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Pharmaceutical Research Jun 1989The bioavailability of L-dopa following rectal administration of a series of short-chain alkyl esters of L-dopa was determined in rats and dogs. The esters were stable...
The bioavailability of L-dopa following rectal administration of a series of short-chain alkyl esters of L-dopa was determined in rats and dogs. The esters were stable (greater than 360 min) to hydrolysis in physiological buffer. In vitro enzymatic hydrolysis of the esters in plasma was species dependent, with the hydrolytic rate being faster in rat plasma (t 1/2 less than 5 min) than dog plasma (t 1/2 = 68-181 min) or human plasma (t 1/2 = 96-238 min). In vivo hydrolysis in dogs, as indicated by the L-dopa plasma profile following intravenous administration of the esters, was very rapid (high extravascular esterase activity). Significant L-dopa bioavailability was observed in rats following rectal administration of the methyl (46%), ethyl (14%), isopropyl (48%), butyl (100%), and 4-hydroxybutyl (13%) esters of L-dopa (rectal L-dopa absorption, less than 5%). In dogs, significant L-dopa bioavailability was also observed for the methyl (28%), isopropyl (30%), butyl (32%), and 4-hydroxybutyl (34%) esters of L-dopa in the presence of carbidopa. The data indicate that these highly water-soluble (greater than 600 mg/ml) esters of L-dopa are potential candidates for controlled-release rectal delivery systems designed to provide more constant plasma L-dopa levels.
Topics: Administration, Rectal; Animals; Biological Availability; Dogs; Humans; Hydrolysis; In Vitro Techniques; Intestinal Absorption; Levodopa; Male; Prodrugs; Rats; Rats, Inbred Strains
PubMed: 2762226
DOI: 10.1023/a:1015924724973 -
La Clinica Terapeutica Jan 1982
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Annals of Internal Medicine Mar 1981Sinemet (a combination of levodopa with carbidopa, a dopa-decarboxylase inhibitor) has replaced levodopa for early treatment of parkinsonism. The blocking of the... (Review)
Review
Sinemet (a combination of levodopa with carbidopa, a dopa-decarboxylase inhibitor) has replaced levodopa for early treatment of parkinsonism. The blocking of the systemic uptake of dopamine has eliminated the previous complications of nausea, vomiting, and cardiac and respiratory arrhythmias; pyridoxine need not now be avoided. However, the earlier appearance of abnormal involuntary movements, hallucinations, occasional psychosis, and a dopa-resistant state limits treatment efficacy. In all-over experience the combination drug offers the best relief for rigidity and akinesia. It has improved the quality of life and reduced mortality by one half. The greatest benefits appear in the first 3 years; then complications set in. The relation of complications to dosage is now better understood, and the ratio of dopa-decarboxylase inhibitor to levodopa inhibitor to levodopa of 1:4 is better than the previous 1:10. Levodopa with or without dopa decarboxylase is not a cure for parkinsonism. Some agonist drugs (bromocryptine, lisuride) are showing promise in the testing stage. The evolving knowledge about neurotransmitters and peptide messengers offers hope for the growing number of patients with parkinsonism.
Topics: Aromatic Amino Acid Decarboxylase Inhibitors; Carbidopa; Chemical Phenomena; Chemistry; Drug Combinations; Follow-Up Studies; Humans; Levodopa; Parkinson Disease; Prognosis
PubMed: 7013595
DOI: 10.7326/0003-4819-94-3-364 -
Neurologia (Barcelona, Spain) 1998
Topics: Antiparkinson Agents; History, 20th Century; Humans; Levodopa; Parkinson Disease
PubMed: 9859684
DOI: No ID Found -
The New England Journal of Medicine Jul 1977
Topics: Diuresis; Humans; Kidney; Levodopa
PubMed: 865569
DOI: 10.1056/NEJM197707142970214 -
Diseases of the Nervous System Mar 1976It is now generally acknowledged that L-Dopa is the therapy of choice for Parkinson's Disease. However, L-Dopa has some short comings: It requires large daily dosage,... (Comparative Study)
Comparative Study
It is now generally acknowledged that L-Dopa is the therapy of choice for Parkinson's Disease. However, L-Dopa has some short comings: It requires large daily dosage, the therapeutic benefits are achieved only after a delayed onset of 1-2 months, and it has a number of side effects both central and peripheral. In the last few years there has been an intense search for agents that are less toxic, more efficient and more rapidly acting that L-Dopa. The ideal agent has not yet been found. However, a combination therapy with L-Dopa and dopa decarboxylase inhibitors has shown promise. The decarboxylase inhibitors used have a large molecule which does not cross the blood brain barrier. Thus when L-Dopa and the decarboxylase inhibitor are given togehher, peripheral production of dopamine from L-Dopa is inhibited, therefore, rendering L-Dopa more readily and rapidly available for brain metabolism. In the present paper we present the results of the treatment of 50 patients on combined therapy using L-Dopa combined with Carbidopa.
Topics: Adult; Aged; Carbidopa; Drug Combinations; Humans; Hydrazines; Levodopa; Male; Middle Aged; Parkinson Disease
PubMed: 1253661
DOI: No ID Found -
Xenobiotica; the Fate of Foreign... Apr 20181. Catechol-O-methyltransferase (COMT) is involved in the O-methylation of l-DOPA, dopamine, and other catechols. The enzyme is expressed in two isoforms: soluble...
1. Catechol-O-methyltransferase (COMT) is involved in the O-methylation of l-DOPA, dopamine, and other catechols. The enzyme is expressed in two isoforms: soluble (S-COMT), which resides in the cytoplasm, and membrane-bound (MB-COMT), which is anchored to intracellular membranes. 2. To obtain specific information on the functions of COMT isoforms, we studied how a complete MB-COMT deficiency affects the total COMT activity in the body, peripheral l-DOPA levels, and metabolism after l-DOPA (10 mg kg) plus carbidopa (30 mg kg) administration by gastric tube in wild-type (WT) and MB-COMT-deficient mice. l-DOPA and 3-O-methyl-l-DOPA (3-OMD) levels were assayed in plasma, duodenum, and liver. 3. We showed that the selective lack of MB-COMT did not alter the total COMT activity, COMT enzyme kinetics, l-DOPA levels, or the total O-methylation of l-DOPA but delayed production of 3-OMD in plasma and peripheral tissues.
Topics: Animals; Carbidopa; Catechol O-Methyltransferase; Levodopa; Methylation; Mice; Mice, Mutant Strains
PubMed: 28375049
DOI: 10.1080/00498254.2017.1315781 -
Biochemical Pharmacology Nov 2001The transport of 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA) across the blood-brain barrier (BBB) and neuronal membranes was compared with that of... (Comparative Study)
Comparative Study
The transport of 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA) across the blood-brain barrier (BBB) and neuronal membranes was compared with that of L-3,4-dihydroxyphenylalanine (L-DOPA) in rats. The carotid injection method was used as a direct measurement of [18F]FDOPA, 1-[14C]-L-DOPA, and 3-[14C]-L-DOPA transport across the BBB, while isolated nerve terminals were used to examine neuronal membrane transport of [3H]-L-DOPA. [18F]FDOPA appeared to use the same large neutral amino acid carrier for BBB transport as L-DOPA and L-phenylalanine. In addition, carbidopa [L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxyphenyl)propionic acid] was found not to have direct interference with the transport carrier on the BBB, but indirectly inhibited aromatic L-amino acid decarboxylase (AAAD) activity in brain endothelium by depletion of pyridoxal phosphate, a necessary cofactor of the enzyme. In striatal and cortical synaptosomes, [3H]-L-DOPA uptake was inhibited by non-radioactive L-DOPA, FDOPA, and 6-fluoro-L-meta-tyrosine (6-FMT). The inhibition was significantly greater in terminals isolated from the striatum than in those from the cerebral cortex. FDOPA, 6-FMT, and L-DOPA equally inhibited the neuronal transport of [3H]-L-DOPA. This suggests that FDOPA and 6-FMT compete with L-DOPA at similar transport sites at the neuronal membrane.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Cell Membrane; Dihydroxyphenylalanine; Fluorine Radioisotopes; Levodopa; Male; Models, Animal; Neurons; Rats; Rats, Sprague-Dawley
PubMed: 11709201
DOI: 10.1016/s0006-2952(01)00787-0 -
Brain Research Sep 1994Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of nigrostriatal dopamine neurons were administered 25 mg/kg L-DOPA methyl ester/2 mg/kg carbidopa once or twice... (Comparative Study)
Comparative Study
Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of nigrostriatal dopamine neurons were administered 25 mg/kg L-DOPA methyl ester/2 mg/kg carbidopa once or twice per day or saline in separate treatment groups for 13 days. Treatment was initiated within 18-20 h postoperative, well-before the onset of denervation supersensitivity. Contralateral rotation emerged as a response to L-DOPA on day 7 postoperative first in the L-DOPA once/day group and then on day 9 for the L-DOPA twice/day group. Thus, early postoperative L-DOPA treatment retarded but did not prevent the development of dopamine receptor supersensitivity. Following a 14-day withdrawal period, these same L-DOPA treated groups exhibited substantially higher rates of contralateral rotation to an L-DOPA challenge as compared to a drug-naive group with comparable 6-OHDA lesions. HPLC-EC measurements of L-DOPA in striatal and cortical tissue samples showed no differences in concentration across the L-DOPA treatment groups. There were several differences, however, in the neurochemical impact of L-DOPA on frontal cortex vs. striatum. In the striatum but not the cortex, L-DOPA concentrations were higher in the 6-OHDA than the intact hemisphere and, L-DOPA increased dopamine concentrations in cortex but not in the striatum. Behaviorally, L-DOPA exerted two diametrically opposite effects linked to the state of dopamine receptors. Prior to the onset of dopamine receptor supersensitivity L-DOPA suppressed locomotor behavior and delayed the emergence of denervation supersensitivity. Once denervation supersensitivity developed, however, the L-DOPA engaged sensitization mechanisms and enhanced locomotor behavior and dopamine receptor supersensitivity. These findings suggest that the initiation of antiparkinsonian treatment prior to the onset of denervated dopamine receptor supersensitivity in the 6-OHDA model is a valuable strategy to determine if a drug treatment retards or facilitates the development of dopamine receptor supersensitivity.
Topics: Animals; Behavior, Animal; Denervation; Functional Laterality; Homovanillic Acid; Levodopa; Male; Methyldopa; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Rotation; Time Factors
PubMed: 7834335
DOI: 10.1016/s0006-8993(09)90020-8 -
Psychopharmacology 1980Mice, pretreated orally with L-DOPA (200 mg/kg) plus benserazide (50 mg/kg) (L-DOPA-B) responded when challenged 24 h later with the same drug combination, with...
Mice, pretreated orally with L-DOPA (200 mg/kg) plus benserazide (50 mg/kg) (L-DOPA-B) responded when challenged 24 h later with the same drug combination, with significantly greater locomotor stimulation than animals pretreated with the vehicle. The enhanced response was not due to an intrinsic effect of benserazide. Nor was it dependent on a change in central dopamine (DA) receptor sensitivity, because the two pretreatment groups (L-DOPA-A and vehicle) did not differ in their locomotor response to a range of apomorphine doses (300--3,000 micrograms/kg, IP). The enhanced response was, however, due to DA receptor stimulation because it was antagonised by premedication of the mice with haloperidol or pimozide. Moreover, the enhanced response to L-DOPA-B chf L-DOPA alone (without benserazide) (1,200 mg/kg, orally). Animals which had been pretreated with L-DOPA-B had significantly higher brain levels of L-DOPA and DA after a subsequent challenge dose of L-DOPA-B administered 24 h later. Thus the enhanced response to L-DOPA-B observed in the present experiment appears to be dependent on some mechanism which produces higher concentrations of L-DOPA (and consequently DA) in the brain.
Topics: Animals; Behavior, Animal; Benserazide; Brain Chemistry; Kinetics; Levodopa; Male; Mice; Motor Activity; Receptors, Dopamine; Stereoisomerism
PubMed: 6771801
DOI: 10.1007/BF00426654