WO2002083115A1 - Treatment of disorders secondary to organic impairments - Google Patents
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- WO2002083115A1 WO2002083115A1 PCT/US2002/012011 US0212011W WO02083115A1 WO 2002083115 A1 WO2002083115 A1 WO 2002083115A1 US 0212011 W US0212011 W US 0212011W WO 02083115 A1 WO02083115 A1 WO 02083115A1
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Definitions
- the present invention relates to the pharmacological treatment of various secondary neurological, behavioral and cognitive symptoms or disorders emanating out of brain or systemic impairments, i.e., primary impairments.
- the secondary symptoms and disorders include as non-limiting examples, tic and behavioral disorders including Tourette's syndrome and severe non-Tourette's motor or vocal tics; Posttraumatic Stress Disorder (PTSD); atypical attention deficit disorder with or without hyperactivity; frontal lobe defects of executive function; oscillopsia; self-mutilation; violence or rage such as in intermittent explosive disorder; asocial behavior; sexual disorders (including gender choice difficulties or hyposexuality); psychological (psychosis, violence, and confusion) and motor symptoms of Huntington's Disease (Huntington's Chorea); fatigue, exhaustion, sleep problems, and pain of Chronic Fatigue Syndrome with or without Fibromyalgia; psychosis with multiple hallucinations and delusions secondary to brain injury; opiate narcotic addiction; Sick Building Syndrome (SBS); Gulf War Syndrome (GWS); Reflex Sympathetic Dystophy Syndrome (RSDS), also known as Complex Regional Pain Syndrome (CRPS); Retinitis Piginentosa (RP); Cerebral Palsy;
- a symptom is a single manifestation while a disorder involves more than one symptom or a cluster of symptoms.
- the symptoms and disorders are secondary to the primary impairments and emanate from neurological diseases or brain lesions including Tourette's Disease, non- Tourette's tic disorders, Asperger's Syndrome, temporal lobe or other focal epilepsy, Huntington's Disease, brain tumors or cysts, systemic lupus erythematosus, viral infections and their resulting neurological injuries, and various psychological disorders such as multiple personality disorder, borderline personality, organic psychosis, and severe traumatic experiences.
- Pharmacologic therapy has included low doses of dopamine-2 blockers and dopamine-antagonists including haloperidol, risperidone, or pimozide. T.M. Hyde et al., JAMA 273: 498-501, 1995.
- a problem with this dopamine-2 blockade is that this may often produce decreased attention, hyperactivity, dysphoria, and extrapyramidal symptoms in T.D. patients.
- dopamine-2 stimulating analeptics such as methylphenidate, dextroamphetamine, or pemoline
- Non-Tourette's tic disorder most commonly arises out of previous analeptic treatment and persists after such treatment.
- Dystonia is a neurological movement disorder characterized by involuntary muscle contractions which force certain parts ofthe body into abnormal, sometimes painful, movements or postures. Dystonia can affect any part ofthe body including the arms and legs, trunk, neck, eyelids, face or vocal cords. Dystonia is the third most common movement disorder after Parkinson's Disease and Tremor, affecting more than 300,000 people in North America. Currently, no medication or therapy can prevent progression of Dystonia from happening. Dystonia will usually stabilize within five years of onset, but symptoms may fluctuate and stressful situations, anxiety or depression may make symptoms temporarily worse. Treatments currently available not only fail to cure this disorder but only moderately abate the symptoms of Dystonia.
- Torticollis which is a neurological movement disorder in which the muscles controlling the neck undergo repetitive or sustained contraction, causing the neck to involuntarily jerk, twist or rotate.
- the abdominal posture caused by Torticollis is often debilitating and painful. Torticollis most commonly begins between age 30-60, and it affects 83,000 people in the United States.
- torticollis There are three types of torticollis: tonic, sustained abnormal posture; clonic, jerky head movements; and mixed, a combination of tonic and clonic movements. Symptoms progress over two to five years and then remain steady, but may worsen during stressful times. There is no cure for Torticollis. The current treatment provides only temporary relief of symptoms for a short time period before new treatment is needed.
- Torticollis is also referred to as spasmodic wryneck, idiopathic cervical Dystonia, ICD, cervical Dystonia and spasmodic Torticollis.
- Dyskinesia is the impairment of muscle movement, or lack of control over ordinary muscle movement. Typical dyskinetic movements are Chorea, rapid movements; or Dystonia, twisting movements, muscle cramps and unusual posturing. Lingual, facial and tardive dyskinesia is characterized by twitching ofthe face and tongue, and involuntary movements ofthe body and limbs. Dyskinesia tends to occur more in people with early onset of Parkinson's disease (before 50 years old). There is no known cure for dyskenesia.
- Posttraumatic Stress Disorder follows exposure to a traumatic experience involving actual or threatened death or injury or threat to the physical integrity of oneself or others.
- PTSD includes characteristic symptoms of reexperience, avoidance of stimuli associated with the trauma, and numbing of general responsiveness or hyperarousal (sleep difficulty, anger, difficulty concentrating, hypervigilance or exaggerated startle response) with clinically significant distress or impairment.
- Studies in the United States demonstrate that 5 to 6 percent of men and 10 to 14 percent of women had had PTSD at some time in their lives, making it the fourth most common psychiatric disorder. It has been established that PTSD is associated with organic changes in the limbic system.
- the reactivity ofthe amygdala and anterior paralimbic region to trauma-related stimuli is increased, and the reactivity ofthe anterior cingulate and orbitofrontal areas decreased. These areas ofthe brain are involved in fear responses. Differences in hippocampal function and in memory processes presumed to be dependent on the hippocampus have been found, suggesting a neuroanatomical substrate for the intrusive recollections and other cognitive problems that characterize PTSD (R. Yehuda, NEnglJMed 346 (2): 108 -113, 2002). The finding of shrinkage in the hippocampus suggests a loss of cell mass.
- cortisol a steriod hormone secreted by the brain in response to emergencies, some researchers believe.
- Cortisol is a major means the body uses, with adrenaline, to arouse itself so quickly, but it cati be toxic and damaging to the hippocampus (D.Goleman, Science, C3, August 1, 1995).
- Pharmacologic therapy for stress disorders has included benzodiazepines (e.g., lorazepam, diazepam, clonazepam), beta adrenergic blockers and anti-seizure medications such as carbamazepine and valproic acid.
- PTSD can induce a long-lasting brainstem dysfunction resulting in loss ofthe normal inhibitory modulation of startle response (E.M. Ornitz et al, Am. J. Psychiatry 146(7): 866- 870, 1989), and clonidine has been used to decrease noradrenergic action and inhibit startle response. Nevertheless, no successful dramatic treatment of PTSD has been discovered for the severe, chronic cases of this crippling disorder. A number of articles describing current developments in PTSD appear in Psychiatric Annals 28:424-468, 1998.
- Concentration Camp Syndrome includes the symptoms associated with PTSD as well as additional symptoms such as psychiatric and social disorders, distortion, disturbance of memory such as amnesia, psychogenic amnesia, hyperamnesia and disturbances of consciousness.
- Dissociative Disorder which includes the existence within the person of two or more distinct personalities which recurrently take full control. There is an extensive inability to recall personal information. Dissociative disorders may occur as acute responses to overwhelming trauma and are common in combat or disasters. There is probably also a relationship between seizures and these disorders. Devinsky et al., Neurology 39:835-840, 1989.
- Borderline personality disorder is characterized by tumultuous interpersonal relationships, labile mood status, and behavioral dyscontrol. Self-mutilation and violent behavior can also be seen with this disorder. Carbamazepine, an anti-convulsant with preferential action on limbic foci, produced decrease in severity of behavioral dyscontrol (R.W. Cowdry et al., Arch. Gen. Psychiatry 45:111-119, 1988) but not in the other multiple symptoms.
- ADHD Primary attention deficit hyperactivity disorder
- the ADHD syndrome is idiopathic (no known secondary cause such as brain injury, dementia or known metabolic disease), begins at birth or soon thereafter, and usually has a strong hereditary basis.
- Violence or rage can also be categorized as an impulse control disorder. There is a loss of control grossly out of proportion to any precipitating psychosocial stresses. Disabling outbursts of rage and violent behavior can be related to chronic brain syndrome associated with irreversible CNS (central nervous system) lesions. Yudofsky et al., Am. J. Psychiatry 138:218-220, 1981. Disorders characterized by severe episodic dyscontrol can result from brain dysfunction, e.g., resulting from a failure of modulation of electrical disturbances in the limbic system (amygdala, hippocampus, hypothalamus), temporal lobe epilepsy (TLE), brain lesions or injuries which can have neurological side effects.
- amygdala, hippocampus, hypothalamus central nervous system
- TLE temporal lobe epilepsy
- brain dysfunction disorders include motor, personality, or behavior patterns arising from, e.g., neurological impairment in the brain, TLE, viral infections, neurotransmitter disorders, amino acid imbalance, brain tumors, chromosomal abnormalities, metabolic disorders including endocrine disorders, diabetes, and genetic disorders such as disease which involves several genes, and chromosomal disorders.
- Dementia or chronic brain syndrome is defined as a group of symptoms involving progressive impairment of all aspects of brain function. Studies have concluded just over 1% ofthe population aged 65-74 suffer from Dementia, and as many as 47% of people over 85 suffer from some form of Dementia. More than half of the people diagnosed with Dementia are classified as having Dementia resulting from Alzheimer-type Dementia generally are expected to live eight years from diagnosis.
- Generally symptoms characterizing Dementia include memory impairment or loss; cognitive disturbances such as alexia, agraphia, aphasia, apraxia, agnosia; emotional disorders, such as depression, anxiety, aggression, apathy, flat affect or social withdrawal; sleep dysfunctions or disturbance; severe mental status fluctuation such as confusion, hallucinations, delusions, disorientation, hyperactivity or limited alertness.
- cognitive disturbances such as alexia, agraphia, aphasia, apraxia, agnosia
- emotional disorders such as depression, anxiety, aggression, apathy, flat affect or social withdrawal
- sleep dysfunctions or disturbance severe mental status fluctuation such as confusion, hallucinations, delusions, disorientation, hyperactivity or limited alertness.
- Temporal lobe lesions may be brain damage produced by injury, disease, viral infection, and surgery, and can produce disturbances characterized, e.g., by seizures, which can include, e.g., motor phenomena, impairment of external awareness, depersonalization, emotional changes, behavioral disturbances, psychosis, multiple cognitive disturbances, distortions or hallucinations of any ofthe five senses, and autonomic disturbances (gastrointestinal, cardiac, sweating, and headache symptoms among others). The symptoms can be severe and difficult to treat.
- the drugs used in treatment depend on the type of seizures and have included phenytoin, carbamazepine, valproic acid, phenobarbital, primidone, felbamate, gabapentin, and lamotrigine.
- Temporal lobe epilepsy poses particular problems which can include simple partial seizures that can be manifested by motor symptoms, sensory symptoms, or psychic symptoms including impairment of consciousness, dysphasia, dysmnesia, illusions, and hallucinations. Complex partial seizures include impaired consciousness and psychic symptoms.
- the drugs used in treatment depend on the type of seizures and have included phenytoin, carbamazepine, valproic acid, phenobarbital, primidone, felbamate, gabapentin, and lamotrigine.
- Temporal lobe epilepsy and other organic brain disorders may be associated with various sexual impairments. See, e.g., D.M. Bear, "Temporal Lobe Epilepsy - A Syndrome of Sensory-Limbic Hyperconnection", Cortex 15:357-84, 1979.
- the most common sexual effect of organic brain problems is a loss of sexual interest and drive (hyposexuality). Less often sexual preference changes can occur and rarely fetishistic, exhibitionistic, or sadomasochistic problems occur. Some patients also develop an obsessive concern about sex and sexual performance. Treatment for these sexual problems is poor with antiepileptic or psychiatric medications but at times has been altered by unilateral temporal lobe surgery, a rather heroic procedure that many, if not most, patients are unable to undergo.
- Damage to frontal lobes can also impair the executive function, that is the ability to plan, initiate, organize, carry out, monitor, and correct one's own behavior.
- W.W. Beatty and N. Monson “Problem Solving By Patients With Multiple Sclerosis”, Journal of the International Neurological Society 2:134-140, 1996; V. Goel and P. Grafman, "Are Frontal Lobes Involved With Planning Functions? Interpreting Data From the Tower of Hanoi", Neuropsychologia 5:623-642, 1995.
- Sexual abnormalities can be associated with epilepsy or other brain diseases. These include a loss of sexual interest and drive (hyposexuaJity); fetishistic, exhibitionistic, or sadomasochistic problems; sexual preference changes (homosexuality, transsexuality, or transvestism); obsessive interest in sex or sexual performance; or compulsive sexual activity. Homosexuality may become a problem for those patients who have difficulty accepting this change or who are under societal pressure. It has been long established that altered sexuality can result from various brain impairments including temporal lobe epilepsy. D. M. Bear, Cortex 15:357-384, 1979.
- RP hereditary or genetic neurological disorder
- a characteristic is that vision is particularly worse in poor light and color vision goes first.
- Approximately 1 in 3000 in the population suffer from inherited retinal degeneration.
- About one in 80 people carry a single copy of a recessive RP gene. There are no known treatments for RP at this time.
- Huntington's Disease is a relatively rare (6/10,000 in U.S. and Europe) fatal neurological disorder of a hereditary nature. It is an autosomal chromosome 4 dominant disorder with full penetrance (50% chance of all children of being affected) which usually begins between age 35-40 years and kills the patient in about 15 years with severe behavioral and neurological impairments in this morbid period. There are no successf l treatments of these behavioral or neurological disorders of H.D. Neither gamma amino butyric acid (GABA) agonists (i.e., carbamazepine or valproic acid) nor antipsychotic medications repair the behavioral or neurological problems of H.D. in any satisfactory fashion.
- GABA gamma amino butyric acid
- Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) are similar problems of unknown cause which lead to considerable suffering and debility over 6 months or more and often for many years.
- the incidence is approximately 250 per 100,000 for CFS and as high as 5% ofthe general medical population for FM.
- the management of FMS involves a multidisciplinary approach including various medication which affect the central nervous system, and addressing each perpetuating factor, such as pain, lack of sleep, fatigue and muscle rigidity, separately. Medications are used along with a program of proper diet, life-style changes, mind work and body work.
- FM and CFS share in common severe fatigue, impaired concentration and memory, exercise intolerance, unrefireshing sleep, muscle and joint pain, malaise, and headaches.
- FM is differentiated from CFS by specific point pain spots in the muscles and CFS differs from FM by having a sore throat, tender cervical or axillary lymph nodes, variably elevated erythrocyte sedimentation rate, occasional low grade temperature, and a variety of immunologic or neuroendocrinologic test values (none of which are consistent or indicative of any known etiologic agent). See, e.g., K. Fukuda et al., Ann. Intern. Med. 121 :953-959, 1994; A. L. Komaroff et al., Rev. Infect. Dis.
- GWS Gulf War Syndrome is a disorder of unknown etiology and affecting about 1% of all Gulf War veterans according to Defense Department research.
- One clue to the cause is that a number of those veterans affected never reached the Gulf War area but contracted the syndrome while training for the war in Europe. This suggests that various injections or protective vaccines may have had some etiological role.
- the symptoms of GWS are very similar to those of Fibromyalgia/Chronic Fatigue Syndrome with the addition of severe allergic complaints. According to the American Legion, symptoms may include: chronic fatigue, headache, muscle pain, sleep disturbance, neuropsychological signs or symptoms (such as memory loss or encephalopathy), and various allergic signs and symptoms including asthma, rash or gastrointestinal problems. There are no successful treatments known for GWS.
- SBS Sick Building Syndrome
- GWS Fibromyalgia/Chronic Fatigue Syndrome. It is of unknown etiology other than it occurs within certain buildings and produces allergic symptoms (skin rashes, asthmatic symptoms, and flu-like complaints), fatigue, cognitive problems, headaches, and muscle aches. It has been assumed that there is some form of allergen or toxic substance that affects those in the building involved, but no particular agent has been identified. There are no successful treatments for SBS other than leaving the building.
- Opioid or narcotic abuse or addiction most particularly addiction to or involving the abuse of heroin, but which also may involve other opiates such as propoxyphene, meperidine, hydromorphine, codeine, levorphanol, methadone, oxycodone, morphine, hydroc ⁇ done bitartrate and other opiate derivatives, represents a major drug problem throughout the world. It probably results from at least two events: (1) a chance or purposeful exposure ofthe addict or abuser to one of these opiates (either through illegal sources or medical sources) with the intake by oral, nasal, or intravenous routes, and (2) the individual exposed may have special needs for drugs which mute pain and distress.
- opiates such as propoxyphene, meperidine, hydromorphine, codeine, levorphanol, methadone, oxycodone, morphine, hydroc ⁇ done bitartrate and other opiate derivatives
- RSDS Reflex Sympathetic Dystrophy Syndrome
- CRPS Complex Regional Pain Syndrome
- RSDS is a syndrome of pain, hyperesthesia, vasomotor disturbances, dystrophic changes, significant central nervous system, and cognitive central nervous system changes such as impaired short-term memory, disorganization, lack of concentration, and confusion.
- RSDS is a progressive disease ofthe autonomic nervous system that can follow trauma, a break or a fracture, a sharp force injury (such as a knife or bullet wound), heart problems, infections, surgery, or spinal injuries. About 5% of CRPS cases arise without apparent injury, known as "spontaneous" CRPS.
- RSDS is a multi-system disorder, most commonly found in women over the age of 50, which affects nerves, skin, muscles, blood vessels, bones and the central nervous system. RSDS affects extremities, the face, shoulders, back, and eyes. There are three stages of RSDS: the acute stage; the dystrophic stage; and the atrophic stage. These stages last around 6 months, but can vary in each individual.
- the acute stage has intense, severe constant, burning pain and neuralgia.
- the dystrophic stage includes, in addition to the symptoms ofthe acute stage, bone changes, hair and nail changes and rigidity and restrictive movement. In the atrophic stage, the pain spreads proximately, and irreversible tissue damage occurs. Severe restriction of function and anatomic dysfunction is experienced.
- the skin appears mottled, becomes easily bruised, and has a shiny red and tight look to it. There is often profuse sweating in the areas involved. Later in the course ofthe illness there is a constriction ofthe vasculature with coldness, loss of skin integrity, low-grade fever, edema, sores, dystonia, tremors, insomnia, emotional disturbance, memory problems, and demineralization ofthe bones in the affected limb.
- the treatments currently available aim at blocking the effects of sympathetic hyperactivity.
- the treatments address individual symptoms and offer temporary relief, such as physical therapy, non-steroidal anti-inflammatory drugs, tricyclic antidepressants, anticonvulsants, and corticosteroid injections.
- Cerebral Palsy is a chronic disability characterized as a range of neuromuscular disorders caused by injury to an infant's brain sustained during late pregnancy, birth or any time during the first two years of life. Approximately 2 per 1,000 individuals in the U.S. have cerebral palsy. Symptoms typically include reduced movement due to stiff or permanently contracted muscles; uncontrolled movements; difficulty with coordination while walking and moving the upper limbs, or inability to speak or swallow.
- Cerebral Palsy causes which lead to Cerebral Palsy are typically prenatal causes such as infection, maternal stroke, exposure to environmental toxins, or brain development problems. Remaining causes are due to adverse events such as traumatic birth delivery, premature birth and complications, meningitis or head injury.
- Sibutramine hydrochloride monohydrate (N, N-Dimethyl-l-[l-4-chlorophenyl cyclobutyl]-3-methylbutylamine hydrochloride monohydrate) available as MERIDIA ® (Knoll Pharmaceutical Co., Mount Olive, New Jersey) has been described for the treatment of obesity and depression (U.S. Patent Nos. 4,746,680, 4,929,629 and 5,436,272), for diabetic hyperglycemia (WO 98/11884), and for hyperlipidemia (WO 98/13034).
- sibutramine' s mode of action is believed to include, among other things, inhibition of serotonin, norepinephrine, and dopamine reuptake. Accordingly, it intensifies all three of these brain neurotransmitters at their post-synaptic receptor sites.
- the invention provides a method of treating secondary neurological, behavioral, and cognitive symptoms or disorders emanating from primary organic impairments.
- the term neuropsychiatric will be used herein to encompass these neurological, behavioral and cognitive symptoms or disorders.
- the conditions to be treated encompass symptoms and disorders including symptoms of Cerebral Palsy; symptoms of Torticollis; symptoms of Dystonia; symptoms of Dyskinesia, Lingual Dyskinesia or facial Dyskinesia, symptoms of Institutionalization Syndrome, Concentration Camp Syndrome or Survivor Syndrome; Dementia or chronic brain syndrome, Alzheimer' s-type Dementia or non- Alzheimer' s-type Dementia; symptoms of Sick Building Syndrome (SBS); symptoms of Gulf War Syndrome (GWS); symptoms of Reflex Sympathetic Dystrophy Syndrome (RSDS); symptoms of Retinitis Pigmentosa (RP); vocal and motor tics, obsessive compulsive behavior, and cognitive and behavior disorders of Tourette's syndrome and non-Tourette's disorders; symptoms of Posttraumatic Stress
- PTSD Attention Deficit Hyperactivity Disorder
- ADHD Attention Deficit Hyperactivity Disorder
- ADD Attention Deficit Disorder
- violence or rage such as seen with an intermittent explosive disorder
- adult or adolescent sexual disorder or sexual dysfunction including hyposexuality, hypersexuality, obsessive-compulsive sexual activity, gender choice problems (including homosexuality), and sexual deviations (fetishism, transvestism, pedophilia, sadomasochistic behavior, exhibitionistic behavior, and frotteurism); self mutilation including self-laceration and other self-abuse; oscillopsia; psychological, behavioral, emotional, cognitive and motor symptoms of Huntington's Disease; severe fatigue, sleep abnormalities, cognitive difficulties, and pain of fibromyalgia and chronic fatigue syndrome; severe psychoses with hallucinations and /or delusions refractory to conventional antipsychotic treatment as caused by primary impairments including trauma, brain tumors, amino acid imbalance, chromosomal abnormalities, metabolic disorders including renal failure and diabetes, and genetic disease;
- the primary impairments which give rise to these symptoms include as non- limiting examples, temporal lobe epilepsy (TLE), Huntington's Disease, Tourette's Disorder, non-Tourette's Disorder, atypical attention deficit disorder with or without hyperactivity, adult or adolescent sexual disorders, Posttraumatic Stress Disorder (PTSD), multiple personality disorder, borderline personality, and organic psychosis.
- the primary impairments can be systemic such as systemic lupus erythematosus; brain disorders from systemic causes such as metabolic, genetic or chromosomal diseases, brain cysts, and tumors; Fibromyalgia, Chronic Fatigue Syndrome; viral infections and resulting neurological injuries.
- the treatment includes administering a pharmacologically effective dose of a dopamine, serotonin and norepinephrine reuptake inhibitor, particularly sibutramine, to a human in need of such treatment.
- the treatment has also been shown to interrupt endorphin- opioid pathology. Patients most advantageously treated are those with severe symptoms. By severe is meant intractable symptoms which have not responded to standard medication sufficiently to control those symptoms.
- the primary impairments include brain impairments such as brain disease, brain lesions, and systemic impairments such as lupus erythematosus, fibromyalgia, and chronic fatigue syndrome.
- DSM-IN Statistical Manual of Mental Disorders
- sibutramine as used herein means compounds of sibutramine hydrochloride monohydrate, more specifically ⁇ , ⁇ -dimethyl- 1 -[ 1 -(4- chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride preferably in its monohydrate form, and enantiomers and analogues thereof, as described in U.S. Patent Nos. 4,746,680, 4,929,629 and 5,436,272.
- Sibutramine is believed to inhibit reuptake of norepinephrine, serotonin and dopamine thereby intensifying their effects in the brain.
- Sibutramine is commercially available as MERIDIA ® , Knoll Pharmaceutical Company, Mount Olive, New Jersey.
- Capsules are presently available with discrete dosages of 5, 10 and 15 mg for oral administration.
- the sibutramine is administered in a pharmaceutically active dose.
- the preferred dosage is about 5 mg three times a day but there is variation between patients for the best dose.
- the cytochrome P450 system differs in individuals and the dose must be determined empirically in each patient. The effect ofthe cytochrome P450 system on metabolism of psychotropic drugs is discussed in "Intercom: The Experts Converse", published by The Journal of Clinical Psychiatry, November 1995.
- the lowest effective dose has been shown to be 0.25 mg daily and the highest dose has been shown to be 45 mg (15 mg 3 times daily). It is possible that higher or lower doses can be used depending upon each individual. Therefore, more flexibility in available dosage is needed.
- the sibutramine, sibutramine salt or derivative thereof is administered, preferably in a pharmaceutical carrier and in a pharmaceutically effective dose, preferably about 5 mg three times a day.
- the dose can vary depending upon the individual, e.g., from about 0.25 mg to 45 mg or more per day.
- sibutramine has been described for the treatment of conditions such as obesity, depression, diabetic hyperglycemia, hyperlipidemia, senile dementia and related conditions, and Parkinson's disease, it has been discovered that sibutramine can be successfully used in treating other problems unrelated to these conditions.
- treating other problems according to the invention for example, rather than demonstrating an anti-obesity effect, most patients gained weight when the changes resulting from the method of the invention were taking place. For example, patients with ADD previously treated with stimulants found it easier to eat when treated with sibutramine and gained weight.
- the improvements according to the invention were rapid and the symptoms were alleviated within minutes or hours of treatment. Therefore, the improvements were seen in the short term, and the improvements continued long term.
- sibutramine acts as a stabilizer or normalizer of the secondary effects of various neuropsychiatric conditions.
- Sibutramine appears to correct multiple secondary, ancillary neurophysiological signs and symptoms of many neuropsychiatric disorders. While it is not intended to be bound by theory, this may be through a "damping" neurological effect which would restrict or mute abnormal impulses emanating from the area of pathology or injury (such as the temporal lobe) to peripheral areas (such as the hypothalamus, the amygdala, the hippocampus, other limbic structures, or motor areas).
- Sibutramine is therefore usually an "add-on" medication to other medications, such as antiepileptic or anti-depressant medications.
- sibutramine activates endorphins or, at the very least, modifies the endorphinergic opioid systems to promote serenity and lack of pain and stress, and to reduce craving for heroin.
- Such a mechanism which was previously unsuspected may have also contributed to the therapeutic effects of sibutramine herein described for PTSD, asocial behavior and fibromyalgic pain which have not been helped by serotonin, dopamine and norepinephrine potentiators.
- sibutramine promotes neurogenesis.
- Neurogenesis is the routine growth of new brain cells which is initiated by the chemical release of serotonin. Serotomn travels from one neuron to another by crossing a gap known as a synapse. Normally, once the receiving neuron is activated, the chemical is reabsorbed by the brain. Sibutramine was discovered to inhibit the reuptake of serotonin which allows serotonin to remain in the synapse and interact with its targets for much longer than it otherwise would. As a consequence, sibutramine can be administered as a means of promoting and/or controlling neurogenesis.
- Neurogenesis has been found to be inhibited by the release of certain hormones, such as glucocorticoids. Studies have found that elevated levels of glucocorticiods, such as those found in depressed patients, actually suppress neurogenesis or even kill existing neurons, especially in the area ofthe hippocampus known as the dentate gyrus. Gary Greenberg, Discover, 65-68, July 2001. Thus, a lack of or decrease in neurogenesis, correlates with a decrease in size ofthe hippocampus, a region in the brain associated with learning, memory and emotion, and consequently, a decrease or inability for the patient to perform mental and physical activities associated with these skills.
- hormones such as glucocorticoids.
- the present invention has also found that patients with Post Traumatic Stress experienced inhibited neurogenesis, as shown by the shrinking hippocampus, due to the stress-induced release of glucocorticoids. Sibutramine not only relieved the symptoms of Post Traumatic Stress but it is believed that it induced neurogenesis, as evidenced by not only an increase in the hippocampus, but enhanced mental and motor skills associated therewith. These benefits were lost rapidly when either the patient was taken off sibutramine or when steroids, such as cortisone were concomitantly administered.
- Enhancement of frontal lobe (executive planning) function (Case Nos. 41 and 78).
- SBS Sick Building Syndrome
- RSDS Reflex Sympathetic Dystrophy Syndrome
- CRPS Complex Regional Pain Syndrome
- TLE head injury temporal lobe epilepsy
- other organic brain disorders may be associated with various sexual impairments.
- the most common sexual effect of organic brain problems is a loss of sexual interest and drive (hyposexuality). Less often sexual preference changes can occur and rarely fetishistic, exhibitionistic, or sadomasochistic problems occur. Some patients also develop an obsessive concern about sex and sexual performance.
- the following case histories 3 through 7 illustrate the rapid repair of these organically based sexual problems with sibutramine.
- a 51 -year-old married man was treated for over two years for a simple partial seizure disorder of post-traumatic TLE (three automobile accidents) with severe mood swings, suicide attempts, obesity (over 300 lbs., and a body mass index of 41), memory problems, decreased organization, concentration problems, decreased sexual drive, and rage attacks.
- SPECT and EEG studies showed diffuse abnormalities in both frontal and parietal lobes. Previous treatment for his mood swings with lithium carbonate was unsuccessful and made his obesity worse. Treatment for his cognitive problems with bupropion, imipramine, nortriptyline, methylphenidate, and dextroamphetamine were unsuccessful.
- Medications that were tried without success included: haloperidol, pimozide, fluphenazine, olanzapine, fenfluramine, dexfrofenfluramirie, carbamazepine, valproic acid, clomipramine, methylphenidate, magnesium pemoline, fluvoxamine, tacrine, donepezil, dextroamphetamine, felbamate, gabapentin, lamotrigine and seligiline. Clozapine was helpful in controlling his behavior and helped somewhat with his verbal tics but produced sedation, worse ADHD, and cognitive problems. (IQ fell 30 points). It also did not help his social behavior.
- Treatment had included phenytoin, phenobarbital, clonidine, carbamazepine, fenfluramine, magnesium penoline, valproic acid, hydroxyzine, methylphenidate, bromocriptine, clomipramine, desipramine, selegiline, propranolol, clozapine, felbamate, tacrine, gabapentin, risperidone, lamotrigine, olanzapine, donepezil, and quetiapine without any good results.
- sibutramine 10 mg Every morning. This rapidly relieved his tics, his aggressive outbursts, and helped his concentration. The donepezil was continued. The effects ofthe sibutramine wore off quickly after noon with a rapid return of all symptoms. The dose of sibutramine was readjusted to 10 mg three times daily and he has continued on this medication to date with the loss of verbal and motor tics, violence, and concentration problems.
- sibutramine was started at 5 mg tid. This stopped both the tics and the OCD symptoms, but only for a few hours. When the sibutramine dose was increased to 10 mg tid, he was free of symptoms throughout the day. Sleep and appetite were not affected. Furthermore, his concentration at school was better than with any ofthe analeptics (dextroamphetamine, methylphenidate, or pemoline) which were all discontinued. Finally, if he misses a single dose of sibutramine, the vocal and motor tics return immediately; this clearly identified the duration of action of sibutramine and was typical for most ofthe 170 patients treated to date.
- PTSD post-traumatic stress disorder
- SPECT brain single photo emission computed tomography
- the patient was started on sibutramine 10 mg in the morning and was seen two days after a very severe thunderstorm with the threat of tornadoes. The patient reported she stayed up four hours of that night watching for tornadoes, completely oblivious of her former psychotic fear of thunder.
- sibutramine was stopped due to problems of dosage due to her deficiency in P-450 cytochrome system enzymes. Even one-half of the smallest capsule (5 mg) was too much and produced drowsiness, sugar craving, and weight gain. She also had not had any PTSD symptoms in many weeks and felt she might be over the disorder. Unfortunately, she immediately noted a rapid return ofthe fear of thunder, sound and light sensitivity, exaggerated startle reflex, headaches, and nightmares of life and death situations. She had to wear ear plugs and be sedated for the psychoses caused by thunderstorms or even the threat of such.
- a 25-year-old male was seen first for a life-long history of severe hyperactivity, distractibility, disorganization, poor memory of studied material, very poor concentration, and school failure despite a high IQ.
- a 46-year-old married woman with a lifelong history of ADHD was treated for four years with multiple medications including methylphenidate, magnesium pemoline, dextroamphetamine, and long-acting amphetamine salts without success and negative side effects.
- the amphetamines made her nervous, jittery, and unable to sleep.
- the methylphenidate and magnesium pemoline on the other hand, made her sleepy.
- These medications did not calm her hyperactivity without sedating her. She was started on sibutramine 10 mg every morning by mouth. Immediately she noted a calming and an alerting effect not seen with the dopamine agonist analeptics. After the first month, her dose was changed to 5 mg three times daily due to a five hour duration of effects. She has continued on the medication to date (over six months) as did her daughter who also failed to respond to all ofthe various analeptic dopaminergic drugs used for ADHD.
- FM and CFS share in common severe fatigue, impaired concentration and memory, exercise intolerance, unrefreshing sleep, muscle and joint pain, malaise, and headaches.
- FM is differentiated from CFS by specific point pain spots in the muscles and CFS differs from FM by having a sore throat, tender cervical or axillary lymph nodes, variably elevated erythrocyte sedimentation rate, occasional low grade temperature, and a variety of immunologic or neuroendocrinologic test values.
- SBS Sick Building Syndrome
- RSDS Reflex Sympathetic Dystrophy Syndrome
- the left lower leg then became red and then black, hot, swollen, and extremely painful.
- RSD was diagnosed and multiple treatments were unsuccessful. After nine months the skin gradually sloughed and the limb turned cold but remained painful, especially to touch.
- the patient also noted profuse swelling ofthe affected left leg, a tremor ofthe left hand, and many visual-spatial problems characteristic of right cerebral dysfunction. She was declared totally disabled. After various unsuccessful treatments, the patient was treated with sibutramine 10 mg. b.i.d. After the sibutramine the patient rapidly became cognitive and had pain relief. This enabled her to discontinue her other medication.
- BTX botulinum toxin
- RSDS Reflex Sympathetic Dystrophy Syndrome
- CRPS Complex Regional Pain Syndrome
- a clonodine patch 0.1 mg patch
Abstract
Description
Claims
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AU2002258820A AU2002258820B2 (en) | 2001-04-17 | 2002-04-17 | Treatment of disorders secondary to organic impairments |
EP02728788A EP1404308A4 (en) | 2001-04-17 | 2002-04-17 | Treatment of disorders secondary to organic impairments |
JP2002580919A JP2004527532A (en) | 2001-04-17 | 2002-04-17 | Treatment of disorders secondary to organ dysfunction |
CA2444269A CA2444269C (en) | 2001-04-17 | 2002-04-17 | Treatment of disorders secondary to organic impairments |
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US10/092,144 US6696495B2 (en) | 1998-12-02 | 2002-03-06 | Treatment of disorders secondary to organic impairments |
US10/092,144 | 2002-03-06 |
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ES2425114T3 (en) * | 2000-03-16 | 2013-10-11 | The Mclean Hospital Corporation | CDP-choline and uridine for the treatment of alcohol abuse |
EP1765364A4 (en) * | 2004-06-10 | 2010-09-22 | Mclean Hospital Corp | Pyrimidines, such as cytidine, in treatments for patients with bipolar disorder |
US7737128B2 (en) * | 2004-06-10 | 2010-06-15 | The Mclean Hospital Corporation | Pyrimidines, such as uridine, in treatments for patients with bipolar disorder |
EP1784199A4 (en) * | 2004-08-11 | 2010-06-23 | Mclean Hospital Corp | Compounds for the treatment of marihuana dependence, withdrawal, and usage |
MX2007003126A (en) * | 2004-09-14 | 2007-08-02 | Ajinomoto Omnichem S A | Topical compositions containing phosphorylated polyphenols. |
US20110046120A1 (en) * | 2006-10-26 | 2011-02-24 | Mclean Hospital Corporation | Treatment of impulse control disorders |
US20100041621A1 (en) * | 2008-08-15 | 2010-02-18 | Perry Renshaw | Methods and compositions for improving cognitive performance |
WO2017168174A1 (en) | 2016-04-02 | 2017-10-05 | N4 Pharma Uk Limited | New pharmaceutical forms of sildenafil |
US11157700B2 (en) * | 2017-09-12 | 2021-10-26 | AebeZe Labs | Mood map for assessing a dynamic emotional or mental state (dEMS) of a user |
US10682086B2 (en) * | 2017-09-12 | 2020-06-16 | AebeZe Labs | Delivery of a digital therapeutic method and system |
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- 2002-03-06 US US10/092,144 patent/US6696495B2/en not_active Expired - Fee Related
- 2002-04-17 WO PCT/US2002/012011 patent/WO2002083115A1/en active Application Filing
- 2002-04-17 AU AU2002258820A patent/AU2002258820B2/en not_active Ceased
- 2002-04-17 JP JP2002580919A patent/JP2004527532A/en active Pending
- 2002-04-17 EP EP02728788A patent/EP1404308A4/en not_active Withdrawn
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EP1404308A4 (en) | 2007-05-02 |
JP2004527532A (en) | 2004-09-09 |
CA2444269A1 (en) | 2002-10-24 |
EP1404308A1 (en) | 2004-04-07 |
AU2002258820B2 (en) | 2006-03-16 |
US6696495B2 (en) | 2004-02-24 |
US20040157934A1 (en) | 2004-08-12 |
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