RESUMO
PURPOSE: This study examines the effects of the tyrosine hydroxylase inhibitor L1-79, a racemic formulation of α-methylparatyrosine, in patients with autism spectrum disorder (ASD) in a prospective case series. The l-isomer formulation of α-methylparatyrosine, metyrosine, is approved for the management of patients with pheochromocytoma. METHODS: Six male and 2 female patients aged 2.75 to 24 years with ASD were treated for 8 weeks at L1-79 doses ranging from 90 to 400 mg thrice daily. Assessments at weekly intervals included the Aberrant Behavior Checklist-Community (ABC-C), Connor's Parent Rating Scale (CPRS), and Clinical Global Impressions (CGI) scale. The Autism Diagnostic Observation Schedule (ADOS) was administered at baseline and week 10. FINDINGS: The ABC-C and CPRS scores improved between baseline and end of study for 7 of 8 participants; most participants' assessment scores decreased. At week 8, the CGI efficacy index was 05 for 6 of 8 participants, indicating modest improvement with at least partial resolution of symptoms and no medication adverse effects, and 09 for 2 participants, indicating minimal improvement and no change in status or care needs, without adverse effects. The mean ADOS scores improved by ≥31% for 4 of the 6 participants tested, with 1 patient experiencing a 47% improvement. Seven of the 8 participants previously taking psychotropic medications were stable without their legacy medications while receiving L1-79, and 1 patient resumed a single legacy medication at a lower dose. Three adverse events were reported; symptoms were mild and resolved without change in therapy. IMPLICATIONS: These results suggest L1-79 may be a tolerable and effective treatment for the core symptoms of ASD, which must be confirmed with double-blind studies.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Metiltirosinas/uso terapêutico , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Adolescente , Adulto , Comportamento/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Metiltirosinas/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
The metabolic fate of the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (alpha-MPT), was studied after oral administration of single and multiple doses to patients with pheochromocytoma and essential hypertension. No major urinary excretion product was found other than the drug itself, which accounted for 44-88% of the fate of single or repeated oral doses. Though less than 1% of the administered drug could be recovered in the urine as catechol metabolites, it was possible to identify alpha-methyldopa, alpha-methyldopamine, and alpha-methylnorepinephrine and to quantify the excretion of the first two of these compounds. This minor route of metabolism required revision of methodology (presented herein) for measuring urinary catecholamines during alpha-MPT treatment since these compounds produce spurious fluorescence in routine methods of assay for catecholamines. The catechol metabolites probably are not present in sufficient amounts to contribute to the biochemical effects of the drug. Determination of plasma concentrations of alpha-MPT during maintenance therapy and considerations of the kinetics of enzyme inhibition enabled a calculation to be made of the degree of inhibition of catecholamine synthesis to be expected in the patient. This was calculated to be about 75% for the highest doses employed and is similar in magnitude to experimentally determined values.
Assuntos
Catecolaminas/biossíntese , Metiltirosinas/metabolismo , Metiltirosinas/uso terapêutico , Isótopos de Carbono , Cromatografia em Papel , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Cinética , Metildopa/urina , Metiltirosinas/administração & dosagem , Metiltirosinas/sangue , Metiltirosinas/urina , Oxigenases de Função Mista/antagonistas & inibidores , Norepinefrina/urina , Normetanefrina/urina , Feocromocitoma/tratamento farmacológico , Feocromocitoma/metabolismo , TrítioRESUMO
Alpha methyltyrosine (alpha-MPT) was administered to 52 patients from 4 days to 10 months; 22 patients were cases of pheochromocytoma and 20 had essential hypertension. Inhibition of catecholamine synthesis in the range of 50-80% was achieved with divided daily drug dosage of from 1.0 to 4.0 g. Striking clinical benefit was noted in patients with pheochromocytoma in whom the drug was used in preparation for surgery and during chronic medical management. The drug appeared to have limited usefulness when used in essential hypertension, unless added to existing therapy with conventional agents. No beneficial effects were noted in thyrotoxicosis, glaucoma, and Raynaud's phenomenon. Untoward effects in order of decreasing incidence were: sedation (with insomnia on withdrawal), anxiety, tremor, diarrhea, and galactorrhea. Drug crystalluria, which has been observed in animals and is currently restrictive of clinical trials, was not observed in these studies. Evidence is presented that the minor conversion of alpha-MPT to methyldopa probably does not contribute significantly to the central and peripheral effects of the drug.
Assuntos
Metiltirosinas/metabolismo , Metiltirosinas/uso terapêutico , Adolescente , Adulto , Idoso , Metabolismo Basal/efeitos dos fármacos , Benzoatos , Pressão Sanguínea/efeitos dos fármacos , Catecolaminas/biossíntese , Catecolaminas/urina , Feminino , Glaucoma/tratamento farmacológico , Glaucoma/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertireoidismo/tratamento farmacológico , Hipertireoidismo/metabolismo , Masculino , Ácidos Mandélicos/urina , Metiltirosinas/efeitos adversos , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/metabolismo , Normetanefrina/urina , Feocromocitoma/tratamento farmacológico , Feocromocitoma/metabolismo , Doença de Raynaud/tratamento farmacológico , Doença de Raynaud/metabolismoRESUMO
Four patients with chronic schizophrenia of stationary character were studied in order to titrate the lowest dose of thioridazine necessary for symptomatic control when the drug is given in combination with the inhibitor of catecholamine synthesis, metyrosine. The study showed 15% to 50% of the pretrial dose level of thioridazine hydrochloride was effective. In the present trial, the 779704 combination was maintained without any alterations in dosage for six months, and the therapeutic effect persisted unchanged. This treatment period was terminated by a double-blind crossover design, and the activity of metyrosine was corroborated in all cases. Plasma drug concentrations and cerebrospinal fluid amine metabolites were measured. The data indicate that schizophrenic symptoms can be profoundly influenced by changes in catecholamine synthesis. Catecholamine-carrying neurons thus seem to be fundamentally involved in those brain functions that are disturbed in schizophrenia. The clinical usefulness of metyrosine in combination with neuroleptic agents deserves more extensive investigation.
Assuntos
Metiltirosinas/administração & dosagem , Esquizofrenia/tratamento farmacológico , Tioridazina/administração & dosagem , Idoso , Doença Crônica , Ensaios Clínicos como Assunto , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Masculino , Metiltirosinas/uso terapêutico , Pessoa de Meia-Idade , Esquizofrenia/líquido cefalorraquidiano , Tioridazina/uso terapêuticoRESUMO
According to the dopamine (DA) hypothesis of schizophrenia, there is a functional excess of dopaminergic activity within unspecified areas of the brain in schizophrenic patients. As a clinical test of this hypothesis, we administered metyrosine for three weeks to symptomatic chronic male schizophrenic patients who were maintained on suboptimal doses of neuroleptic agents. Metyrosine inhibits tyrosine hydroxylase, the rate-limiting enzymatic step in the synthesis of DA. No clinical improvement was observed, using the National Institute of Mental Health Inpatient Behavioral Rating Scale or the Brief Psychiatric Rating Scale. Central inhibition of DA synthesis by metyrosine was suggested, however, by (1) the development of extrapyramidal side effects and (2) a significant increase in plasma prolactin concentrations. Plasma chlorpromazine concentrations remained unchanged during metyrosine treatment. There was, nevertheless, a significant improvement on the scores of the Wechsler Adult Intelligence Scale Comprehension subtest, which measures judgment and common sense. This finding suggests that DA may be involved in the regulation of subtle psychological processes. The results are discussed in light of the DA hypothesis of schizophrenia and previous reports suggesting that metyrosine potentiates the antipsychotic effect of neuroleptics in schizophrenia.
Assuntos
Química Encefálica/efeitos dos fármacos , Dopamina/biossíntese , Metiltirosinas/farmacologia , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/farmacologia , Encéfalo/metabolismo , Doença Crônica , Ensaios Clínicos como Assunto , Método Duplo-Cego , Sinergismo Farmacológico , Humanos , Masculino , Metiltirosinas/uso terapêutico , Fenotiazinas , Escalas de Graduação Psiquiátrica , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Tirosina 3-Mono-Oxigenase/antagonistas & inibidoresRESUMO
In a 54-year-old man with a norepinephrine-secreting pheochromocytoma, resistance developed to the alpha-adrenergic blocking agent, phenoxybenzamine hydrochloride. Dosages of 240 mg/day were ineffective. Intravenous phentolamine mesylate reduced his BP at first, but resistance developed to this also. Therapy with alpha-methylparatyrosine, an inhibitor of catecholamine biosynthesis, finally controlled his BP, and the tumor was removed.
Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Antagonistas Adrenérgicos alfa/uso terapêutico , Feocromocitoma/tratamento farmacológico , Resistência a Medicamentos , Humanos , Hipertensão/tratamento farmacológico , Masculino , Metiltirosinas/uso terapêutico , Pessoa de Meia-Idade , Fenoxibenzamina/uso terapêutico , Fentolamina/uso terapêutico , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , alfa-MetiltirosinaRESUMO
Following an acute spontaneous hypertensive crisis and shock a patient with pheochromocytoma was found to have an exceedingly high catecholamine excretion rate. After this episode, the patient remained normotensive and urinary excretion of catecholamines returned to normal. During surgery, a large pheochromocytoma was found and removed that showed avascualr necrosis. In phenochromocytoma, a sudden and exceedingly high rate of catecholamine release may cause intense vasoconstriction both generally and within the tumor itself. In this patient, avascular tumor necrosis led to a spontaneous remission of clinical symptoms.
Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Regressão Neoplásica Espontânea , Feocromocitoma/patologia , Adolescente , Neoplasias das Glândulas Suprarrenais/diagnóstico , Epinefrina/urina , Humanos , Masculino , Metiltirosinas/uso terapêutico , Necrose , Feocromocitoma/diagnóstico , Ácido Vanilmandélico/urinaRESUMO
BACKGROUND: Severe hemodynamic instability may occur during surgery for removal of pheochromocytoma, unless there is preoperative pharmacological treatment. OBJECTIVE: To evaluate the effects of metyrosine (alpha-methyl-p-tyrosine), a catecholamine synthesis inhibitor, and alpha-blockade with prazosin or phenoxybenzamine on cardiovascular morbidity during surgery for pheochromocytoma. METHODS: A retrospective analysis was made of patients followed up at the Medical College of Georgia, Augusta, during 28 years who received metyrosine and prazosin (n = 6), metyrosine and phenoxybenzamine alone (n = 14), phenoxybenzamine alone (n = 6), or no medication (n = 7) during 3 weeks before tumor removal. The percentage of patients not requiring pressors or phentolamine during the intraoperative period as well as the perioperative peak systolic pressures and peak heart rates were estimated in each group. RESULTS: There was a significant (P < .05) increase in intraoperative peak systolic pressures without preoperative treatment (mean +/- SD, 243 +/- 40 mm Hg) vs metyrosine (mean +/- SD, 168 +/- 27 mm Hg). Ninety-five percent of patients who received metyrosine did not require pressors intraoperatively vs 50% with phenoxybenzamine alone. Eighty-one percent of patients pretreated with metyrosine did not require intraoperative phentolamine vs 33% with phenoxybenzamine alone and 29% without medications. Two patients in the no medication group died as a results of hypertensive crisis. CONCLUSIONS: The combination of alpha-metyrosine and alpha-blockade results in better blood pressure control and less need for use of antihypertensive medication or pressors during surgery, compared with the classical method of single-agent adrenergic blockade. Preoperative treatment with metyrosine along with an alpha-blocker is a useful strategy for decreasing the surgical morbidity in patients with pheochromocytoma and assumes greater importance as long as the availability of phentolamine for intraoperative use is a problem.
Assuntos
Neoplasias das Glândulas Suprarrenais/cirurgia , Agonistas alfa-Adrenérgicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Hipertensão/prevenção & controle , Complicações Intraoperatórias/prevenção & controle , Metiltirosinas/uso terapêutico , Fenoxibenzamina/uso terapêutico , Feocromocitoma/cirurgia , Prazosina/uso terapêutico , Adolescente , Neoplasias das Glândulas Suprarrenais/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Catecolaminas/metabolismo , Criança , Quimioterapia Combinada , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Complicações Intraoperatórias/etiologia , Complicações Intraoperatórias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Feocromocitoma/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento , alfa-MetiltirosinaRESUMO
Dopamine beta-hydroxylase (DBH) deficiency is a genetic disorder in which affected patients cannot synthesize norepinephrine, epinephrine, and octopamine in either the central nervous system or the peripheral autonomic neurons. Dopamine acts as a false neurotransmitter in their noradrenergic neurons. Neonates with DBH deficiency have had episodic hypothermia, hypoglycemia, and hypotension, but survivors sometimes cope relatively well until late childhood when overwhelming orthostatic hypotension profoundly limits their activities. The hypotension may be so severe that clonic seizures supervene. Most currently recognized patients are young or middle-aged adults. The diagnosis is established by the observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than one.
Assuntos
Dopamina beta-Hidroxilase/deficiência , Adulto , Diagnóstico Diferencial , Dopamina/metabolismo , Dopamina beta-Hidroxilase/genética , Droxidopa/uso terapêutico , Epinefrina/deficiência , Humanos , Hipotensão Ortostática/diagnóstico , Lactente , Recém-Nascido , Metiltirosinas/uso terapêutico , Norepinefrina/deficiência , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , alfa-MetiltirosinaRESUMO
The author analyzes parkinsonism and hyperkinesia in psychiatric patients with tardive dyskinesia before and during treatment with alpha-methyl-p-tyrosine (AMPT, a dopamine antagonist), biperiden (an acetylcholine antagonist), and baclofen (a GABA agonist); and in patients with paralysis agitans and L-dopa-induced hyperkinesia. AMPT and baclofen had similar influences on oral dyskinesia, resulting in reduced frequency, unchanged or slightly reduced amplitude, and increased duration of each movement. The author concludes that: 1) reduced dopaminergic activity may be the primary pathogenetic background for tardive dyskinesia; 2) dopaminergic hypersensitivity and/or cholinergic hypofunction is necessary before hyperkinesia breaks through; and 3) the neurotoxic effects of neuroleptics may be associated with age-dependent changes in nigrostriatal regions representing oral innervation.
Assuntos
Aminobutiratos/uso terapêutico , Baclofeno/uso terapêutico , Biperideno/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Metiltirosinas/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Piperidinas/uso terapêutico , Fatores Etários , Gânglios da Base/fisiopatologia , Colina/metabolismo , Dopamina/metabolismo , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/metabolismo , Discinesia Induzida por Medicamentos/fisiopatologia , Humanos , Levodopa/efeitos adversos , Boca/inervação , Doença de Parkinson/metabolismo , Tranquilizantes/efeitos adversosRESUMO
A variety of biologic studies have demonstrated abnormal regulation of the norepinephrine (NE) system in patients with major depression, suggesting a role for NE in the etiology of depression. Brain NE and dopamine levels can be rapidly reduced by blocking synthesis with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). In the current investigation, AMPT was administered to drug-free depressed patients to evaluate the effect on mood of diminished catecholamine levels. Seventeen drug-free patients meeting DSM-III-R criteria for major depressive episode were tested with AMPT and an active placebo control, diphenhydramine. Testing was accomplished in a double-blind, crossover fashion, with random assignment to test conditions. Each test included baseline evaluation, 2 days with administration of either AMPT or diphenhydramine, and a follow-up day. Diphenhydramine was used as an active control because of the significant sedation associated with AMPT. Behavioral ratings, including visual analogue scales for a variety of feeling states, the Hamilton Depression Rating Scale (HDRS), and plasma for 3-methoxy-4-hydroxyphenelethyleneglycol (MPHG) and homovanillic acid (HVA) levels, were obtained. AMPT significantly reduced plasma HVA by 70% and MHPG by 50%, but it had no significant effects on the HDRS. AMPT also significantly increased visual analogue ratings of "tired" and decreased ratings of "energetic." Diphenhydramine significantly decreased HDRS scores, but the change was small and was not clinically apparent. The lack of AMPT effects on depressed mood, in conjunction with a prior report that large reductions in plasma tryptophan do not systematically alter depressed mood, indicate that monoamine deficiency by itself is insufficient explanation of the cause of depression. The role of the noradrenergic system needs to be considered in relationship to the many other neurobiologic factors that could be involved in the pathophysiology of depression.
Assuntos
Transtorno Depressivo/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Metiltirosinas/uso terapêutico , Adulto , Idoso , Difenidramina/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , alfa-MetiltirosinaRESUMO
alpha-Methyl-p-tyrosine is an orally active inhibitor of catecholamine synthesis which inhibits the hydroxylation of tyrosine to dopa. At dosages of 600 to 3500 mg daily it is effective in controlling the hypertensive episodes and symptoms of catecholamine excess in phaeochromocytoma during preparation for surgery. Limited published experience suggests that it is effective in controlling hypertension and symptoms in malignant phaeochromocytoma, but further long term experience is needed. Concomitant administration of phenoxybenzamine and propranolol may be desirable in some patients and treatment with phentolamine is usually necessary to control hypertension during manipulation of the tumour.
Assuntos
Metiltirosinas/farmacologia , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Metabolismo dos Carboidratos , Catecolaminas/biossíntese , Interações Medicamentosas , Humanos , Absorção Intestinal , Cinética , Metiltirosinas/efeitos adversos , Metiltirosinas/metabolismo , Metiltirosinas/uso terapêutico , Feocromocitoma/tratamento farmacológico , alfa-MetiltirosinaRESUMO
The investigation and management of pheochromocytoma have been of special interest at the Mayo Clinic since 1926, when Dr. C. H. Mayo successfully removed an adrenal tumor. Recent clinical developments include the detection of asymptomatic paroxysms of hypertension by 24-hour ambulatory monitoring, detailed characterization of catecholamine cardiomyopathy by echocardiography, and further experience with Carney's triad and other polyglandular and multiple neoplasia syndromes associated with pheochromocytoma. Refinement in interpretation of catecholamine measurements and the development of radionuclide scanning with m-[131I]iodobenzylguanidine, computed tomography, and magnetic resonance imaging have greatly enhanced our diagnostic acumen. Developments in antihypertensive drug therapy and chemotherapy have improved our management of cathecholamine hypersecretion and tumor growth, respectively, in inoperable patients and in the preparation of patients for anesthesia and surgical treatment. Flow cytometry to detect abnormal DNA histograms may prove particularly useful in predicting the malignant nature of the tumors.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/mortalidade , Neoplasias das Glândulas Suprarrenais/terapia , Humanos , Labetalol/uso terapêutico , Metiltirosinas/uso terapêutico , Feocromocitoma/mortalidade , Feocromocitoma/terapia , Pré-Medicação , Taxa de Sobrevida , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , alfa-MetiltirosinaRESUMO
Despite the plethora of clinical drug trials in tardive dyskinesia, few consistent findings have emerged. One possible reason for this is that there have been no serious attempts to define the role of major neurotransmitter systems (dopamine, norepinephrine, acetylcholine, serotonin, GABA) in one specific population of tardive dyskinesia patients. This study reports a series of five controlled drug trials in a population of patients with persistent tardive dyskinesia; each drug probed one of four neurotransmitter systems. The intra- and interpatient responses are analyzed and the implications of the pharmacologic response profiles for the clinical management of tardive dyskinesia are discussed.
Assuntos
5-Hidroxitriptofano/uso terapêutico , Colina/uso terapêutico , Di-Hidroxifenilalanina/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Metiltirosinas/uso terapêutico , Ácido Valproico/uso terapêutico , Adulto , Idoso , Ensaios Clínicos como Assunto , Dopamina/fisiologia , Discinesia Induzida por Medicamentos/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/fisiologia , Placebos , Transmissão Sináptica/efeitos dos fármacosRESUMO
An approach to treating tardive dyskinesia and tardive akathisia was tested in 33 patients. The common denominator was the elimination of antipsychotic drugs. In 7 of 8 patients with mild tardive dyskinesia and no akathisia who were treated by drug abstinence, gradual lessening of tardive dyskinesia occurred. Complete remission was seen after 2-4 years in 5 of these 8. Treatment with reserpine and discontinuance of antipsychotic drugs was useful for patients with severe symptoms of tardive dyskinesia or akathisia; complete remission with elimination of all drugs was achieved in 4 of 19 treated patients, without recurrence of symptoms. Although tetrabenazine masked symptoms in 5 of 7 patients to whom it was administered, none was able to achieve remission of tardive dyskinesia when taken off the drug. Seven of the total 33 patients received a course of levodopa; 2 of these 7 developed recurrence of their underlying psychosis. This agent should be used with caution.
Assuntos
Antipsicóticos/administração & dosagem , Discinesia Induzida por Medicamentos/terapia , Adulto , Idoso , Acatisia Induzida por Medicamentos , Antipsicóticos/efeitos adversos , Colite/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/etiologia , Feminino , Humanos , Levodopa/efeitos adversos , Masculino , Metiltirosinas/uso terapêutico , Pessoa de Meia-Idade , Náusea/tratamento farmacológico , Transtornos Paranoides/tratamento farmacológico , Agitação Psicomotora/tratamento farmacológico , Agitação Psicomotora/terapia , Psicoses Induzidas por Substâncias/etiologia , Transtornos Psicóticos/tratamento farmacológico , Receptores Dopaminérgicos/efeitos dos fármacos , Reserpina/uso terapêutico , Tetrabenazina/uso terapêutico , Fatores de TempoRESUMO
Huntington's disease (Huntington's chorea), a degenerative disorder of the central nervous system, is inherited in an autosomal dominant pattern. Since there is no cure for this genetic disorder, therapy has been focused on pharmacologic manipulation of the involved neurotransmitter systems. In Huntington's disease, there is a functional predominance of striatal dopaminergic activity over antagonist cholinergic and possibly GABA-minergic systems. Many dopaminergic antagonists and cholinergic and GABA-minergic agonists are currently used in treatment. Supportive psychiatric care for affected persons and their families is an important therapeutic adjunct in the management of Huntington's disease. The eventual therapy will depend upon accurate identification of the primary genetic defect.
Assuntos
Doença de Huntington/terapia , Acetilcolina/uso terapêutico , Adolescente , Adulto , Butirofenonas/uso terapêutico , Criança , Clorpromazina/uso terapêutico , Antagonistas de Dopamina , Haloperidol/uso terapêutico , Humanos , Doença de Huntington/tratamento farmacológico , Metiltirosinas/uso terapêutico , Fenotiazinas/uso terapêutico , Psicoterapia , Reserpina/uso terapêutico , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
About 2.5% of patients treated with neuroleptic drugs develop acute dystonia within 48 h of commencing therapy. The symptoms remit on drug withdrawal or following anticholinergic therapy. Acute dystonia can also be reliably induced in many primate species by neuroleptic treatment with comparable time course, symptomatology and pharmacological characteristics to those observed in man. In general, New World monkeys appear more susceptible to acute dystonia than Old World primates. It is at present not clear whether all primates, including man, would exhibit dystonia if a sufficiently high dose of neuroleptic was administered. Alternatively, some unknown, possibly species-specific or even genetic, factors may determine an individual's susceptibility to develop dystonia. Use of a rodent model of dystonia might enable more detailed analysis of biochemical correlates of dystonic behaviour. Whilst rodents do not exhibit overt dystonic behaviour after neuroleptic treatment, they may develop oral dyskinesias which bear a close pharmacological similarity to dystonia in man and primates. However, it is not known whether chewing induced by neuroleptic drugs in rats resembles acute dystonia in primates or whether this is another movement disorder possibly unique to rodent species. The pathophysiology of acute dystonia remains unknown, but may involve striatal dopaminergic and cholinergic function. In view of the close similarity between dystonia in man and other primates, studies on the mechanisms whereby neuroleptic drugs cause acute dystonic reactions in monkeys may give some clues to the pathogenesis of spontaneous dystonia in man.
Assuntos
Antipsicóticos/efeitos adversos , Distonia/induzido quimicamente , Doença Aguda , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/antagonistas & inibidores , Encéfalo/fisiopatologia , Clorpromazina/efeitos adversos , Modelos Animais de Doenças , Sinergismo Farmacológico , Distonia/tratamento farmacológico , Distonia/fisiopatologia , Flufenazina/efeitos adversos , Haloperidol/efeitos adversos , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Levodopa/efeitos adversos , Mastigação , Metiltirosinas/uso terapêutico , Transtornos dos Movimentos/induzido quimicamente , Parassimpatolíticos/uso terapêutico , Fisostigmina/administração & dosagem , Primatas , Ratos , alfa-MetiltirosinaRESUMO
Metastatic pheochromocytoma, a rare complication of pregnancy, was managed from 30 weeks' gestation until delivery three weeks later with a combination of alpha-adrenergic blockade (Minipres) beta-adrenergic blockade (Timolol), and dopamine synthesis inhibition (Demser). The biophysical parameters of fetal heart rate (FHR) baseline, variability, and reactivity, as well as fetal breathing movements, body movements, tone, and amniotic fluid volume were followed sequentially during this period. A 1450-g growth-retarded infant, who subsequently did well, was delivered by cesarean section; the mother received combined surgical and medical therapy for her metastatic disease in the postpartum period. The initial fetal biophysical alteration observed was a reduction in mean FHR baseline rate; further biophysical test abnormalities appeared only after overt fetal compromise was evident. Sequential multiple parameter biophysical testing in such circumstances appears to be a valid and valuable approach to antepartum management.
Assuntos
Feto/efeitos dos fármacos , Feocromocitoma/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Simpatolíticos/uso terapêutico , Adulto , Catecolaminas/sangue , Quimioterapia Combinada , Feminino , Coração Fetal/efeitos dos fármacos , Monitorização Fetal , Frequência Cardíaca/efeitos dos fármacos , Humanos , Metiltirosinas/uso terapêutico , Feocromocitoma/secundário , Prazosina/uso terapêutico , Gravidez , Simpatolíticos/efeitos adversos , Timolol/uso terapêutico , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , alfa-MetiltirosinaRESUMO
Neurochemical and histological studies suggest that methylamphetamine (MA) administered continuously or in high doses is toxic to dopaminergic and serotonergic nerve terminals. Degeneration of the dopaminergic or serotonergic cell bodies themselves has not been reported, however. In the present study, administration of a single 100 mg/kg dose of MA was toxic to a subpopulation of neurons in the somatosensory cortex, an area of the brain which does not contain catecholaminergic or serotonergic cell bodies. This dose of MA also produced a long-lasting depletion of serotonin (5-HT) but not norepinephrine in the somatosensory cortex. Dopamine levels in the somatosensory cortices of control animals were virtually undetectable and therefore were not studied further. Administration of alpha-methyltyrosine (alpha-MT), a catecholamine synthesis inhibitor, prior to the injection of MA blocked both the depletion of 5-HT and the degeneration of cortical perikarya produced by MA alone. Since the MA-induced depletion of 5-HT and the MA-induced degeneration of cortical perikarya are correlated, we suggest that the serotonergic system may be involved in the toxic effects of MA on the cortical neurons.
Assuntos
Metanfetamina/toxicidade , Metiltirosinas/uso terapêutico , Córtex Somatossensorial , Animais , Encefalopatias/induzido quimicamente , Encefalopatias/metabolismo , Masculino , Metanfetamina/antagonistas & inibidores , Norepinefrina/análise , Ratos , Ratos Endogâmicos , Serotonina/análise , Córtex Somatossensorial/análise , alfa-MetiltirosinaRESUMO
We studied the effect of intracerebroventricular infusion of dopamine and dopamine agonists in animal models of dopamine deficiency as an experimental approach to the treatment of levodopa induced fluctuations in Parkinson's disease. Dopamine deficiency was produced in rats by unilateral lesion of the nigrostriatal pathway or by chronic treatment with reserpine. Monkeys were lesioned by intravenous injection of MPTP. The animals were treated with intracerebral infusions of dopamine (with or without associated intraperitoneal administration or intracerebroventricular infusion of pargyline), lisuride and pergolide. The intracerebroventricular infusion of these drugs was performed with osmotic minipumps in rats and with infusaid pumps in the monkeys. The infusion of dopamine or dopamine agonists in rats with unilateral lesions by 6-OH-dopamine produced a persistent rotation contralateral to the lesioned and implanted side. The infusion of dopamine reversed reserpine-induced akinesia only when pargyline was associated. In the range of concentration used, maximum allowed by solubility of compounds, the effects of dopamine were more potent than those of the agonists. In spite of the stability of dopamine "in vitro" when dissolved in antioxidants and at low pH, a pigment, product of autooxidation, was found in the brains of the animals infused with dopamine. The monkeys were implanted with infusaid pumps and infused for up to 3 weeks. The pump was not well tolerated due to its huge size for the animals. One monkey showed reversal of the MPTP-induced akinesia while the other, whose catheter had moved from the correct implantation site, remained unchanged. In both monkeys there was evidence of autooxidation of dopamine. Intracerebral infusion of dopamine agonists may be a possible experimental alternative to the treatment of levodopa induced fluctuations in Parkinson's disease but stable and soluble dopamine agonists and suitable delivery systems are needed.