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Upsala Journal of Medical Sciences Jun 2017This review will illustrate the process of moving from an idea through preclinical research and Galenic developments into clinical investigations and finally to approval... (Review)
Review
This review will illustrate the process of moving from an idea through preclinical research and Galenic developments into clinical investigations and finally to approval by regulatory agencies within the European Union. The two new treatment strategies described, levodopa/carbidopa intestinal gel and levodopa/carbidopa microtablets, for advanced Parkinson's disease, have been developed in collaborative research within departments at Uppsala University. With this historical approach, reference priority is given to reports considered to be of special importance for this more than two decades long process 'from bedside to bench to bedside'.
Topics: Animals; Carbidopa; Central Nervous System; Drug Approval; Drug Combinations; Drug Delivery Systems; Drug Design; European Union; Gels; History, 20th Century; History, 21st Century; Humans; Levodopa; Parkinson Disease; Randomized Controlled Trials as Topic; Tablets
PubMed: 28276779
DOI: 10.1080/03009734.2017.1285374 -
British Journal of Clinical Pharmacology Oct 2018SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor... (Comparative Study)
Comparative Study Randomized Controlled Trial
Pharmacokinetics, metabolism and safety of deuterated L-DOPA (SD-1077)/carbidopa compared to L-DOPA/carbidopa following single oral dose administration in healthy subjects.
AIMS
SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077.
METHODS
Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16).
RESULTS
Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for C , AUC , and AUC were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P < 0.0001) for C and AUC and a concomitant reduction in the ratio of 3,4-dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O-methyltransferase (COMT) reaction, 3-methoxytyramine (3-MT) and 3-O-methyldopa (3-OMD) with GMRs (90% CI) for SD-1077/CD to L-DOPA/CD for 3-MT exposure of 1.33 (1.14-1.56; P = 0.0077) and 1.66 (1.42-1.93; P < 0.0001) for C and AUC , respectively and GMRs (90% CI) for 3-OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for C and AUC . SD-1077/CD exhibited comparable tolerability and safety to L-DOPA/CD.
CONCLUSIONS
SD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.
Topics: Administration, Oral; Adult; Antiparkinson Agents; Area Under Curve; Carbidopa; Cross-Over Studies; Deuterium; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Healthy Volunteers; Humans; Levodopa; Male; Parkinson Disease; Prodrugs
PubMed: 29959802
DOI: 10.1111/bcp.13702 -
Clinical and Experimental Immunology Jun 1980Alpha-methyldopa binds to human erythrocyte membrane proteins. A portion of this binding is readily dissociable in SDS but a significant amount is very tightly bound and...
Alpha-methyldopa binds to human erythrocyte membrane proteins. A portion of this binding is readily dissociable in SDS but a significant amount is very tightly bound and does not come off even under rigorous conditions. The binding is increased under oxidizing conditions and very much inhibited in the presence of reducing agents as well as superoxide dismutase and catalase. Haemoglobin competes with membrane peptides for alpha-methyldopa binding. It is postulated that haemoglobin acts as a 'sink' for the drug in the intact cell and that the first step in the pathogenesis of Coombs positivity and haemolytic anaemia results from an alteration of a critical membrane peptide secondary to binding of the drug during normal membrane breakdown.
Topics: Binding, Competitive; Chromatography, Gel; Erythrocyte Membrane; Erythrocytes; Hemoglobins; Humans; Membrane Proteins; Methyldopa; Oxidation-Reduction
PubMed: 7418265
DOI: No ID Found -
Brain and Behavior Aug 2017Levodopa-carbidopa intestinal gel (LCIG) infusion has demonstrated to improve motor fluctuations. The aim of this study is to assess the long-term safety and... (Observational Study)
Observational Study
INTRODUCTION
Levodopa-carbidopa intestinal gel (LCIG) infusion has demonstrated to improve motor fluctuations. The aim of this study is to assess the long-term safety and effectiveness of LCIG infusion in advanced Parkinson's disease (PD) patients with motor fluctuations and its effect in nonmotor symptoms.
METHODS
Adverse events (AE) and their management, clinical motor, and nonmotor aspects were assessed up to 10 years. Thirty-seven patients were treated with LGIC; in three subsets of patients, specific batteries of tests were used to assess cognitive and behavior assessment for 6 months, quality of sleep for 6 months, and quality of life and caregiver burden for 1 year.
RESULTS
There was a high number of AE, but manageable, most of mild and moderate severity. All patients experienced significant improvement in motor fluctuations with a reduction in mean daily time of 4.87 hr after 3 months ( = 37) to 6.25 hr after 9 years ( = 2). Diskynesias remained stables in 28 patients (75.7%) and improved in 5 patients (13.5%). There was no neuropsychological deterioration, but an improvement in attentional functions, voluntary motor control, and semantic fluency. Quality of sleep did not worsen, and there was an improvement in the subjective parameters, although overnight polysomnography did not change. There was a significant sustained improvement of 37% in PD-Q39 after 3 months and to 1 year, and a significant reduction in caregiver burden of 10% after 3 months.
CONCLUSION
LCIG infusion is a safe and efficacious treatment for the control of motor fluctuations, and for improvement or nonworsening of nonmotor aspects, long-term sustained, and feasible for use in routine care.
Topics: Aged; Antiparkinson Agents; Carbidopa; Drug Administration Routes; Drug Combinations; Drug Monitoring; Female; Gels; Humans; Intestinal Absorption; Levodopa; Male; Middle Aged; Neuropsychological Tests; Parkinson Disease; Prospective Studies; Quality of Life; Spain; Time; Treatment Outcome
PubMed: 28828219
DOI: 10.1002/brb3.758 -
Journal of Parkinson's Disease 2022In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg three times per day for 40 weeks (delayed-start).
OBJECTIVE
This paper reports the results of the economic evaluation performed alongside the LEAP-study.
METHODS
Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson's Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up.
RESULTS
212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of € 59 per patient (BCa 95% CI: -829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated.
CONCLUSION
From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa.
Topics: Antiparkinson Agents; Carbidopa; Cost-Benefit Analysis; Humans; Levodopa; Parkinson Disease
PubMed: 35938258
DOI: 10.3233/JPD-223247 -
British Medical Journal Dec 1973
Topics: Chronic Disease; Depression; Humans; Methyldopa; Reserpine; Time Factors
PubMed: 4758504
DOI: 10.1136/bmj.4.5891.553-a -
The Journal of Clinical Psychiatry 2018Although levodopa is effective for treating Parkinson disease, physicians and patients face significant management challenges related to disease progression. Patients...
Although levodopa is effective for treating Parkinson disease, physicians and patients face significant management challenges related to disease progression. Patients may develop fluctuations in motor symptoms and dyskinesias as well as nonmotor symptoms. Review this CME Brief Report activity to learn about new and emerging treatment options to manage patients' symptoms.
Topics: Antiparkinson Agents; Carbidopa; Disease Progression; Drug Combinations; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease
PubMed: 29999254
DOI: 10.4088/JCP.PP17030TX1C -
British Medical Journal Jan 1973
Topics: Drug Interactions; Humans; Methyldopa; Phenobarbital
PubMed: 4683647
DOI: 10.1136/bmj.1.5844.49-a -
British Medical Journal Oct 1973
Topics: Depression; Humans; Methyldopa; Surveys and Questionnaires; Synaptic Transmission
PubMed: 4355469
DOI: 10.1136/bmj.4.5884.110-c -
British Medical Journal (Clinical... Aug 1985
Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Female; Humans; Hypertension; Methyldopa; Pregnancy; Pregnancy Complications, Cardiovascular
PubMed: 2861881
DOI: 10.1136/bmj.291.6492.365