Patent Abstract:
the compound carvedilol has the chemical formula : ñ - 1 -- 3 - ethyl ] amino ]- 2 - propanol . it exists in the form of optical isomers r - and s - carvedilol , and as mixtures of these isomers . it , or one of its optical isomers , is administered , preferably orally , several times per day in tablets of 3 - 25 mg for the treatment , prevention and clinical arrest of movement disorders associated with medications which block dopamine receptors , including many antipsychotic and antiemetic medications . such movement disorders include tardive dyskinesia , tardive dystonia , and tardive akathisia . the compound carvedilol is also administered to improve the treatment of mental disorders in which dopamine - blocking medications are used , such as manic episodes , major depressive episodes , and psychoses such as schizophrenia and schizoaffective disorder .

Detailed Description:
it exists in the form of optical isomers r - and s - carvedilol , and as mixtures of these isomers . because carvedilol &# 39 ; s antioxidant activity is exceptionally potent , this activity has been speculated to be responsible for carvedilol &# 39 ; s beneficial effects in diminishing heart failure and preventing recurrence of myocardial infarction . carvedilol &# 39 ; s antioxidant activity has been w observed in several ways . it protects against injury by oxygen free radicals to endothelial cells ( the inner linings of blood vessels ), vascular smooth muscle , and neurons , including during ischemia and during reperfusion after ischemia . its antioxidant activities include inhibition of several actions : 1 ) direct toxic effects of oxygen radicals , 2 ) the ability of oxygen radicals to counteract nitrogen oxide - mediated vasodilation , 3 ) activation by oxygen radicals of genes associated with inflammation and 4 ) dna fragmentation . carvedilol also produces increases in body levels of endogenous antioxidants such as glutathione , which indicates replenishment of antioxidant defense mechanisms . as outlined above , carvedilol has several other actions which are beneficial to injured brain . among these is blockade of the l - type calcium channel current ( cheng et al . 1999 ), an effect rarely mentioned in publications about carvedilol . antagonists of the l - type calcium channel are neuroprotective ( mcleod et al 1998 ). from the opposite direction , activation of the calcium channel in neuronal tissues is a critical step towards neuronal injury and degeneration ( kobayashi & amp ; mori 1998 ). accordingly , we reason that l - type calcium channel blockade by carvedilol in neuronal tissues should shield the brain from injury and degeneration , and thereby allow it to recover and regenerate from previous injury . blockade of the l - type calcium channel is the primary effect of the pharmaceutical nimodipine , and it is reasonable to expect that carvedilol has effects similar to nimodipine . so it is relevant to note that administration of nimodipine for 12 weeks improved memory in patients who had experienced stroke , when started 1 to 2 weeks after the stroke ( sze et al . 1998 ). nimodipine improved memory , performance , and mood in a 12 week trial on elderly patients with dementia ( ban et al . 1990 ), and it diminished essential tremor in most cases ( biary et al 1995 ). similarly , l - type calcium channels contribute to dystonias in several animal models , and nimodipine mitigated these dystonias ( richter & amp ; loscher 1996 ; campbell & amp ; hess 1999 ). nimodipine provided benefit to patients with major depressive disorder and bipolar mood disorder ( pazzaglia et al . 1998 ; 1993 ). overall , its l - type calcium channel blockade activity provides another rationale for activity by carvedilol against neuronal injury and degeneration , and for its mitigation of neuropsychiatric disorders including movement disorders . blockade of alpha - and beta - adrenergic receptors might contribute to carvedilol &# 39 ; s mitigation of tardive dyskinesia , but probably only in conjunction with carvedilol &# 39 ; s other effects . only long - term and not brief duration of beta - blockade by itself diminished td ( karniol & amp ; portela 1982 ; schrodt et al . 1982 ); as described below , carvedilol had an extremely rapid onset of effectiveness against td , so this rapidity is not attributable to beta - blockade alone . in an animal model of td , one - day and two - week trials of the beta - blocker propranolol did not diminish orofacial movements caused by the antipsychotic dopamine - receptor blocker haloperidol ( takeuchi et al 1998 ). blockade of alpha - 1 adrenergic receptors produces dilation of arteries and arterioles , which tends to increase blood flow and thereby dilute and carry away locally high concentrations of toxic species , such as reactive oxygen , which are produced by injured brain tissue . this should diminish toxic self - injurious “ positive - feedback ” cycles , as can occur with neuronal releases of calcium and glutamate . in contrast to the lack of benefit from beta - blockers alone in tardive dyskinesia , beta - blockers diminish akathisia ( sachdev & amp ; loneragan 1993 ). this effect is separate from a decrease in dyskinesia , just as akathisia is separate from dyskinesia . nevertheless , carvedilol provides a unique action to diminish both tardive dyskinesia and tardive akathisia with a single pharmaceutical agent . none of the pharmaceutical actions of carvedilol are specific to sexual function , sexual characteristics , or gender . accordingly , carvedilol should have similar beneficial effects in both males and females . in the present invention , carvedilol is orally administered to decrease , prevent , or diminish the progression of the movement disorders that can be caused by medication which blocks dopamine receptors . the movement disorders include tardive dyskinesia and tardive dystonia , and they also include the agitated movements that accompany tardive akathisia . it is reasonable to expect that these particular signs and symptoms represent particular similar pathological brain states regardless of the cause of those brain states , one of which is exposure to medication which blocks dopamine receptors . the beneficial effects of carvedilol on these mental signs and symptoms and on td should be seen in patients regardless of diagnosis or apparent causative factors . patients for whom these symptoms or signs are a source of substantial distress or impairment should experience diminution of these symptoms and signs from a suitable dose of carvedilol , with associated decreases in symptoms , complaints , or impairments . such mental disorders include schizophrenia , schizoaffective disorder , schizophreniform disorder , mood disorders such as major depressive disorder and bipolar disorder , obsessive - compulsive disorder , delusional disorder , anxiety disorders , psychoses consequent to chronic medical conditions , and tourette &# 39 ; s syndrome . this 47 year old caucasian female was seen in the hospital . on examination she showed choreic ( jerking ) and athetotic ( writhing ) movements of the tongue , including repeated prominent protrusion of the tongue from the mouth . these movements were consistent with tardive dyskinesia . she also showed substantial agitation , as a sign of tardive akathisia . she mentioned having been told by several psychiatrists that she has tardive dyskinesia , and that she &# 39 ; d previously taken numerous different antipsychotic drugs , including risperidone , olanzapine , and clozapine . clozapine is recognized as a drug that , because of dangerous side - effects , is reserved as the last resort after the failure of long courses and high doses of several other antipsychotic medications . on the third hospital day , a friday ( nov . 13 , 1998 ), the tongue protrusion movements continued unchanged . carvedilol 6 . 25 mg once daily was then started . on 11 / 15 the carvedilol dose was increased to 6 . 25 mg twice daily . when next evaluated , at 9am on monday 11 / 16 , the tongue protrusions were absent . the absence of dyskinesia persisted despite the patient &# 39 ; s repeated expressions of anxiety and anxious thoughts . with the lack of any faintness or bradycardia , the dose of carvedilol was increased to 6 . 25 mg in the morning and 12 . 5 mg at bedtime . agitation then decreased , a sign of improvement in tardive akathisia . on the ninth hospital day carvedilol was discontinued . the patient was discharged on the 15th hospital day , without recurrence of any tongue protrusion , and without observable agitation . this 37 year old caucasian female seen in the hospital had been taking high doses of haloperidol for several years , including 30 mg / day orally and depot haloperidol decanoate intramuscularly 50 mg / week , to treat bipolar mood disorder and an anxiety disorder . administration of haloperidol was discontinued three months prior to this hospitalization , so that the effects of depot haloperidol decanoate were nearly worn off . on examination she showed a prominent tongue protrusion every two minutes , felt to be a severe manifestation of tardive dyskinesia . she spontaneously complained that children in her neighborhood mocked her and called her a witch because of the tongue movements . she stated that she avoids leaving the house because of harassment by the children . she also showed the agitated movements that accompany tardive akathisia . on the first hospital day carvedilol 3 . 125 mg twice daily was started . on interview the next day no extensions of the tongue out of the mouth occurred , and she was discharged that day . she was rehospitalized 11 days later , and had not been taking carvedilol . prominent tongue protrusions were seen every 2 to 3 minutes . carvedilol was then restarted . beginning on the next day tongue protrusions were no longer seen . the patient was discharged after one week ; at the time of discharge there were no agitated movements consistent with tardive akathisia . the patient said that with the disappearance of these unwanted movements she felt calmer and happier overall , and her mood problems and anxiety symptoms were less . carvedilol was continued for a month . during this time no tongue protrusions or agitated movements were seen , and the patient did not experience an episode of mood disorder ; thus , it both diminished and prevented the progression of the symptoms of td and tardive akathisia . the good clinical condition of the patient suggests that carvedilol also contributed to the prevention of recurrence of manic episodes and depressive episodes . carvedilol was then discontinued and the symptoms of td and tardive akathisia returned within a week . this 64 year old caucasian female was admitted to the hospital for the treatment of an anxiety disorder whose symptoms included insomnia , nightmares , unhappiness , suicidality , continual worry , and panic attacks . she had previously taken the antidepressants nortriptyline and fluoxetine , and was taking nefazodone 375 mg / day for one year . she was also taking the antihypertensive medication benazepril 40 mg / day , and the sleeping medication zaleplon 10 mg / day . on examination she showed prominent choreic tongue protrusion , athetotic chewing movements with an empty mouth , and pouting and puckering of the lips . on the abnormal involuntary movement scale ( aims ) she was rated with a score of 11 . she then received carvedilol 3 . 125 mg twice daily . twenty - four hours later , after two doses , chewing movements were gone , lip and tongue movements were in normal range , and the aims score fell to 6 . carvedilol was then discontinued and the symptoms returned just as they were prior to treatment . this 53 - year - old caucasian male was in the hospital because of difficulty swallowing . this began about a year prior to hospitalization while taking haloperidol and lithium medications . increasingly he would cough while eating or drinking . he had taken haloperidol and lithium for many years to treat bipolar manic - depressive illness . the swallowing difficulty worsened despite replacement of lithium and haloperidol with divalproex and olanzapine . in the hospital testing by the speech therapy department found that when he tried to swallow he would aspirate fluid into his lungs . this aspiration put him at risk of aspiration pneumonia , which is disabling and can be life - threatening . for him to receive water and food a tube was surgically inserted between his stomach and the outside of his abdomen . on examination he showed prominent dystonia of the neck and head , with frequent abrupt obvious extension movements of the neck muscles of moderate degree . when he tried to drink water from a cup these movements obviously interfered with swallowing . he also showed mild dystonia of the eyebrows and forehead muscles , which were displaced upward . his tongue showed moderate dyskinesia ; he could not hold it still . on the abnormal involuntary movement scale ( aims ) he scored 13 . he then received carvedilol 6 . 25 mg twice daily . twenty - eight hours later , after three doses , his swallowing was rated by the speech therapy department as 70 % improved . the neck dystonia had decreased from moderate to mild , the facial dystonia had disappeared , the tongue dyskinesia had decreased from mild to marginal , and the aims score was 8 . all four cases indicate that carvedilol can treat the physical manifestations of td . the first three cases indicate treatment of tardive akathisia . in the first two cases td disappeared from one regular workday to the next , a weekday in one case and a weekend in the other case . in the third case , all observable abnormal movements disappeared in one day , and only a few slight similar movements that did not appear clearly abnormal remained . the movements associated with tardive akathisia observable in the first two cases also improved with carvedilol administration . debilitating tardive dystonia decreased importantly with carvedilol administration in the fourth case . the stability of response and good mood observed in the second case indicates that carvedilol may act to prevent manic episodes , depressive episodes , and psychosis in patients with a history of these . the extreme rapidity and extent of response seen exceeds what can be attributed to carvedilol &# 39 ; 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