one central nervous ’ ’ ’ ' ’ ’ 653, 454/464; system stimulant for the reduction or prevention of alcohol ’ and narcotic Withdrawal side effects of dizziness, (56) References Cited drowsiness, depression, lethargy, orthostatic hypotension, Weakness in the extremities, and difficulty in being mobile, US. PATENT DOCUMENTS caused by therapeutic agents utilized for the treatment of 4 829 070 A 5/1989 Bodor 514607 alcohol or narcotic Withdrawal symptoms in patients over 5:288:497 A 2/1994 Stanley et al...... 424/440 Coming alcohol or narcotic addiction 5,474,783 A 12/1995 Miranda et al. 424/448 5,668,117 A 9/1997 Shapiro ...... 514/55 63 Claims, 1 Drawing Sheet

CENTRAL AND PERIPHERAL ANXIETY NERVE AGITATIUN

GENTRALLY ACTING ALPIHA ANTI ANXIULYTIC AGENT AGENT

DRUWSINESSILETHARGYIDIZZINESSI URTHOSTATIC HYPUTENSIUN DEPRESSIUNIWEAKNESS IN THE EXTREMITIESIDIFFICULTY BEING MOBILE ____.___K / CENTRAL NERVOUS SYSTEM STIMULANT AGENT U.S. Patent Jan. 7, 2003 US 6,503,950 B1

CENTRAL AND PERIPHERAL ANXIETY NERVE AGITATIUN

CENTRALLY ACTING ALPIHA ANTI- ANXIULYTIC AGENT ADRENERGIC AGENT

DRUWSINESSILETHARGYIDIZZINESSI URTHUSTATIC HYPDTENSIUN DEPRESSIONIWEAKNESS IN THE EXTREMITIESIDIFFICULTY BEING MOBILE

CENTRAL NERVOUS SYSTEM STIMULANT AGENT

FIG. I US 6,503,950 B1 1 2 TRIPLE DRUG THERAPY FOR THE mobile occurs. Drug Facts and Comparisons. 1999 ed., TREATMENT OF NARCOTIC AND 1998, p. 967—68, 1444—45. This further exacerbates the need ALCOHOL WITHDRAWAL SYMPTOMS for in-patient care due to the increased risk of injury to patients and liability to healthcare personnel treating such The present application claims priority to Provisional patients. Application Serial No. 60/150,249 ?led on Aug. 23, 1999. US. Pat. No. 5,668,117 to Shapiro, discloses a method of treating neurological diseases and etiology by utiliZing BACKGROUND OF THE INVENTION carbonyl-trapping agents in combination With previously 1. Field of the Invention knoWn medicaments. Shapiro discloses the ability of com The present invention relates to the treatment of alcohol 10 bining a carbonyl-trapping agent With either a benZodiaZ and narcotic WithdraWal symptoms associated With alcohol epine or a centrally acting alpha antiadrenergic agent. and narcotic addiction. Prior art US. Pat. No. 4,829,070 to Boder, discloses the 2. Description of the Related Art/Background Information use of a redox carrier system for the site-speci?c delivery of a centrally acting therapeutic agent to the brain. Boder Alcohol and narcotic WithdraWal symptoms associated 15 With patient populations undergoing drug abuse treatment discloses the ability of attaching a centrally acting alpha has become an important concern to those patients and their antiadrenergic agent or benZodiaZepine to the redox carrier families as Well as treating health care personnel. Due to system and delivering those agents to the brain. alcohol and narcotic abuse, use, and the high rate of relapse US. Pat. No. 5,855,908 to Stanley, discloses a non dissolvable dosage form for use in the transdermal delivery to regular use, the management of WithdraWal side effects is 20 becoming increasingly important for the long-term rehabili of a drug to a patient Which includes clonidine or a benZo tation of patients overcoming drug abuse addiction. Current diaZepine agent, such as loraZepam, to be carried by such a treatment modalities for drug abuse can create or potentiate transdermal system. side effects from those medications used to treat alcohol or US. Pat. No. 5,474,783 to Miranda, discloses a pressure sensitive adhesive transdermal drug delivery system Which narcotic WithdraWal. Frequently encountered side effects 25 include depression, diZZiness, orthostatic hypotension, includes an adhesive carrier that holds a therapeutic agent droWsiness, lethargy, dif?culty in being mobile, and Weak such as a centrally acting alpha antiadrenergic agent or ness in the extremities. Such negative side effects prolong anxiolytic agent, or central nervous system stimulant agent patient therapy or interfere With detoxi?cation procedures, to be delivered to the human body. Which leads to further use, abuse, and relapses to regular use, 30 Prior art clinical addiction treatment literature includes requiring subsequent detoxi?cation. treatment episodes. many descriptions of patients having an incipient form of a The prior art teaches the use of benZodiaZepines sepa disease, such as alcohol or narcotic addiction, Who shoW the rately for the treatment of anxiety caused by a variety of recogniZed symptoms of the disease, such as WithdraWal. It conditions, including WithdraWal. For example, the drug should be understood by those skilled in the art that a monograph for benZodiaZepines listed Within the Drug Facts 35 narcotic is a drug that dulls the senses, relieves pain, and and Comparisons, 1999 ed., Wolters KulWar Co. 1998, p. produces sleep, such as an opiate or benZodiaZepine. Treat 1600—03, indicates that such agents, through interaction With ment options for side effects associated With conventional gamma-aminobutyrate (GABA) and BZ1 and BZ2 receptors drug therapies used to treat the established clinical With in the human body, create a calming effect and subsequent draWal side effects of alcohol and narcotic addiction have reduction or prevention of anxiety. The prior art also teaches 40 not been reported. the use of aZaspirodecanediones, such as , as an Prior art clinical neurology literature includes many anxiolytic agent, because of their calming effect caused by descriptions of patients having increased droWsiness, interaction With 5-HT1A and GABA receptors in the human diZZiness, depression, Weakness in the extremities, lethargy, body. Id. Finally, the prior art also teaches the use of orthostatic hypotension, and dif?culty in being mobile asso derivatives, such as , to create a 45 ciated With treatments utiliZing anxiolytic agents and cen calming effect in the human body through interaction With trally acting alpha antiadrenergic agents for the reduction or spasmogenic receptors for serotonin, acetylcholine and his prevention of alcohol or narcotic WithdraWal symptoms such tamine. Id. at 1604—07. Yet, all these anxiolytic agents, due as anxiety, central and peripheral nerve agitation, and hyper to their drug chemistry, cause the side effects of droWsiness, tension associated With alcohol and narcotic addiction. depression, lethargy, and difficulty in being mobile in Dunagan, W. and Ridner, M., Manual of Medical patients undergoing drug abuse treatment. Such negative Therapeutics, 26th ed., Boston, Little, BroWn, 1989, p. 6—7, side effects frequently increase the need to treat such patients 474—75. Clinical cardiology literature in the prior art in an in-patient only setting to prevent the risk of injury. includes many descriptions of patients experiencing ortho The individual use of centrally acting alpha antiadrenergic static hypotension and other side effects associated With agents to reduce central and peripheral nerve agitation and 55 centrally acting alpha antiadrenergic agents utiliZed to treat increased blood pressure associated With narcotic and alco and central and peripheral nerve agitation hol WithdraWal has been taught by the prior art. The use of experienced during alcohol or narcotic WithdraWal manage such agents can decrease central and peripheral nerve ment. Woodley, M. and Whalen A., Manual of Medical agitation, yet, frequently cause depression, diZZiness, Therapeutics, 27th ed., Boston, Little, BroWn, 1992, p. droWsiness, lethargy, orthostatic hypotension, and Weakness 60 64—75. in the extremities. Drug Facts and Comparisons. 1999 ed., Due to the lack of clinical literature and study of With 1998, p. 967—68, 1444—45. In addition, When a centrally draWal side effect management, such as depression, acting alpha antiadrenergic agent, such as clonidine, is diZZiness, droWsiness, Weakness in the extremities, lethargy, added to an existing drug treatment regimen, already con orthostatic hypotension, and dif?culty in being mobile asso taining an anxiolytic agent, an additive effect for diZZiness, 65 ciated With the use of centrally acting alpha antiadrenergic droWsiness, depression, lethargy, Weakness in the agents and anxiolytic agents, many patients do not initiate or extremities, orthostatic hypotension, and dif?culty in being continue an alcohol or narcotic abuse treatment program. US 6,503,950 B1 3 4 Further, due to the increased orthostatic hypotension asso extremities, lethargy, orthostatic hypotension, and difficulty ciated With the use of centrally acting alpha antiadrenergic in being mobile associated With therapeutic agents utiliZed agents, an increased risk of syncope and injurious fall to to treat alcohol and narcotic WithdraWal symptoms of alco patients undergoing abuse treatment has been frequently hol and narcotic addiction. observed. This increased risk further prompts the need to The anxiolytic agent utiliZed in the preferred embodiment treat such patients in an in-patient only setting to decrease consists essentially of an effective amount of a the risk of liability for health care personnel providing benZodiaZepine, aZaspirodecanedione, or piperaZine deriva treatment. Yet, in doing so, healthcare costs are substantially tive. Suitable benZodiaZepine agents include, but are not increased. limited to, diaZepam, alpraZolam, chlordiaZepoxide, 10 clonaZepam, cloraZepate, halaZepam, lorpam, oxaZepam, SUMMARY OF THE INVENTION derivatives thereof, and pharmaceutically acceptable salts thereof. Suitable aZaspirodecanedione agents include, but A pharmaceutical kit, composition, and method of treat are not limited to, buspirone, derivatives thereof, and phar ment regimen for alcohol and narcotic WithdraWal side maceutically acceptable salts thereof. Suitable piperaZine effects of therapeutic agents used to treat alcohol or narcotic derivatives include, but are not limited to, hydroxyZine 15 WithdraWal symptoms has been discovered, utiliZing a cen pamoate and hydroxyZine hydrochloride, derivatives trally acting alpha antiadrenergic agent, a central nervous thereof, and pharmaceutically acceptable salts thereof. system stimulant agent (CNS), and an anxiolytic agent in The preferred anxiolytic agent for the management of combination. The present invention reduces or prevents the alcohol WithdraWal symptoms is about 50 to 60 mg of side effects of depression, diZZiness, droWsiness, lethargy, chlordiaZepoxide given to a human being about every 6—8 Weakness in the extremities, difficulty in being mobile, and 20 hours around the clock initially, and gradually tapered by orthostatic hypotension associated With therapeutic agents about 10 mg per day for a period of about 5—14 days to used to treat alcohol and narcotic WithdraWal Without com reduce or prevent the WithdraWal symptom of anxiety and promising the positive clinical effects of those same thera seiZure and to prevent patient addiction to chlordiaZepoxide, peutic agents. as a substitute for alcohol. 25 By reducing or preventing these side effects, the present Those skilled in the art Will appreciate and Will be able to invention also decreases the risk of injury to patients and adjust the dose, dosing interval, and dosing length/treatment liability to healthcare personnel treating such patient popu period of the anxiolytic agent of the preferred embodiment lations. Further, by reducing the risk to patient and health in the treatment of alcohol WithdraWal symptoms, based personnel alike, the present invention increases the oppor 30 upon the clinical response and therapeutic value required to tunity for out-patient treatment settings, Which in turn reduce or prevent WithdraWal anxiety and seiZure for a decreases overall healthcare costs. Finally, by minimizing particular patient undergoing alcohol abuse treatment. One side effects to patients undergoing alcohol or narcotic abuse skilled in the art Will appreciate and be able to adjust the treatments With the present invention, incidences of relapse dose, dosing interval, and length of treatment With the to regular use during a detoxi?cation treatment episode are 35 anxiolytic agent of the preferred embodiment based upon the reduced or prevented. liver and kidney function of the patient and the amount of The present invention can be embodied in a variety of CNS stimulant used Within the preferred embodiment. pharmaceutically acceptable immediate and sustained The preferred anxiolytic agent for the management of release dosage forms and can be delivered to the human narcotic WithdraWal symptoms is about 0.25 to 10 mg of body via a variety of medically and pharmaceutically 40 loraZepam given to a human being about every 4—10 hours, acceptable administration routes. preferably about every 6—10 hours, and most preferably These and other features, advantages and objects of the about every 6—8 hours during the day and about every 3—4 present invention Will be further understood and appreciated hours at night, up to a typical maximum dose of about 10 mg by those skilled in the art by reference to the folloWing per day or greater, most preferably a maximum of about 7 speci?cation, claims and appended draWings. A more 45 mg per day. Total daily dosing Will occur over about 5—14 detailed description of the present invention shall be dis days, With initial doses maximiZing at about 7—10 mg per cussed further beloW. day and tapering thereafter by about 1 mg or greater each day of treatment until dosing is completed Within a period of BRIEF DESCRIPTION OF THE DRAWING about 5—14 days. Those skilled in the art Will appreciate and be able to FIG. 1 is a flow diagram indicating the prevention or adjust the dose, dosing interval, and dosing length/treatment reduction of side effects associated With therapeutic agents period of the anxiolytic agent of the preferred embodiment used to treat alcohol or narcotic WithdraWal symptoms of in the treatment of narcotic WithdraWal symptoms based alcohol and narcotic addiction, through the use of the triple upon the clinical response and therapeutic value required to drug kit, composition, and method of treatment of the 55 reduce or prevent WithdraWal anxiety for a patient, liver and present invention, Without compromising the positive clini kidney function of the patient, and the amount of CNS cal effects of those same therapeutic agents. stimulant used Within the preferred embodiment. As the dose of the CNS stimulant is increased or the DETAILED DESCRIPTION OF THE PRESENT INVENTION interval of dosing is decreased, the anxiolytic agent dose can 60 be decreased and dosing interval increased. In addition, it The preferred embodiment is comprised of a pharmaceu should be understood by those skilled in the art that the dose tical kit, composition, and method of treatment regimen of the CNS stimulant can be increased to achieve therapeutic containing a combination of effective amounts of an anxi efficacy in managing side effect outcomes of the anxiolytic olytic agent, centrally acting alpha antiadrenergic agent, and agent of the preferred embodiment as the dose of the central nervous system (CNS) stimulant agent for the reduc 65 anxiolytic agent is increased to treat the WithdraWal symp tion or prevention of the WithdraWal side effects of tomology of a particular patient undergoing alcohol or droWsiness, diZZiness, depression, Weakness in the narcotic abuse treatment. US 6,503,950 B1 5 6 The centrally acting alpha antiadrenergic agent of the every 12 hours or once daily Without a rescue dose given preferred embodiment consists essentially of an effective during the night, for a total treatment period of about 5—14 amount of , clonidine, , guanabenZ, days. , derivatives thereof, or pharmaceutically accept In an alternative embodiment, for those patients requiring able salts thereof. It is recognized that lofexidine is not a non-amphetamine based central nervous system stimulant currently approved for use in the US. by the FDA, but is agent or those Who cannot receive additional or increased approved for use in Europe. The preferred centrally acting amphetamine doses due to cardiovascular risk concerns, a alpha antiadrenergic agent for treatment of alcohol and centrally acting alpha-1 agonist, such as moda?nil, can be narcotic WithdraWal side effects is about 0.05—0.7 mg of used as a substitute or adjunct for an amphetamine(s), as the clonidine given to a human being about every 6—8 hours for 10 central nervous system stimulant agent of the preferred a period of about 5—14 days. Use of such agents reduces or embodiment. prevents central and peripheral nerve agitation associated Centrally acting alpha-1 agonists such as moda?nil With alcohol and narcotic WithdraWal. Typical maximal (Provigil®) act postsynaptically at alpha-1 adrenergic recep dosages of clonidine can be about 2 mg per day or higher tors and may also bind to carriers to increase stimulation and mental alertness Within the human body depending upon the particular patient response required for 15 the particular detoxi?cation setting, liver and kidney func usually Without altering the body’s blood pressure and heart tion of the patient, and the dose and dosing interval of the rate excessively like that of amphetamines. Further, cen central nervous system stimulant agent of the preferred trally acting alpha-1 agonists do not decrease stage 2 and embodiment during that patient’s alcohol or narcotic abuse REM sleep like amphetamines, and thus offer a treatment treatment course. alternative for the practitioner When choosing a central As the dose of the CNS stimulant is increased or the nervous stimulant agent of the preferred embodiment. dosing interval is decreased, the centrally acting alpha In the alternative embodiment, the preferred central ner antiadrenergic agent dose can be decreased and dosing vous system stimulant agent for the treatment of side effects interval increased. In addition, it should be understood by associated With therapeutic agents used to treat alcohol and those skilled in the art that the dose of the CNS stimulant can 25 narcotic WithdraWal symptomology is about 50—400 mg, be increased to achieve therapeutic efficacy in managing preferably about 100—300 mg, and most preferably about side effect outcomes of the centrally acting alpha antiadr 200 mg or higher per day of moda?nil administered to a energic agent of the preferred embodiment as the dose of the human being every 12 hours, more preferably once daily in centrally acting alpha antiadrenergic agent is increased to the morning, for a period of 5—14 days. treat the WithdraWal symptomology of a particular patient It should be understood by those skilled in the art that the undergoing abuse treatment. Those skilled in the art Will preferred embodiment of the present invention can utiliZe appreciate and Will be able to adjust the dose, dosing any of the central nervous system stimulant agents alone or interval, and dosing length treatment period of the centrally in combination With one another as the central nervous acting alpha antiadrenergic agent of the preferred embodi system stimulant agent component of the preferred embodi ment based upon the factors listed above, to reduce or 35 ment. For example, a practitioner administering the pre prevent central and peripheral nerve agitation for a particular ferred embodiment containing an amphetamine initially as patient undergoing alcohol or narcotic detoxi?cation treat the central nervous system stimulant agent could add ment. moda?nil as an adjunct central nervous system stimulant to The central nervous system stimulant agent of the pre a particular patient’s drug treatment therapy Where use of an ferred embodiment consists essentially of an effective additional amphetamine Would not be desirable and dosing amount of an amphetamine, such as amphetamine sulfate, of the current amphetamine could not be increased due to dextroamphetamine sulfate, methamphetamine blood pressure and heart rate considerations. hydrochloride, combinations of amphetamines, derivatives Those skilled in the art can appreciate and Would be able and pharmaceutically salts thereof; pemoline, derivatives to adjust the dose, dosing interval, and dosing length treat and pharmaceutically acceptable salts thereof; 45 ment period of the central nervous system stimulant of the methylphenidate, derivatives and pharmaceutically accept preferred embodiment based upon the clinical and therapeu able salts thereof; caffeine, derivatives and pharmaceutically tic response desired for a particular patient undergoing acceptable salts thereof; and centrally acting alpha-1 ago alcohol or narcotic abuse treatment, liver and kidney func nists such as moda?nil, epinephrine, , tion of that patient, as Well as drug interactions betWeen the , derivatives thereof and pharmaceutically central nervous system stimulant agent and other compo acceptable salts thereof to reduce or prevent diZZiness, nents of the preferred embodiment. depression, difficulty in being mobile, droWsiness, lethargy, All of the components of the preferred embodiment can Weakness in the extremities, and orthostatic hypotension be used separately, but administered contemporaneously and associated With anxiolytic and centrally acting alpha antia can be given via a singular pharmaceutically acceptable drenergic agents utiliZed to treat alcohol and narcotic With 55 dosage form for each component or combination of all the draWal symptomology. components as an immediate release or controlled release The preferred central nervous system stimulant agent for dosage form. Contemporaneously means the three agents are the treatment of side effects associated With therapeutic administered separately over time, but have a combined agents used to treat alcohol and narcotic WithdraWal symp effect together after their individual administrations. Suit toms is about 1—20 mg dextroamphetamine sulfate in an able pharmaceutical dosage forms for the preferred embodi immediate release dosage form given to a human being ment include, but are not limited to, tablets, capsules, about every 4—8 hours, preferably about every 4—6 hours at caplets, dose-paks, solutions, syrups, suppositories, trans regular spaced intervals during the day and up to about 5 mg dermal applications, creams, lotions, emulsions, poWders as a rescue dose during the night if needed for a period of and the like. Preferred dosage forms for the present inven about 5—14 days. In a controlled release dosage form, the 65 tion include tablets, caplets, capsules, dose-paks, solutions, central nervous system stimulant, dextroamphetamine and transdermal applications With a tablet, caplet, or capsule sulfate, is dosed as 1—20 mg given to a human being about being the most preferred. US 6,503,950 B1 7 8 The triple drug therapeutic composition, kit, and method to those skilled in the art and to those Who make or use the of treatment of the preferred embodiment can be adminis invention. Therefore, it is. understood that the embodiments tered to the human body via a variety of medically and shoWn in the draWings and described above are merely for pharmaceutically acceptable administration routes. Those illustrative purposes and not intended to limit the scope of routes include, but are not limited to, the oral, rectal, the invention, Which is de?ned by the folloWing claims as intravenous, intradermal, subcutaneous, cutaneous, interpreted according to the principles of patent laW, includ intramuscular, buccal, transdermal, and other pharmaceuti ing the Doctrine of Equivalents. cally and medically acceptable routes of administration for The invention claimed is: the human body. Preferred routes of administration for the 1. A pharmaceutical kit for treatment of alcohol With preferred embodiment are the oral, rectal, intravenous and draWal symptoms comprising the folloWing three separate intramuscular routes, With the oral route being most pre 10 ingredients, combined in a kit: ferred. at least one anxiolytic agent; By combining the pharmaceutical medicaments of the at least one centrally acting alpha antiadrenergic agent; preferred embodiment in a kit, composition, and method of and treatment regimen, the preferred embodiment achieves far at least one central nervous system stimulant agent. 15 superior alcohol and narcotic WithdraWal side effect man 2. The pharmaceutical kit of claim 1, Wherein said kit agement results than can be achieved With current conven contains an effective amount of said anxiolytic agent to tional prior art treatment modalities. Current treatment reduce anxiety and seiZure, an effective amount of said modalities for alcohol and narcotic WithdraWal symptoms centrally acting alpha antiadrenergic agent to reduce or utiliZe anxiolytic agents and centrally acting alpha antiadr prevent central and peripheral nerve agitation, and an effec energic agents to reduce or prevent anxiety and central and tive amount of said central nervous system stimulant agent peripheral nerve agitation for patients undergoing alcohol or to reduce or prevent negative WithdraWal side effects asso narcotic abuse treatment. Current treatment modalities do ciated With alcohol WithdraWal treatment. not, hoWever, prevent or reduce the negative WithdraWal side 3. The pharmaceutical kit of claim 2, Wherein said anxi olytic agent comprises at least one member selected from the effects of droWsiness, diZZiness, lethargy, depression, diffi 25 group consisting of a benZodiaZepine, aZaspirodecanedione, culty in being mobile, Weakness in the extremities, and piperaZine derivative, derivatives thereof, and pharmaceuti orthostatic hypotension caused by anxiolytic agents and cally acceptable salts thereof. centrally acting alpha antiadrenergic agents used to treat 4. The pharmaceutical kit of claim 3, Wherein said ben alcohol or narcotic WithdraWal symptoms. ZodiaZepine comprises at least one member selected from As a result, most patients become non- or mal-compliant the group consisting of diaZepam, alpraZolam, clonaZepam, in taking such medications because of these negative side cloraZepate, chlordiaZepoxide, halaZepam, loraZepam, effect outcomes Which, in turn, can cause an increase in the oxaZepam, derivatives thereof, and pharmaceutically accept incidence of relapse for alcohol or narcotic abuse requiring able salts thereof. further treatment. In addition, these negative side effects 5. The pharmaceutical kit of claim 4, Wherein said ben associated With the use of anxiolytic and centrally acting 35 ZodiaZepine is chlordiaZepoxide. alpha antiadrenergic agents place patients at a greater risk of 6. The pharmaceutical kit of claim 5, Wherein said effec injury, and health personnel at a greater risk of liability tive amount of said chlordiaZepoxide is about 50—60 mg per prompting the increased use of in-patient treatment settings dose. only. Such increased risks and liability further increase 7. The pharmaceutical kit of claim 3, Wherein said ben healthcare costs. ZodiaZepine is loraZepam and said effective amount of said Although not being bound to any particular theory, it is loraZepam is about 0.25—10 mg per dose. believed that the preferred embodiment reduces or prevents 8. The pharmaceutical kit of claim 2, Wherein said cen the negative WithdraWal side effects of droWsiness, trally acting alpha antiadrenergic agent comprises of at least diZZiness, depression, difficulty in being mobile, lethargy, one member selected from the group consisting of Weakness in the extremities, and orthostatic hypotension 45 methyldopa, clonidine, guanfacine, lofexidine, guanabenZ, associated With the use of centrally acting alpha antiadren derivatives thereof and pharmaceutically acceptable salts ergic agents and anxiolytic agents used to treat alcohol and thereof. narcotic WithdraWal symptoms through the use of a central 9. The pharmaceutical kit of claim 8, Wherein said cen nervous system stimulant agent or agents to stimulate the trally acting alpha antiadrenergic agent is clonidine and said release of norepinephine from central nonadrenergic effective amount of said clonidine is about 0.05—0.7 mg per neurons, epinephrine from adrenergic neurons, and the dose. release of dopamine from the mesolimbic system of the 10. The pharmaceutical kit of claim 2, Wherein said human central nervous system to counteract the negative central nervous system stimulant agent comprises of at least WithdraWal side effects of agents used to treat alcohol or one member selected from the group consisting of an narcotic WithdraWal symptomology. 55 amphetamine, methylphenidate, pemoline, caffeine, cen Thus, patients become more compliant With their therapy trally acting alpha-1 agonist, derivatives thereof, and phar by experiencing feWer of the negative WithdraWal side maceutically acceptable salts thereof. effects caused by anxiolytic and centrally acting alpha 11. The pharmaceutical kit of claim 10, Wherein said antiadrenergic agents, thereby decreasing the incidence of central nervous system stimulant is dextroamphetamine sul relapse and the need for additional cycles of abuse treatment. fate and said effective amount of said dextroamphetamine Further, by increased central nervous system stimulation, sulfate is about 1—20 mg per dose. patients are at a reduced risk of syncope alloWing for the 12. The pharmaceutical kit of claim 11, Wherein said increased use of out-patient treatment settings for these dextroamphetamine sulfate is in a sustained release form. individuals, thereby decreasing the overall cost of health 13. The pharmaceutical kit of claim 10, Wherein said care. 65 central nervous system stimulant agent is moda?nil and said The above description is considered that of the preferred effective amount of said moda?nil is about 50—400 mg or embodiments only. Modi?cations of the invention Will occur greater per dose. US 6,503,950 B1 10 14. The pharmaceutical kit of claim 13, wherein said from the group consisting of a benZodiaZepine, effective amount of said moda?nil is about 200 mg per dose. aZaspirodecanedione, piperaZine derivative, derivatives 15. The pharmaceutical kit of claim 2, Wherein said thereof, or pharmaceutically acceptable salts thereof. anXiolytic agent comprises at least one member selected 25. The pharmaceutical composition of claim 24, Wherein from the group consisting of a benZodiaZepine, said benZodiaZepine comprises at least one member selected aZaspirodecanedione, piperaZine derivative, derivatives from the group consisting of diaZepam, alpraZolam, thereof, and pharmaceutically acceptable salts thereof; clonaZepam, cloraZepate, chlordiaZepoXide, halaZepam, Wherein said centrally acting alpha antiadrenergic agent loraZepam, oXaZepam, derivatives thereof, or pharmaceuti comprises at least one member selected from the group cally acceptable salts thereof. consisting of methyl dopa, clonidine, guanfacine, lofeXidine, 10 26. The pharmaceutical composition of claim 25, Wherein guanabenZ, derivatives thereof and pharmaceutically accept said benZodiaZepine is chlordiaZepoXide. able salts thereof; Wherein said central nervous system 27. The pharmaceutical composition of claim 26, Wherein stimulant agent comprises of at least one member selected said effective amount of said chlordiaZepoXide is about from the group consisting of an amphetamine, 50—60 mg or less per dose. methylphenidate, pemoline, caffeine, centrally acting 15 28. The pharmaceutical composition of claim 25, Wherein alpha-1 agonist, derivatives thereof and pharmaceutically said benZodiaZepine is loraZepam and said effective amount acceptable salts thereof; and further Wherein said benZodi of said loraZepam is about 0.25—10 mg per dose. aZepine comprises of at least one member selected from the 29. The pharmaceutical composition of claim 23, Wherein group consisting of diaZepam, alpraZolam, clonaZepam, said centrally acting alpha antiadrenergic agent comprises of chloraZepate, chlordiaZepoXide, halaZopam, loraZepam, at least one member selected from the group consisting of oXaZepam, derivatives thereof, and pharmaceutically accept methyldopa, clonidine, guanfacine, guanabenZ, lofeXidine, able salts thereof. derivatives thereof and pharmaceutically acceptable salts 16. The pharmaceutical kit of claim 15, Wherein said thereof. combination comprises about 0.25—10 mg of loraZepam, 30. The pharmaceutical composition of claim 29, Wherein about 0.05—0.7 mg of clonidine, and about 1—20 mg of 25 said centrally acting alpha antiadrenergic agent is clonidine deXtroamphetamine sulfate per dose of said combination. and said effective amount of said clonidine is about 0.05—0.7 17. The pharmaceutical kit of claim 15, Wherein said mg per dose. combination comprises about 50—60 mg of 31. The pharmaceutical composition of claim 23, Wherein chlordiaZepoXide, about 0.05—0.7 mg of clonidine, and about said central nervous system stimulant agent comprises of at 1—20 mg of deXtroamphetamine sulfate per dose of said least one member selected from the group consisting of an combination. amphetamine, methylphenidate, pemoline, caffeine, cen 18. The pharmaceutical kit of claim 15, Wherein said trally acting alpha-1 agonist, derivatives thereof, and phar combination comprises: about 0.25—10 mg of said maceutically acceptable salts thereof. loraZepam, about 0.05—0.7 mg of said clonidine, and about 32. The pharmaceutical composition of claim 31, Wherein 50—400 mg or greater of moda?nil per dose of said combi 35 said central nervous system stimulant is deXtroamphetamine nation. sulfate and said effective amount of said deXtroamphetamine 19. The pharmaceutical kit of claim 15 Wherein said sulfate is about 1—20 mg per dose. combination comprises about 50—60 mg of said 33. The pharmaceutical composition of claim 32, Wherein chlordiaZepoXide, about 0.05—0.7 mg of clonidine, and about said effective amount of said deXtroamphetamine sulfate is 50—400 mg or greater of moda?nil per dose of said combi in a sustained release form. nation. 34. The pharmaceutical composition of claim 31, Wherein 20. The pharmaceutical kit of claim 15, Wherein said said central nervous system stimulant agent is moda?nil and combination comprises about 0.25—10 mg of loraZepam, said effective amount of said moda?nil is about 50—400 mg about 0.05—0.7 mg of clonidine, about 50—400 mg or greater or greater per dose. of said moda?nil, and about 1—20 mg of deXtroamphetamine 45 35. The pharmaceutical composition of claim 34, Wherein sulfate per dose of said combination. said effective amount of said moda?nil is about 200 mg per 21. The pharmaceutical kit of claim 15, Wherein said dose. combination comprises about 50—60 mg chlordiaZepoXide, 36. The pharmaceutical composition of claim 35, Wherein about 0.05—0.7 mg of clonidine, about 1—20 mg deXtroam said composition comprises about 0.25—10 mg loraZepam, phetamine sulfate, and about 50—400 mg or greater of about 0.05—0.7 mg clonidine, and about 1—20 mg dextro moda?nil per dose of said combination. amphetamine sulfate per dose of said combination. 22. A pharmaceutical composition for the treatment of 37. The pharmaceutical composition of claim 36, Wherein alcohol and narcotic WithdraWal symptoms comprising a said combination comprises about 100 mg or less combination of at least one anXiolytic agent; at least one chlordiaZepoXide, about 0.05—0.7 mg clonidine, and about centrally acting alpha antiadrenergic agent; and at least one 55 1—20 mg deXtroamphetamine sulfate per dose of said com central nervous system stimulant agent. bination. 23. The pharmaceutical composition of claim 22, Wherein 38. The pharmaceutical composition of claim 36, Wherein said composition comprises of an effective amount of said said combination comprises about 0.25—10 mg loraZepam, anXiolytic agent to reduce or prevent anxiety and seiZure, an about 0.05—0.7 mg clonidine, and about 50—400 mg or effective amount of said centrally acting alpha antiadrener greater of moda?nil per dose of said combination. gic age to reduce or prevent central and peripheral nerve 39. The pharmaceutical composition of claim 36, Wherein agitation, and an effective amount of said central nervous said combination comprises about 50—60 mg system stimulant agent to reduce or prevent negative With chlordiaZepoXide, 0.05—0.7 mg clonidine, and about 50—400 draWal side effects associated With narcotic or alcohol mg or greater of moda?nil per dose of said combination. WithdraWal treatment. 65 40. The pharmaceutical composition of claim 36, Wherein 24. The pharmaceutical composition of claim 23, Wherein said combination comprises about 0.25—10 mg of said anXiolytic agent comprises at least one member selected loraZepam, about 0.05—0.7 mg of clonidine, about 50—400 US 6,503,950 B1 11 12 mg or greater of moda?nil, and about 1—20 mg deXtroam able salts thereof; Wherein said central nervous system phetamine sulfate per dose of said combination. stimulant agent comprises of at least one member selected 41. The pharmaceutical composition of claim 36, Wherein from the group consisting of an amphetamine, said combination comprises about 50—60 mg methylphenidate, pemoline, caffeine,.centrally acting chlordiaZepoXide, about 0.05—0.7 mg clonidine, about 1—20 alpha-1 agonist,. derivatives thereof and pharmaceutically mg of deXtroamphetamine sulfate, and about 50—400 mg or acceptable salts thereof; and further Wherein said benZodi greater moda?nil per dose of said combination. aZepine comprises of at least one member selected from the 42. A pharmaceutical kit for treatment of narcotic With group consisting of diaZepam, alpraZolam, clonaZepam, draWal symptoms comprising the folloWing three separate chloraZepate, chlordiaZepoXide, halaZopam, loraZepam, ingredients, combined in a kit: 1O oXaZepam, derivatives thereof, and pharmaceutically accept at least one anXiolytic agent; able salts thereof. at least one centrally acting alpha antiadrenergic agent; 53. A pharmaceutical composition for the treatment of and narcotic WithdraWal symptoms comprising a combination of at least one central nervous system stimulant agent. at least one anXiolytic agent; at least one centrally acting 43. The pharmaceutical kit of claim 42, Wherein said kit 15 alpha antiadrenergic agent; and at least one central nervous contains an effective amount of said anXiolytic agent to system stimulant agent. reduce anxiety and seiZure, an effective amount of said 54. The pharmaceutical composition of claim 53, Wherein centrally acting alpha antiadrenergic agent to reduce or said composition comprises of an effective amount of said prevent central and peripheral nerve agitation, and an effec anXiolytic agent to reduce anXiety and seiZure, an effective tive amount of said central nervous system stimulant agent amount of said centrally acting alpha antiadrenergic agent to to reduce or prevent negative WithdraWal side effects asso reduce or prevent central and peripheral nerve agitation, and ciated With narcotic WithdraWal treatment. an effective amount of said central nervous system stimulant 44. The pharmaceutical kit of claim 43, Wherein said agent to reduce or prevent negative WithdraWal side effects anXiolytic agent comprises at least one member selected associated With narcotic WithdraWal treatment. from the group consisting of a benZodiaZepine, 25 55. The pharmaceutical composition of claim 54, Wherein aZaspirodecanedione, piperaZine derivative, derivatives said anXiolytic agent comprises at least one member selected thereof, and pharmaceutically acceptable salts thereof. from the group consisting of a benZodiaZepine, 45. The pharmaceutical kit of claim 44, Wherein said aZaspirodecanedione, piperaZine derivative, derivatives benZodiaZepine comprises at least one member selected thereof, or pharmaceutically acceptable salts thereof. from the group consisting of diaZepam, alpraZolam, 56. The pharmaceutical composition of claim 55, Wherein clonaZepam, cloraZepate, chlordiaZepoXide, halaZepam, said benZodiaZepine comprises at least one member selected loraZepam, oXaZepam, derivatives thereof, and pharmaceu from the group consisting of diaZepam, alpraZolam, tically acceptable salts thereof. clonaZepam, cloraZepate, chlordiaZepoXide, halaZepam, 46. The pharmaceutical kit of claim 44, Wherein said loraZepam, oXaZepam, derivatives thereof, or pharmaceuti benZodiaZepine is loraZepam and said effective amount of 35 cally acceptable salts thereof. said loraZepam is about 0.25—10 mg per dose. 57. The pharmaceutical composition of claim 56, Wherein 47. The pharmaceutical kit of claim 43, Wherein said said benZodiaZepine is loraZepam and said effective amount centrally acting alpha antiadrenergic agent comprises of at of said loraZepam is about 0.25—10 mg per dose. least one member selected from the group consisting of 58. The pharmaceutical composition of claim 54, Wherein methyldopa, clonidine, guanfacine, lofeXidine, guanabenZ, said centrally acting alpha antiadrenergic agent comprises of derivatives thereof and pharmaceutically acceptable salts at least one member selected from the group consisting of thereof. methyldopa, clonidine, guanfacine, guanabenZ, lofeXidine, 48. The pharmaceutical kit of claim,Wherein said centrally derivatives thereof and pharmaceutically acceptable salts acting alpha antiadrenergic agent is clonidine and said thereof. effective amount of said clonidine is about 0.05—0.7 mg per 45 59. The pharmaceutical composition of claim 58, Wherein dose. said centrally acting alpha antiadrenergic agent is clonidine., 49. The pharmaceutical kit of claim 43, Wherein said and said effective amount of said clonidine is about 0.05—0.7 central nervous system stimulant agent comprises of at least mg per dose. one member selected from the group consisting of an 60. The pharmaceutical composition of claim 54, Wherein amphetamine, methylphenidate, pemoline, caffeine, cen said central nervous system stimulant agent comprises of at trally acting alpha-1 agonist, derivatives thereof, and phar least one member selected from the group consisting of an maceutically acceptable salts thereof. amphetamine, methylphenidate, pemoline, caffeine, cen 50. The pharmaceutical kit of claim 49, Wherein said trally acting alpha-1 agonist, derivatives thereof, and phar central nervous system stimulant agent is moda?nil and said maceutically acceptable salts thereof. effective amount of said moda?nil is about 50—400 mg or 55 61. The pharmaceutical composition of claim 60, Wherein greater per dose. said central nervous system stimulant agent is moda?nil and 51. The pharmaceutical kit of claim 50, Wherein said said effective amount of said moda?nil is about 50—400 mg effective amount of said moda?nil is about 200 mg per dose. or greater per dose. 52. The pharmaceutical kit of claim 43, Wherein said 62. The pharmaceutical composition of claim 61, Wherein anXiolytic agent comprises at least one member selected said effective amount of said moda?nil is about 200 mg per from the group consisting of a benZodiaZepine, dose. aZaspirodecanedione, piperaZine derivative, derivatives 63. The pharmaceutical composition of claim 62, Wherein thereof, and pharmaceutically acceptable salts thereof; said composition comprises about 0.25—10 mg loraZepam, Wherein said centrally acting alpha antiadrenergic agent about 0.05—0.7 mg clonidine, and about 1—20 mg dextro comprises at least one member selected from the group 65 amphetamine sulfate per dose of said combination. consisting of methyl dopa, clonidine, guanfacine, lofeXidine, guanabenZ, derivatives thereof and pharmaceutically accept * * * * * UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 6,503,950 B1 Page 1 of 1 DATED : January 7, 2003 INVENTOR(S) : David M. Ockert

It is certified that error appears in the above-identi?ed patent and that said Letters Patent is hereby corrected as shown below:

Column 1 Line 31, after “detoxification” delete “.”.

Column 1 1 Line 43, after “claim” insert -- 47

Column 12 Line 4, after “caffeine,” delete “.”. Line 5, after “agonist” delete “.”.

Signed and Sealed this

Seventeenth Day of June, 2003

JAMES E. ROGAN Director ofthe United States Patent and Trademark O?‘i'ce