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Advances in Pharmacology (San Diego,... 1995
Review
Topics: Animals; Brain; Humans; Levodopa; Neurotransmitter Agents; Parkinson Disease
PubMed: 7748801
DOI: 10.1016/s1054-3589(08)61019-4 -
Journal of Materials Chemistry. B May 2021Parkinson's disease (PD) is a progressive neurodegenerative disease, the 2nd most common after Alzheimer's disease, the main effect of which is the loss of dopaminergic...
Parkinson's disease (PD) is a progressive neurodegenerative disease, the 2nd most common after Alzheimer's disease, the main effect of which is the loss of dopaminergic neurons. Levodopa or l-Dopa is an amino acid used in the treatment of PD that acts as the immediate precursor to dopamine. However, over time the efficacy of the medication gradually decreases requiring modified delivery methods. One of the major challenges for the medication to work is to achieve a gradual continuous supply of l-Dopa to the brain to minimise symptoms. Herein, mesoporous silica nanoparticles (MSNs) were engineered through the concept of drug-structure-directing agents (DSDAs) with inherent therapeutic activity. The DSDA used was l-Dopa drug modified by amidation with fatty acids to build anionic surfactants that were able to form micelles as templates for the assembly of inorganic precursors to form the silica framework. This templating route produced MSNs with tunable sizes ranging from 100 nm to 1 μm and with different shapes: spherical, with either solid structures with radial mesopores and porous shells, or hollow-shells with inside large void cavities; and elongated, characterized by long hollows covered by mesoporous shells. The concept of using DSDAs to synthesize drug nanocarriers can be used to avoid the surfactant removal and subsequent drug loading steps involved in the synthesis of conventional MSNs. We hypothesized that the l-Dopa released from MSN materials is mediated by the size and solubility of the DSDAs, and the surface chemical interactions between the DSDAs and MSN hosts. Different pHs (acidic and neutral) simulating gastrointestinal tract conditions were tested, and the results showed hardly any release for gastric conditions at pH 1.2, avoiding the premature release in the stomach typical of conventional MSNs, while for intestinal conditions of pH 7.4, the release of l-Dopa occurred in a continuous and sustained manner, which is well suited to the drug's application and delivery route, and matches well with achieving a sustained l-Dopa delivery to relief symptoms. This could open up new uses for MSNs synthesized by this approach to treat PD.
Topics: Antiparkinson Agents; Drug Liberation; Humans; Levodopa; Nanoparticles; Parkinson Disease; Particle Size; Porosity; Silicon Dioxide; Surface Properties
PubMed: 33989370
DOI: 10.1039/d1tb00481f -
Movement Disorders : Official Journal... Jan 2015Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh... (Review)
Review
Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that levodopa (l-dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the l-dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,l-dopa. As reported in his 1967 article, d,l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of l-dopa, and almost 50 years later l-dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success.
Topics: Antiparkinson Agents; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Levodopa; Male; Neurology; Nobel Prize; Parkinson Disease; Pharmacology
PubMed: 25488030
DOI: 10.1002/mds.26120 -
Andrologia 1978A clinical investigation of L-Dopa on idiopathic oligozoospermia is carried out. Thirty nine male oligozoospermic patients with primary sterility were divided in two...
A clinical investigation of L-Dopa on idiopathic oligozoospermia is carried out. Thirty nine male oligozoospermic patients with primary sterility were divided in two groups. The first group of 25 patients was treated with 500 mg a day during two months. The second group of 14 patients received 750 mg a day for the same time. In the first group we find 14 improvements, 9 at the first month and 5 at the second month. In the second group 8 improvements were observed, 5 in the first month and 3 in the second months. It would seem that L-Dopa has a stimulatory effect on spermatogenesis possibly through hypophysis when it is administered at these dosis and for these periods of time, and it was also observed similar results for longer terms of treatment.
Topics: Adult; Drug Evaluation; Humans; Levodopa; Male; Oligospermia; Spermatogenesis; Time Factors
PubMed: 629418
DOI: 10.1111/j.1439-0272.1978.tb01320.x -
Yakubutsu, Seishin, Kodo = Japanese... Jun 1993L-3,4-Dihydroxyphenylalanine (DOPA) is believed to be an inert precursor for dopamine (DA). Contrary, transmitter-like endogenous DOPA is released from in vitro and in... (Review)
Review
Review on the relationship between nicotinic acetylcholine receptors and dopaminergic neurotransmission in the central nervous system--dopa is an endogenous neuroactive substance.
L-3,4-Dihydroxyphenylalanine (DOPA) is believed to be an inert precursor for dopamine (DA). Contrary, transmitter-like endogenous DOPA is released from in vitro and in vivo striata: DOPA is released by neuronal activities under physiological conditions from striata of conscious rats. Furthermore, exogenous nanomolar DOPA itself produces an in vitro presynaptic response to facilitate the catecholamine release. An in vivo postsynaptic depressor response is elicited by DOPA microinjected into the nucleus tractus solitarii. These responses are antagonized by L-DOPA methyl ester, a competitive DOPA antagonist. In striata, DOPA is an endogenous potentiator for presynaptic beta-adrenoceptors to facilitate the DA release and also probably for postsynaptic D2-receptors to increase locomotor activities. Nicotine releases DA and transmitter-like DOPA in vitro and in vivo striata. Nicotine (0.1-1.0 mg/kg, sc) dose-dependently increases locomotor activities. This increase is stereoselective and mecamylamine (1.0 mg/kg, sc)-sensitive but not antagonized by L-DOPA methyl ester (200 micrograms, ivt). Then, a selective low ip dose of alpha-methyl-p-tyrosine (alpha-MPT) to inhibit the basal release of DOPA without decreasing the basal release of DA was explored in vivo striata: it was 3 mg/kg. Pretreatment with this dose did inhibit the nicotine-induced increases in locomotor activities. This result suggests that endogenously released DOPA is in part relevant to nicotine-induced behavior in rats.
Topics: Animals; Catecholamines; Corpus Striatum; Dihydroxyphenylalanine; In Vitro Techniques; Levodopa; Motor Activity; Nicotine; Rats; Receptors, Nicotinic; Synapses
PubMed: 8237136
DOI: No ID Found -
Reviews in the Neurosciences 1997Accumulating evidence suggests that L-dihydroxyphenylalanine (L-DOPA) has neurotransmitter-like and/or neuromodulatory properties in the CNS. Such evidence is based on a... (Review)
Review
Accumulating evidence suggests that L-dihydroxyphenylalanine (L-DOPA) has neurotransmitter-like and/or neuromodulatory properties in the CNS. Such evidence is based on a wide range of findings including the existence of specific L-DOPAergic neurons in several regions of the CNS, neurotransmitter-like characteristics and specific pharmacological effects. This review attempts to outline the main evidence for this conception and to relate such findings to L-DOPA treatment effects in Parkinson's disease. In this context L-DOPA in itself has been shown to potentiate D2 receptor-mediated effects, inhibit acetylcholine release and increase the release of L-glutamate, neuropharmacological effects which can be linked to treatment side-effects in advanced Parkinson's disease. It is suggested that supersensitive L-DOPA-mediated effects contribute to the pathogenesis underlying L-DOPA-induced motor complications in advanced Parkinson's disease. However, since specific L-DOPA receptors have yet to be identified, the assessment of the relative importance of L-DOPA-mediated effects in this clinical context must be regarded as incomplete.
Topics: Central Nervous System; Humans; Levodopa; Parkinson Disease; Receptors, Neurotransmitter
PubMed: 9548232
DOI: 10.1515/revneuro.1997.8.3-4.195 -
Journal of Biotechnology Mar 2010Parkinson's disease is caused by a deficiency of the neurotransmitter dopamine. Since l-DOPA (l-3,4-dihydroxyphenylalanine) is a precursor of dopamine and can pass...
Parkinson's disease is caused by a deficiency of the neurotransmitter dopamine. Since l-DOPA (l-3,4-dihydroxyphenylalanine) is a precursor of dopamine and can pass across the blood-brain barrier, it has been used as a treatment for Parkinson's disease. Hundreds tons of l-DOPA are produced per year, and most of the current supply is produced by a chemical method of asymmetric synthesis. However, the chemical process for l-DOPA synthesis requires an expensive metal catalyst and shows low conversion rates and low enantioselectivity. In this study, we developed a novel technology for the production of l-DOPA, an electroenzymatic synthesis with a tyrosinase-immobilized cathode under the reduction potential of DOPAquinone, which is -530 mV. Compared to other approaches for l-DOPA synthesis reported previously, this electroenzymatic system showed the highest conversion rate and a highly enhanced productivity of up to 95.9% and 47.27 mg l(-1)h(-1), respectively.
Topics: Bioreactors; Electrochemical Techniques; Electrodes; Enzymes, Immobilized; Kinetics; Levodopa; Linear Models; Monophenol Monooxygenase; Parkinson Disease; Tyrosine
PubMed: 20083145
DOI: 10.1016/j.jbiotec.2010.01.002 -
British Medical Journal Nov 1974
Topics: Aromatic Amino Acid Decarboxylase Inhibitors; Drug Combinations; Humans; Levodopa; Nausea; Parkinson Disease; Vomiting
PubMed: 4425849
DOI: 10.1136/bmj.4.5939.250 -
Neurobiology of Disease Nov 2012L-DOPA is currently the standard treatment for alleviating the motor symptoms in Parkinson's disease. The therapeutic efficacy, however, diminishes as the disease... (Review)
Review
L-DOPA is currently the standard treatment for alleviating the motor symptoms in Parkinson's disease. The therapeutic efficacy, however, diminishes as the disease progresses. It has been suggested that the beneficial effect of L-DOPA could be reestablished by changing the mode of administration. Indeed, continuous delivery of l-DOPA has been shown to be an effective way to circumvent many of the side effects seen with traditional oral administration, which results in an intermittent supply of the dopamine precursor to the brain. However, all currently tested continuous dopaminergic stimulation approaches rely on peripheral administration. This is not ideal since it gives rise to off target effects and is difficult to maintain long-term. Thus, there is an unmet need for an effective continuous administration method with an acceptable side effect profile. Viral-mediated gene therapy is a promising alternative paradigm that can meet this demand. Encouraging preclinical studies in animal models of Parkinson's disease showed therapeutic efficacy after expression of the genes encoding the enzymes required for biosynthesis of dopamine. Although the first phase I clinical trials using these approaches have been conducted, clear positive data in placebo controlled efficacy studies is still lacking. We are now at a critical junction and need to carefully review the preclinical data from the clinical translation perspective and identify the key factors that will determine the potential for success in gene therapy for Parkinson's disease.
Topics: Animals; Antiparkinson Agents; Aromatic-L-Amino-Acid Decarboxylases; Brain Chemistry; Dependovirus; Dihydroxyphenylalanine; Drug Delivery Systems; Genetic Therapy; Genetic Vectors; Humans; Levodopa; Parkinson Disease; Tyrosine 3-Monooxygenase
PubMed: 22048069
DOI: 10.1016/j.nbd.2011.10.017 -
Archives of Neurology May 1999
Review
Topics: Antiparkinson Agents; Clinical Trials as Topic; Evidence-Based Medicine; Humans; Levodopa; Neurology; Outcome Assessment, Health Care; Parkinson Disease; Practice Patterns, Physicians'
PubMed: 10328247
DOI: 10.1001/archneur.56.5.529