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WO1999009828A1 - Traitement de la phobie sociale - Google Patents

Traitement de la phobie sociale Download PDF

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Publication number
WO1999009828A1
WO1999009828A1 PCT/US1998/017210 US9817210W WO9909828A1 WO 1999009828 A1 WO1999009828 A1 WO 1999009828A1 US 9817210 W US9817210 W US 9817210W WO 9909828 A1 WO9909828 A1 WO 9909828A1
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WIPO (PCT)
Prior art keywords
social phobia
apomorphine
social
dopaminergic
administered
Prior art date
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Ceased
Application number
PCT/US1998/017210
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English (en)
Inventor
Ragab El-Rashidy
Bruce Ronsen
Ashraf Youssef
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Pentech Pharmaceuticals Inc
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Pentech Pharmaceuticals Inc
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Publication date
Application filed by Pentech Pharmaceuticals Inc filed Critical Pentech Pharmaceuticals Inc
Priority to AU89155/98A priority Critical patent/AU8915598A/en
Publication of WO1999009828A1 publication Critical patent/WO1999009828A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • the invention relates to the pharmacological treatment of phobias, and in particular, social phobia.
  • Victims of social phobia fear attending social functions, meetings, especially among new or unfamiliar persons, formal performance situations, and assertiveness situations. Public speaking or performance are especially likely to elicit social phobia behavior. Academic testing and the failure to perform well on testing has been associated with social phobia.
  • Social phobia also known as social anxiety disorder
  • social anxiety disorder is a common psychological problem which on occasion involves or may involve physiological manifestations.
  • Clinically, social phobia may be misdiagnosed since many of the physiological manifestations are similar to those of other psychological disorders.
  • physical symptoms which may include sweating, shaking, palpitations, nausea and diarrhea are occurrences reported in patients suffering from social phobia, and may be thought to arise from other illnesses.
  • patients with social phobia tend to have a greater frequency of blushing, muscle twitching, stammering, and dry mouth, and a lower incidence of dizziness or respiratory symptoms.
  • the hallmark of social phobia is its cognitive features, specifically the negative evaluation and fears of humiliation and/ or embarrassment. This fear is most obviously expressed as a "fear of saying the wrong thing" or speaking awkwardly. Generalization of this fear includes concerns the patient may show symptoms of anxiety, twitches, spilling things, as well as the anticipation of these fears. A very specific situation or circumstance may elicit the fear, such as taking a test or speaking to a group of three or more persons. Alternatively, a global set of fears may affect a significant part of the patient's waking hours. Further complicating the disorder is the overlay of other disorders, for example, the co- morbidity of social phobia with alcohol or drug abuse, anxiety disorders, secondary depression, and suicidal ideation.
  • Cognitive processing by a person suffering from social phobia is characterized by a large amount of negative thoughts correlated to the levels of anxiety and phobic severity. Dodge, C.S., et al., Daily heterosocial interactions of high and low socially anxious college students, Behavior Therapy. 18: 90-96 (1987).
  • the victim of social phobia may also experience physical symptoms characteristic of autonomic nervous system activation: dry mouth, blushing, palpitations, sweating, trembling and nausea.
  • a social phobic attack may also include other physical symptoms such as twitching and stammering.
  • Social phobia may be focused or generalized. In focused cases, the person usually fears a specific discrete setting, i.e. , performance anxiety or stage fright. Generalized social phobia relates to a fear of most social situations. Because of the anticipatory nature of these events, anxiety can overwhelm the patient, rendering him unable to perform social obligations.
  • the diagnosis of the social phobia begins with a physiological and psychological assessment of the patient.
  • the problem in establishing a diagnosis of social phobia is the issue of diagnostic thresholds.
  • Avoidant personality disorder as defined in the DSM-IV appears to be a more severe form of social phobia, but groups of patients have not been found to differ qualitatively in any substantive way. Schneier, F.R. , Clinical assessment strategies for social phobia, Psychiatric Annals. 25: 550-553 (1995). Rather than trying to differentiate between both disorders, it is more useful to code a diagnosis of social phobia in Axis I and a diagnosis of avoidant personality disorder in Axis II, where warranted.
  • CBGT cognitive-behavioral group treatment
  • Neurobiologv of Social Phobia Observations from Pharmacotherapy. Alcohol has played an informal role in the pharmacotherapy of social discomfort for centuries. Jefferson, J.W., Social Phobia: A Pharmacologic Treatment Overview, J. Clin. Psychiatry. 56 (Suppl. 5): 18-24 (1995). The substantial comorbidity of alcohol abuse and social phobia may reflect a role in the self-medication of social phobics. Id. However, alcohol abuse has not been suggested as an acceptable drug therapy for social phobia. ⁇ -adrenergic receptor blocking agents (“beta-blockers”) have been reported to be effective in a special form of social phobia, performance anxiety.
  • beta-blockers ⁇ -adrenergic receptor blocking agents
  • beta-blockers Since not all beta-blockers effectively cross the blood-brain barrier, it may be that the efficacy of beta-blockers in performance anxiety is due to a reduction in autonomic symptoms such as palpitations and tremors, and not due to a central reduction in anxiety, den Boer, J.A. et al. , Recent Developments in the Psychopharmacology of Social Phobia, Eur. Arch. Psychiatry Clin. Neurosci. 244: 309-316 (1995). Beta- blockers have not been shown to be superior to a placebo in double-blind studies of performance anxiety and in studies of generalized social phobia (Jefferson (1995), page 19).
  • Beta-blockers have recognized adverse effects on the cardiovascular system, the pulmonary system (especially in asthmatics), the central nervous system and the metabolism (especially in diabetics). Hoffman, B.B., and Lefkowitz, R.J., Catecholamines, Sympathomimetic Drugs and Adrenergic Receptor Antagonists, pp. 239-240, in Hardman, J.G. et al. , editors, Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th Ed., McGraw-Hill, New York (1996). The adverse side effects and minimal efficacy in treating generalized social phobia severely limits the therapeutic potential of beta-blockers.
  • MAOI monoamine oxidase inhibitors
  • Serotonin selective reuptake inhibitors such as fluoxetine have also been used to treat social phobia. Leibowitz, M.R. , Pharmacotherapy of Social Phobia, J. Clin. Psychiatry. 54 (Suppl. 12): 31-35 (1993).
  • Tancer has reviewed evidence from pharmacological challenge studies (Tancer, M. E. , Neurobiology of Social Phobia, J. Clin. Psychiatry. 54 (Suppl. 12): 26-30 (1993)).
  • pharmacological challenge studies Tancer, M. E. , Neurobiology of Social Phobia, J. Clin. Psychiatry. 54 (Suppl. 12): 26-30 (1993)).
  • a challenge of normal volunteers and of social phobia patients with levodopa produced the same changes, as measured by prolactin levels and rate of eyeblink. Id. at 29. No evidence of dopaminergic dysfunction was found in social phobia patients. Id.
  • Tancer found that the cortisol response to fenfluramine suggested that patients with social phobia may exhibit dysregulation in serotonergic neurotransmission
  • SSRI have varying degrees of selectivity for 5-HT reuptake by the presynaptic neuron compared to other aryl amine re-uptake transporters. While the basic mechanism of action is thought to involve inhibition of re-uptake of serotonin, the family of SSRI drugs also inhibit the re-uptake of norepinephrine and dopamine.
  • Neurobiologv of Social Phobia Animal Models.
  • Animal models have been applied to various behavior models. The animal models have been used to measure various types of behavioral and psychological conditions including open field studies, feeding studies, and social interaction studies. Several animal models based at least partially on dopaminergic systems, including the nigrostriatal dopaminergic are especially relevant, including sexual interaction studies (Pomerantz, S.M., Apomorphine Facilitates Male Sexual Behavior of Rhesus Monkeys, Pharm. Biochem. & Behav.. 35: 659-664 (1990)), social biological models for depression (Jones, I.H. , et al. , Toward A Sociological Model of Depression, A Marsupial Model, Brit. J. of Psychiatry.
  • a dopaminergic model of social phobia is consistent with the actions of other drugs known to act on dopaminergic systems.
  • Psychoactive drugs such as cocaine and amphetamines affect dopamine transmission by respectively blocking the re-uptake transporter and by depleting dopamine storage in the presynaptic neuron. Both of these drugs produce changes in socialization of individuals, and can induce clinical anxiety.
  • the mesolimbic system has been identified as the system in the brain of mammals responsible for goal-oriented behavior.
  • the primary anatomic structures involved in processing and regulating goal-oriented behavior are the nucleus accumbens, habenula, amygdala, septum, olfactory tubercle, and the bed nucleus of the stria terminalis.
  • the ventral tegmental area (VTA) of the midbrain interconnects and integrates these regions of the brain. Neurons connecting these structures to the VTA are predominantly dopaminergic. Bjorklund, A, & Lindvall, O., Dopamine- containing systems in the CNS, In: Handbook of Chemical Neuroanatomy. Vol. 2, Classical Transmitters in the CNS. Part I. Bj ⁇ rklund, A. & Hokfelt, T. , eds. , Elsevier, Amsterdam (1984) pp. 55-122.
  • Dopamine has been shown to have a role in drug and alcohol addiction, male sexual function, locomotion, and goal-oriented behavior in animals. Electrophysiological and neurochemical measurements of the extracellular concentration of dopamine in the VTA, the medial preoptic area of the hypothalamus, in the nucleus accumbens and the amygdala have clearly shown correlations between stimuli evoking behavior (e.g. , sexual behavior) and an increase in dopamine levels (Hull, Elaine M. , Dopaminergic influences on male rat sexual behavior, In: Neurobiological Effects of Sex Steroid Hormones. Erectile Dysfunction. Micevych, P.E. & and Hammer, R.P., eds., Cambridge University Press, Boston (1995)).
  • TIDA tubero infundibular dopaminergic
  • PLD A periventricular-hypophyseal dopaminergic
  • IHDA incertohypothalmic dopaminergic
  • Dopamine receptors classified pharmacologically into the groups D r through D 5 , as well as the dopamine autoreceptor, have been studied. Kiyatkin, E.A. , Functional Significance of Mesolimbic Dopamine, Neurosci. and Biobehav. Reviews. 19: 573-598 (1995). Selective agonists and antagonists to the major dopamine receptors, D j and D 2 have been used to measure the effects of dopamine.
  • the dopamine autoreceptor found on the presynaptic dopaminergic nerve has been postulated in the regulation of dopamine transmission through the central nervous system.
  • Dopamine released at the synaptic junction between the efferent and afferent neurons is either diffused into extracellular space, or metabolized, or taken up by the presynaptic neuron for reprocessing and/or metabolism.
  • Animals treated with dopamine D 2 antagonists such as haloperidol become more sensitive to dopamine and exogenous dopaminergic drugs.
  • Gordon, J.J., & Diamond, B. Enhancement of Hypophysectomy-Induced Dopamine Receptor Hypersensitivity in Male Rats by Chronic Haloperidol Administration, Neurochem. , 42: 523-528 (1984). This behavior known as supersensitivity is seen with chronic administration of dopamine agonists, such as apomorphine.
  • a dopaminergic agonist such as apomorphine reduces the patient's inability to engage in social interactions that characterizes social phobia.
  • Treatment regimens that achieve a target plasma concentration of the dopaminergic agonist in the range of about 0.5 ng/mL to about 10 ng/mL at C max with chronic therapy of 2 or more treatments provide a therapeutically effective dose that produces amelioration of social phobia in a patient.
  • the dopaminergic agonist may be formulated as a sublingual tablet, buccal patch, intranasal formulation, transdermal composition or composition for intravenous injection.
  • Suitable dopaminergic agonists are apomorphine, piribedil, bromocriptine, and the like.
  • FIGURE 1 is a simplified diagram illustrating the relationships of the anatomical brain structures believed to be involved in social phobia
  • FIGURE 2 is a graph showing the cumulative number of successful interactions accomplished by male rats receiving daily subcutaneous injections of vehicle alone (control) and apomorphine at either 0.2 mg/kg/day, 0.8 mg/kg/day or 2.0 mg/kg/day;
  • FIGURE 3 is a graph showing the percent of male rats showing signs of hyperactivity during chronic subcutaneous apomorphine treatment
  • FIGURE 4 is a graph showing the C max values measured in rats receiving chronic subcutaneous apomorphine on Day 1 and on Day 63;
  • FIGURE 5 is a graph showing the area under the curve (AUC) values measured in rats receiving chronic subcutaneous apomorphine on Day 1 and on Day 63.
  • a dopaminergic agonist such as apomorphine hydrochloride, formulated as a sublingual tablet, buccal patch, intranasal preparation, rectal suppository, transdermal drug, or given parenterally by intravenous or subcutaneous injection, ameliorates social phobia.
  • the amelioration of social phobia is believed to be due to reduction in the fear response of avoidance and self-abusive tendencies of the patient suffering from social phobia.
  • Apomorphine is the preferred drug for the practice of this invention.
  • other mixed dopamine agonists D : dopamine receptor agonists, or D 2 dopamine receptor agonists may be used to modulate extracellular dopamine concentrations in a similar manner.
  • illustrative agonists are piribedil, bromocriptine, lysergide, and pergolide.
  • the effective amount of dopaminergic agonist required for the amelioration of social phobia is a function of the potency of the substance on central nervous system dopamine receptors.
  • a therapeutically effective treatment of social phobia is associated with dosages and treatment regimens that achieve a target plasma concentration of apomorphine of about 0.5 ng/ml to about 10 ng/ml.
  • Apomorphine is administered chronically with a single daily dose or multiple daily doses.
  • the dosage level is dependent upon the bioavailability; for example, a bioavailability of about 10% to about 15% would require a dosage of about 30 mg/day to about 50 mg/day. Different routes of administration are associated with correspondingly different bioavailability.
  • the target plasma concentration of apomorphine of about 0.5 ng/ml to about 10 ng/ml may be achieved by a sublingual dosage of apomorphine in the range of about 8 mg/day to about 60 mg/day.
  • the same target plasma concentration may be achieved by intravenous injection of about 3 mg/day to about 5 mg/day.
  • the amount of other dopamine agonists used is inversely proportional to the effectiveness of the agonist compared to apomorphine hydrochloride. Duration of treatment is at least about four weeks.
  • a preferred treatment regimen for apomorphine hydrochloride in sublingual tablet dosage form is a chronic administration of from about 4 to about 120 mg/day of apomorphine hydrochloride in single or multiple doses, administered daily for a time period of at least about four weeks, typically for a period of about six months to about twelve months.
  • Transdermal formulations provide an effective mode of administering apomorphine; see, for example, U.S. Patent No. 5,562,917 to Durif et al. , incorporated herein by reference.
  • Apomorphine hydrochloride and the like can also be administered by subcutaneous injection at a dosage from about 0.002 mg/kg to about 0.5 mg/kg in a single bolus injection or multiple injections. Continuous intravenous infusion at a rate of about 0.001 mg/kg/hour to about 4 mg/kg/hour is another suitable mode of administering apomorphine HC1.
  • a treatment regimen that comprises a combination of modes of administration is also suitable for the treatment of social phobia.
  • Such treatment regimens include an initial subcutaneous injection followed by chronic treatment by administration via sublingual tablets.
  • an initial subcutaneous injection can be followed by chronic treatment by administration of the active ingredient via a transdermal patch.
  • Apomorphine exists in a free base form or as an acid addition salt.
  • apomorphine hydrochloride is preferred; however, other pharmacologically acceptable moieties thereof can be utilized as well.
  • the term "apomorphine" as used herein includes the free base form of this compound as well as the pharmacologically acceptable acid addition salts thereof.
  • other acceptable acid addition salts are the hydrobromide, the hydroiodide, the bisulfate, the phosphate, the acid phosphate, the lactate, the citrate, the tartrate, the salicylate, the succinate, the maleate, the gluconate, and the like.
  • Additional preparations such as conjunctival, rectal, iontophoretic, etc. , as a means to deliver apomorphine are provided by the present invention.
  • Formula and process variations such as the inclusion of ascorbic acid, glutathione, tocopherol, sodium metabisulfite or any other antioxidant acceptable for human or animal use and added to expressly preserve the drug substance are considered part of this invention.
  • Sublingual and/or buccal formulations comprising those described by El-Rashidy et al. in U.S. Patent No. 5,624,677, incorporated by reference, may be useful considerations for delivering apomorphine by these routes.
  • dopaminergic drugs may alternatively be used in a similar manner as the active ingredient in the practice of the present invention.
  • active ingredients and suitable dosage forms are piribedil mesylate, e.g. in tablets for oral treatment (20 to 50 milligrams per tablet) as well as parenteral preparations of piribedil mesylate (3 mg/mL) and other dosage forms.
  • EXAMPLE 1 Social Interaction Study
  • the pre-conditioned rats were then chronically treated with morning daily subcutaneous injections of apomorphine hydrochloride prepared in a stabilizing vehicle once daily for four weeks prior to social interaction experimentation.
  • the stabilizing vehicle was 0.75% NaCl aqueous solution containing 1 % ascorbic acid and 0.05% sodium metabisulfite with a pH between 3.0 and 4.0 and aseptically filtered through a presteralized 0.22 ⁇ m membrane filter.
  • each male rat was caged together with a nulliparous female rat of the same strain that had been preconditioned for six weeks.
  • Female rats were preconditioned to the same light / dark cycle synchronized to that of the male rats. No visual contact was made between rats of different genders prior to the experiment. No apomorphine was administered to the female rats.
  • the normal rat estrous cycle period is about three to five days from estrous to estrous.
  • the estrous period can be modified by external influences; for example, housing female rats in the same room, as in this case, would be expected to synchronize estrous cycles.
  • housing female rats in the same room, as in this case would be expected to synchronize estrous cycles.
  • female rats assume a copulatory position allowing the male to mount.
  • the data show greater success in social interactions after chronic apomorphine therapy. Since rats are about 5 to 20 times less sensitive to apomorphine than humans, the corresponding therapeutic dosage range for humans is from about 0.01 mg/kg/day to about 0.4 mg/kg/day.
  • Example 1 for a period of two weeks.
  • the pre-conditioned rats were placed into groups that received subcutaneous apomorphine hydrochloride in the same vehicle used in Example 1 at the doses of 0.1, 0.3, 0.8 and 2.0 mg/kg/day in addition, vehicle alone (Placebo group) or were untreated (Control).
  • Each dosage group consisted of 70 male rats.
  • the fraction of the group involved in hyperactivity for each dosage group was recorded. Hyperactivity was defined as excessive stereotypic head movements (sniffing, licking or gnawing), circling, rearing, and thrusting in the cage.
  • FIGURE 3 shows the increase in hyperactivity in the groups treated with apomorphine hydrochloride at 0.8 and 2.0 mg/kg/day.
  • apomorphine hydrochloride 0.8, 2 or 8 mg/kg/day
  • t max 0.25 hour for each dose tested on each day
  • t 1/2 0.16 hour to 0.39 hour
  • AUC area under the curve

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Abstract

La présente invention concerne un traitement convenant à des patients souffrant de troubles tels que la phobie sociale. Lorsqu'on a identifié un patient souffrant de phobie sociale, le traitement consiste à lui administrer une quantité suffisante d'un agoniste dopaminergique tel que l'hydrochlorure d'apomorphine.
PCT/US1998/017210 1997-08-25 1998-08-19 Traitement de la phobie sociale Ceased WO1999009828A1 (fr)

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AU89155/98A AU8915598A (en) 1997-08-25 1998-08-19 Method for amelioration of social phobia

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US08/921,893 1997-08-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
US11564935B2 (en) 2019-04-17 2023-01-31 Compass Pathfinder Limited Method for treating anxiety disorders, headache disorders, and eating disorders with psilocybin
US12459965B2 (en) 2017-10-09 2025-11-04 Compass Pathfinder Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5562917A (en) * 1994-12-23 1996-10-08 Pentech Pharmaceuticals, Inc. Transdermal administration of apomorphine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5562917A (en) * 1994-12-23 1996-10-08 Pentech Pharmaceuticals, Inc. Transdermal administration of apomorphine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HJORTH S., ENGEL J. A., CARLSSON A.: "ANTICONFLICT EFFECTS OF LOW DOSES OF THE DOPAMINE AGONIST APOMORPHINE IN THE RAT.", PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR., ELSEVIER., US, vol. 24., 1 January 1986 (1986-01-01), US, pages 237 - 240., XP002913510, ISSN: 0091-3057, DOI: 10.1016/0091-3057(86)90344-8 *

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ZA987642B (en) 1999-02-24

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