ABSTRACT
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.
Subject(s)
Autism Spectrum Disorder/drug therapy , Methyltyrosines/therapeutic use , Tyrosine 3-Monooxygenase/antagonists & inhibitors , Adolescent , Adult , Behavior/drug effects , Child , Child, Preschool , Female , Humans , Male , Methyltyrosines/adverse effects , Treatment Outcome , Young AdultABSTRACT
Five of 24 (21%) normal men (volunteers) administered alpha-methyl-para-tyrosine (AMPT), a catecholamine-depleting agent, developed acute dystonic reactions. The finding that catecholamine depletion without receptor blockade is sufficient to cause acute dystonia suggests that a variety of neurotransmitter imbalances may lead to idiopathic primary dystonia.
Subject(s)
Dystonia/chemically induced , Methyltyrosines/adverse effects , Tyrosine 3-Monooxygenase/antagonists & inhibitors , Acute Disease , Adolescent , Adult , Humans , Male , alpha-MethyltyrosineABSTRACT
Fourteen patients with TD, all but one also having tardive akathisia, were evaluated on presynaptically acting dopamine-depleting drugs, reserpine, TBZ, and AMT. Initially, the drugs were evaluated individually, but later AMT was used in combination with reserpine and with TBZ, since their different mechanisms of action allowed for increased potency when they were used in this combination. All but one patient responded to this therapeutic approach. Parkinsonism was easily induced, however. Most patients varied during the day between mild parkinsonism and mild dyskinesia-akathisia. It was difficult to have patients at the normal level between these two conditions. The addition of carbidopa/levodopa in one patient not only relieved the side effect of parkinsonism but may have also accelerated a remission from TD and akathisia. Although postural hypotension was a common adverse effect in patients receiving reserpine, especially in combination with AMT, it did not develop in patients taking TBZ, either alone or in combination with AMT. This observation suggests that TBZ may be less effective depleting monoamines in the periphery than in the central nervous system. Since reserpine is available commercially in the United States whereas TBZ is not, reserpine may be the drug of choice in treating patients with TD or tardive akathisia. The addition of AMT will increase the potency of this form of treatment.
Subject(s)
Dopamine Antagonists , Dyskinesia, Drug-Induced/drug therapy , Synapses/drug effects , Adult , Aged , Carbidopa/therapeutic use , Dopamine/metabolism , Drug Therapy, Combination , Female , Humans , Levodopa/therapeutic use , Male , Methyltyrosines/adverse effects , Methyltyrosines/therapeutic use , Middle Aged , Parkinson Disease/drug therapy , Parkinson Disease, Secondary/chemically induced , Reserpine/adverse effects , Reserpine/therapeutic use , Tetrabenazine/therapeutic use , alpha-MethyltyrosineABSTRACT
Clinical and experimental evidence suggests that alpha methylparatyrosine (AMPT), an inhibitor of tyrosine hydroxylase, can potentiate the effects of other dopamine antagonists. We therefore treated patients having various forms of dystonia and chorea with tetrabenazine (TBZ), and then added AMPT to determine if further improvement could be obtained. Side effects of both drugs were common, and they often necessitated withdrawal of the drug. Patients with Huntington's chorea and tardive dyskinesia were improved by TBZ. They obtained additional benefit from the combination of AMPT and TBZ. The results in the dystonia patients were disappointing with both drugs. Although a small number of patients did improve, and short- and long-term remissions occurred in a few, most patients with dystonia were not benefited by either drug.
Subject(s)
Methyltyrosines/therapeutic use , Movement Disorders/drug therapy , Tetrabenazine/therapeutic use , Adult , Chorea/drug therapy , Drug Therapy, Combination , Dystonia/drug therapy , Female , Humans , Male , Methyltyrosines/adverse effects , Middle Aged , Movement Disorders/physiopathology , Tetrabenazine/adverse effects , Tyrosine 3-Monooxygenase/antagonists & inhibitors , alpha-MethyltyrosineABSTRACT
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.
Subject(s)
Methyltyrosines/pharmacology , Adrenal Gland Neoplasms/drug therapy , Animals , Blood Pressure/drug effects , Carbohydrate Metabolism , Catecholamines/biosynthesis , Drug Interactions , Humans , Intestinal Absorption , Kinetics , Methyltyrosines/adverse effects , Methyltyrosines/metabolism , Methyltyrosines/therapeutic use , Pheochromocytoma/drug therapy , alpha-MethyltyrosineSubject(s)
Antidepressive Agents, Tricyclic/therapeutic use , Brain/metabolism , Depression , Monoamine Oxidase Inhibitors/therapeutic use , Neurotransmitter Agents/metabolism , Addison Disease/complications , Adrenal Cortex Hormones/adverse effects , Amphetamines/therapeutic use , Animals , Bipolar Disorder/drug therapy , Brain/drug effects , Cushing Syndrome/complications , Cyclic AMP/metabolism , Depression/chemically induced , Depression/drug therapy , Depression/metabolism , Electroconvulsive Therapy , Humans , Lithium/therapeutic use , Methyltyrosines/adverse effects , Reserpine/adverse effects , Tryptophan/therapeutic useSubject(s)
Dopamine/physiology , Movement Disorders/physiopathology , Parasympathetic Nervous System/physiopathology , Adult , Age Factors , Aged , Biperiden/therapeutic use , Clinical Trials as Topic , Dihydroxyphenylalanine/therapeutic use , Female , Humans , Male , Methyltyrosines/adverse effects , Middle Aged , Movement Disorders/chemically induced , Physostigmine/adverse effects , Physostigmine/therapeutic use , Scopolamine/therapeutic use , Time FactorsSubject(s)
Depression/etiology , Disease Models, Animal , Models, Psychological , Psychotic Disorders/etiology , Age Factors , Amines/physiology , Animals , Avoidance Learning , Brain/physiology , Cats , Chlorpromazine/therapeutic use , Depression/chemically induced , Dogs , Electroshock , Haplorhini , Humans , Methyltyrosines/adverse effects , Mice , Psychotic Disorders/drug therapy , Rabbits , Rats , Sheep , Social Behavior , Social IsolationSubject(s)
Amphetamine/pharmacology , Deficiency Diseases/chemically induced , Iron/blood , Amphetamine/adverse effects , Animals , Body Temperature/drug effects , Chlorpromazine/adverse effects , Chlorpromazine/pharmacology , Dextroamphetamine/pharmacology , Guanethidine/adverse effects , Guanethidine/pharmacology , Haloperidol/adverse effects , Haloperidol/pharmacology , Male , Methyltyrosines/adverse effects , Methyltyrosines/pharmacology , Mononuclear Phagocyte System/drug effects , Rats , Rats, Inbred Strains , Reserpine/adverse effects , Reserpine/pharmacologySubject(s)
Methyltyrosines/therapeutic use , Neoplasm Metastasis/drug therapy , Pheochromocytoma/drug therapy , Adult , Bone Neoplasms/drug therapy , Catecholamines/metabolism , Female , Humans , Kidney Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Methyltyrosines/adverse effects , Pheochromocytoma/surgery , Preoperative Care , Vena Cava, InferiorSubject(s)
Adrenal Gland Neoplasms/drug therapy , Methyltyrosines/therapeutic use , Pheochromocytoma/drug therapy , Adrenal Gland Neoplasms/complications , Adult , Bone Neoplasms , Catecholamines/metabolism , Female , Humans , Hypertension/etiology , Kidney Diseases/etiology , Liver Neoplasms , Methyltyrosines/adverse effects , Neoplasm Metastasis , Nephrectomy , Pheochromocytoma/complications , Tyrosine 3-Monooxygenase/antagonists & inhibitors , Vanilmandelic Acid/urine , Vena Cava, InferiorSubject(s)
Dopamine/physiology , Drug-Related Side Effects and Adverse Reactions , Extrapyramidal Tracts/drug effects , Movement Disorders/chemically induced , Synaptic Transmission/drug effects , Antiparkinson Agents/adverse effects , Apomorphine/adverse effects , Basal Ganglia Diseases/chemically induced , Benztropine/adverse effects , Dihydroxyphenylalanine/adverse effects , Dopamine/metabolism , Haloperidol/adverse effects , Humans , Methyltyrosines/adverse effects , Phenothiazines/adverse effects , Phenylacetates/metabolism , Probenecid/adverse effects , Reserpine/adverse effects , Tetrabenazine/adverse effects , Tranquilizing Agents/adverse effects , Trihexyphenidyl/adverse effectsSubject(s)
Catatonia/chemically induced , Tremor/chemically induced , Animals , Cerebellum/physiopathology , Cerebral Cortex/physiopathology , Dihydroxyphenylalanine/adverse effects , Dopamine/metabolism , Haplorhini , Humans , Mesencephalon/physiopathology , Methyltyrosines/adverse effects , Movement Disorders/chemically induced , Phenothiazines/adverse effects , Reserpine/adverse effectsSubject(s)
Bipolar Disorder/drug therapy , Catecholamines/metabolism , Methyltyrosines/therapeutic use , Adult , Aged , Bipolar Disorder/urine , Catecholamines/cerebrospinal fluid , Catecholamines/urine , Depression/drug therapy , Depression/urine , Dopamine/urine , Female , Humans , Male , Methyltyrosines/adverse effects , Middle Aged , Placebos , Sleep/drug effects , Time Factors , Vanilmandelic Acid/cerebrospinal fluid , Vanilmandelic Acid/urineSubject(s)
Methyltyrosines/therapeutic use , Norepinephrine/antagonists & inhibitors , Spinal Cord Injuries/drug therapy , Acute Kidney Injury/chemically induced , Animals , Cats , Methyltyrosines/adverse effects , Necrosis/prevention & control , Norepinephrine/metabolism , Tyrosine 3-Monooxygenase/antagonists & inhibitorsSubject(s)
Methyltyrosines/therapeutic use , Norepinephrine/metabolism , Spinal Cord Injuries/metabolism , Animals , Hemorrhage/prevention & control , Methyltyrosines/administration & dosage , Methyltyrosines/adverse effects , Microscopy, Fluorescence , Necrosis/prevention & control , Paraplegia/metabolism , Paraplegia/pathology , Spinal Cord/pathology , Uremia/chemically inducedABSTRACT
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.