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The combination of levodopa-carbidopa and occlusion improves visual function more than levodopa-carbidopa alone in older amblyopic children.
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Some non-antibiotic drugs, e.g. cytostatics, anaesthetics or vasodilators may also show the antimicrobial activity. The aim of this study was to detect and characterise the antimicrobial activity expressed by selected non-antibiotic drugs analysed during state control performed in the Drug Institute. Over 60 drugs were randomly chosen from different groups. The surveillance study was performed on standard microbial strains: S. aureus ATCC 6538P, E. coli ATCC 8739, P. aeruginosa ATCC 15442 and C. albicans ATCC 10231. It was found that the drugs listed below inhibited growth at least one of the examined strains: Acesan 0.075 tabl., Benuron 500 mg tabl., Chlorchex 0.5 aerosol, Methotrexat-Ebewe 500 mg amp., Naproxen 500 mg tabl., Nospa Forte 60 mg tabl., Platamine 50 mg amp., Platidiam 50 mg amp., Sensit 50 mg drag., Septofervex 2 mg tabl., Seractil 400 mg tabl., Sermion 4 mg amp., Sinemet 125 mg tabl., Tarproxen 500 mg tabl. and Zyban 150 mg tabl. It was interesting, that strong antimicrobial activity of methotrexate was limited to Staphylococcus aureus strain. Minimal inhibitory concentration of methotrexate was determined by agar dilution method with the use of 54 clinical S. aureus strains (MRSA-32 and MSSA-22). For MSSA strains, MIC50 and MIC90 were 10 micrograms/ml and 20 micrograms/ml, respectively (range: 10-20 micrograms/ml). For MRSA strains, MIC50 and MIC90 were 20 micrograms/ml and 100-> 100 micrograms/ml, respectively (range: 10-< 100 micrograms/ml).
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A single-dose, open, randomized, 3-way crossover study was performed in 19 healthy subjects. Concentrations of levodopa, carbidopa, and the metabolite 3-O-MD in plasma were determined after intake of 100 mg of levodopa, that is, one tablet of reference formulations and 20 microtablets of the new formulation.
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Within few days after DAs withdrawal, all 4 patients developed apathy, anhedonia and depression, despite the marked reduction of dyskinesias and the improvement of motor fluctuations after LCIG introduction. We unsuccessfully tried to manage these and other DAWS symptoms by increasing LCIG flow. Within 6 months, all patients spontaneously presented a slow but gradual improvement of DAWS symptoms, not requiring any further treatment strategy or LCIG discontinuation.
Five patients with advanced Parkinson's disease and fluctuations in therapeutic response to levodopa participated in, and four completed, an open label study of the efficacy of Sinemet CR5. Reductions in the number of daily doses and "off" periods as well as the increase in interdose interval and percent "on" time versus standard Sinemet were comparable to those achieved with Sinemet CR4 in these same patients. As compared with Sinemet CR4, there was a greater delay in the occurrence of peak plasma levodopa concentrations, and relative bioavailability was reduced. Sinemet CR5 appears to offer no advantages over Sinemet CR4 in the treatment of response fluctuations in Parkinson's disease.
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GDNF is a pleitropic neurotrophic factor which stimulates the dopaminergic phenotype in vitro and in vivo by way of activation of the GDNF/RET receptor complex. The pharmacologic profile of GDNF in two well-characterized animal models of Parkinson's disease suggests that the molecule may be useful in the treatment of neurodegenerative diseases involving dopaminergic dysfunction such as Parkinson's disease. This review summarizes the preclinical development path which was taken to develop GDNF as a novel therapeutic approach to treat Parkinson's disease based on GDNF's ability to regenerate dopamine neurons, including a description of the pharmacologic/biologic activities of GDNF. The overall aim will be to discuss these issues in the context of their potential therapeutic usefulness of GDNF to treat Parkinson's disease.
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Although certain classes of agents are commonly reported as causing SS among patients receiving linezolid, there are no specific case reports detailing this reaction with CL. Linezolid combined with CL should generally be avoided; however, if linezolid must be used, discontinuation of other agents with serotonergic activity is recommended with careful monitoring for signs and symptoms of SS.
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Physicians modify drug schedules in response to their patients' clinical responses. Failure to relieve patients' symptoms or the emergence of drug-related side effects may reflect nonadherence to a prescribed drug schedule rather than incorrect therapeutic physician decisions. Using a medication questionnaire and a computerized medication event monitoring system (MEMS) to monitor medication use, nonadherence of drug use was examined in subjects with Parkinson's disease (PD). We report that prescription nonadherence in PD subjects was common and approximated that reported in other chronic diseases. During a 28-day observation period, only 4 of 39 subjects had complete schedule adherence, i.e., no missed, extra, or mistimed doses. Using a questionnaire, 24.3% of subjects acknowledged missing any doses but the computerized MEMS recorded that 51.3% of subjects missed at least one dose per week and 20.5% of subjects missed three or more doses per week. Mistiming of doses was admitted by 73% of subjects but 82.1% had recorded mistimed doses. Of multiple sociodemographic and disease-related items examined, only gender and level of education were statistically related to nonadherence.
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Prospective single movement disorder center study using pre-set selection criteria, unified PD scale (UPDRS III), non-motor symptoms scale (NMSS), and PD questionnaire-8 (PDQ-8) to evaluate the efficacy, safety, and long-term treatment outcomes using levodopa-carbidopa intestinal gel (LCIG) infusion in patients with advanced PD, who were followed up every 6 months.
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Ever since its early clinical use in the 1960s, levodopa has remained the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Motor response fluctuations and drug-induced dyskinesias seriously compromise the unparalleled symptomatic efficacy of l-dopa during long-term treatment. Discontinuous drug delivery resulting from the short half-life of l-dopa and erratic gastrointestinal absorption plays a major role in the pathophysiology of these motor complications. Several approaches to improve the pharmacokinetics and ways of administration of l-dopa are in different stages of clinical development and include novel formulations as well as nonoral routes of drug delivery. IPX066 is a novel extended-release l-dopa capsule that has successfully completed phase III clinical trials while the l-dopa prodrug XP21279 and a gastric retention formulation ("accordion pill") are in earlier phases of clinical development. Novel enzyme inhibitors enhancing l-dopa efficacy and half-life are also still being developed, including a novel catechol-O-methyltransferase inhibitor with once-daily pharmacokinetics, and there are studies testing the effects of increasing the dose of amino acid decarboxylase inhibitors given concomitantly with l-dopa. Intrajejunal infusion of a gel formulation of l-dopa/carbidopa is in clinical use in Europe, and its efficacy to smooth out motor fluctuations has recently been shown in a randomized, controlled trial. Subcutaneous and intrapulmonal delivery routes of l-dopa have reached phase III of clinical development. After more than 50 years of clinical use, l-dopa not only remains the gold standard of symptomatic efficacy, but it also remains a drug in active clinical development.
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A severe parkinsonian syndrome developed in four monkeys after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). One monkeys subsequently remained untreated, and each of the three others were treated daily for at least one month with Sinemet, bromocriptine or SKF 38393. An intact control monkey (not MPTP-treated) was also included in the experiment. Sinemet and bromocriptine relieved the parkinsonian symptoms, whereas SKF 38393 was ineffective. The animal treated with Sinemet developed dyskinesia while those treated with bromocriptine or SKF 38393 did not. MPTP decreased dopamine levels by more than 99% in the striatum of all monkeys. Striatal D-1 and D-2 dopamine receptor densities as evaluated by autoradiography of [3H]SCH 23390 and [3H]spiperone binding were increased by 66 and 51%, respectively, after MPTP. Sinemet, bromocriptine or SKF 38393 treatment decreased D-2 receptor density, respectively, by 17, 84 and 35% and D-1 receptor density by 28, 33 and 6% vs. that in MPTP-treated animals. Our results suggest that dopamine receptor changes could be implicated in the loss of efficacy and in the side-effects of these treatments.
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Controlled release carbidopa/levodopa (CSR-1) was compared to standard carbidopa/levodopa in a double-blind, crossover study of 20 Parkinson's disease patients. The most consistent finding in a variety of clinical measurements was the superiority of standard carbidopa/levodopa to CSR-1. Increased dosages of CSR-1 resulted in reduced Parkinson symptoms, suggesting that a more potent controlled-release formulation might prove to be more efficacious than CSR-1.
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At baseline, all patients had motor fluctuations despite a stable regimen of CL + E or CD-LD-entacapone combination tablets (CLE). The study included a 6-week conversion from CL + E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL + E), the other on CL + E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily "off" time during waking hours (from patient diaries).
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This preliminary study investigated dopamine (DA) function in six hospitalized cocaine-dependent subjects (DSM-III-R) who received 1.5 mg/kg of active cocaine by mouth, t.i.d., for 3 days followed by 9 days of placebo cocaine. During early and late abstinence from cocaine, plasma growth hormone (GH), homovanillic acid (HVA), prolactin, and 3-methoxy-4-hydroxyphenethyleneglycol responses to the placebo-controlled administration of oral L-dopa 250 mg/carbidopa 25 mg (Sinemet) were measured. Sinemet caused significantly greater placebo-corrected increases in GH and HVA during early as compared with late abstinence. Acute abstinence from cocaine may be associated with increased DA responsivity, which normalizes over time.
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The results of 6-[18F]fluorodopamine positron-emission tomography and neurochemical analyses support a new clinical pathophysiologic classification of dysautonomias, based on the occurrence of sympathetic neurocirculatory failure, signs of central neurodegeneration, and responsiveness to levodopa-carbidopa.
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Several controlled-release carbidopa/levodopa preparations have been formulated to achieve a more stable and extended antiparkinsonian action. The most effective is Sinemet CR (Sinemet CR4), with an erodible polymer matrix that retards release of levodopa. In 19 parkinsonians with prominent dose-by-dose fluctuations, double-blind crossover trials comparing 8-week regimens of standard carbidopa/levodopa (25/100) to Sinemet CR (50/200) showed comparable clinical outcomes, with mean daily dosing for optimal control reduced from 10.2 to 5.4 (although mean daily levodopa dosage increased from 1,340 to 1,781 mg/day). Most patients improved on the Sinemet CR regimen in hours "on" and in ratings of clinical state and disability. With pharmacokinetic studies correlated to clinical ratings, plasma levodopa was less variable during Sinemet CR treatment, and clinical responses showed greater uniformity. Compared to standard Sinemet 25/100, time to peak levodopa concentration (2.3 versus 1.1 hrs), onset of maximal clinical improvement (2.2 versus 1.1 hrs), and other indices were significantly delayed with Sinemet CR. Levodopa bioavailability and clearance were similar between formulations. Although onset of clinical response is slower, the Sinemet CR formulation lessens peak-dose and "wearing-off" responses occurring with conventional carbidopa/levodopa and offers substantial improvement for some parkinsonians.
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Fluctuations (wearing-off, on off phenomenon, dyskinesias) are a big challenge in the long term treatment of parkinsonian patients. We describe the current strategies for prevention and treatment of fluctuations. Special emphasis is put on two new methods which will soon be available. The new dopamine agonist Rotigotine (Neupro) can be transdermally applied. This is a rather simple way to achieve a continuous dopaminergic stimulation. The same goal is achieved by direct application of levodopa-/carbidopa-gelsuspension (Duodopa) in the duodenum by the help of an electronic pump.
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Seven patients with a sensorimotor peripheral neuropathy followed years later by extrapyramidal manifestations are presented. This appears to be a separate genetic disorder(s) from that described as Machado-Joseph disease. In five subjects, other relatives had similar multisystem involvement. None was of known Portuguese ancestry. The extrapyramidal syndrome was mainly parkinsonian. Pain was prominent in five subjects. In all cases, low or moderate doses of levodopa/carbidopa ameliorated both the pain and the parkinsonian features. In one patient, a randomized placebo-controlled trial of levodopa/carbidopa was found to significantly improve most symptoms and neurologic dysfunction scores related to the extrapyramidal syndrome.
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A pharmacodynamic model is presented to describe the motor effects (tapping rate, Unified Parkinson's Disease Rating Scale [UPDRS] Part III, and investigator-rating of ON/OFF, including dyskinesia) of levodopa (LD) in patients with advanced idiopathic Parkinson's disease (PD) treated with immediate-release (IR) carbidopa-levodopa (CD-LD) or an extended-release (ER) formulation of CD-LD (IPX066). Twenty-seven patients participated in this open-label, randomized, single- and multiple-dose, crossover study. The pharmacodynamic models included a biophase effect site with a sigmoid E(max) transduction for tapping and UPDRS and an ordered categorical model for dyskinesia. The pharmacodynamics of LD was characterized by a conduction function with a half-life of 0.59 hours for tapping rate, and 0.4 hours for UPDRS Part III and dyskinesia. The LD concentration for half-maximal effect was 1530 ng/mL, 810 ng/mL, and 600 ng/mL for tapping rate, UPDRS Part III, and dyskinesia, respectively. The sigmoidicity of the transduction was 1.53, 2.5, and 2.1 for tapping rate, UPDRS Part III, and dyskinesia, respectively. External validation of the pharmacodynamic model using tapping rate indicated good performance of the model.
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The multiple-dose (200 mg levodopa t.i.d.) pharmacokinetic profile of two controlled-release products of levodopa (Madopar HBS and Sinemet CR) was compared to conventional Madopar capsules in 18 healthy volunteers in a cross-over, randomized design. A pronounced controlled-release profile of the Madopar HBS and Sinemet CR product was demonstrated compared to conventional Madopar capsules with a significant (p < 0.001) decrease (-40 and -55%) in Cmax and a significant (p < 0.001) increase (+237 and +256%) in morning Cmin for the 200 mg t.i.d. dosage schedule. Almost equivalent bioavailability (85-90%) of levodopa was demonstrated for the controlled-release formulations relative to that of conventional Madopar capsules. The Madopar HBS formulation was bioequivalent with Sinemet CR with respect to levodopa, but it exhibited a moderately higher fluctuation index compared to Sinemet CR as a result of somewhat higher Cmax and lower Cmin values for the Madopar HBS formulation. 3-OMD (a metabolite of levodopa) levels were significantly (p < 0.05) higher for Madopar HBS and Madopar compared to Sinemet CR. The higher 3-OMD levels for the levodopa/benserazide combinations are consistent with a more potent decarboxylase inhibitory activity of benserazide as compared to carbidopa. The number of adverse events was highest for conventional Madopar (n = 18) compared to the controlled-release formulations (n = 12 for Sinemet CR and only 2 for Madopar HBS). A more efficient inhibition of dopamine formation from levodopa (resulting in higher 3-OMD levels) by Madopar HBS was consistent with the superior tolerability (especially for initial nausea) observed for the Madopar HBS formulation as compared to Sinemet CR.
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Following concomitant administration with levodopa/carbidopa CR 200 mg/50 mg, single doses of nebicapone 50 mg, 100 mg and 200 mg significantly and dose-dependently inhibited S-COMT activity, increased systemic exposure to levodopa, and reduced 3-OMD formation.
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From baseline to the follow-up test trial, both groups improved in visual acuity in the amblyopic eyes (occlusion group 20/116 to 20/76, P < .001; no occlusion group 20/90 to 20/73, P < .01) and dominant eyes (occlusion group 20/18 to 20/15, P > .05; no occlusion group 20/20 to 20/16, P < .01). The occlusion group exhibited a significant decrease in the difference in acuity between the dominant and amblyopic eyes of 1.3 lines (P < .02), whereas the no occlusion group revealed no significant effect. A comparison between groups revealed a significantly greater improvement in visual acuity in the amblyopic eye in the occlusion group compared with the no occlusion group (P = .01). In contrast, there was no significant difference between groups in terms of the change in visual acuity in the dominant eye (P = .15). Mean log contrast sensitivity in the amblyopic eye significantly improved in the occlusion group and did not significantly change in the no occlusion group. Fusion changed similarly in both groups. The improvements in visual function were maintained 4 weeks after the termination of all treatment. Adverse side effects were minimal in both groups.
The investigators conducted a single-dose pharmacokinetic (PK) study of levodopa/carbidopa delivered from novel gastric-retentive extended-release (ER) tablets versus a comparator ER tablet (M-ER) in patients with Parkinson's disease. Two levodopa/carbidopa (200 mg/50 mg) gastric-retentive ER formulations (4 hours and 6 hours) and M-ER were administered orally with food. Blood samples were collected for up to 24 hours post dose to determine levodopa and carbidopa concentrations. Tolerability was assessed by monitoring adverse events and measuring vital signs. PK modeling was conducted to estimate the release characteristics for future gastric-retentive ER formulations to achieve a less fluctuating plasma concentration profiles. Compared with M-ER, both gastric-retentive ER formulations exhibited a longer time to reach a lower maximal plasma concentration for levodopa and carbidopa. The 4-hour formulation demonstrated a similar area under the concentration-time curve compared with M-ER, whereas the 6-hour formulation demonstrated a lower area under the concentration-time curve. All formulations were well tolerated. Modeling suggests that a gastric-retentive ER formulation with a longer release duration administered twice daily may achieve a less fluctuating levodopa concentration profile than M-ER administered 3 times daily. This study demonstrates that gastric-retentive ER dosage forms may reduce dose frequency while minimizing the plasma peak-to-trough fluctuation and consequently reduce motor fluctuation in patients with Parkinson's disease.
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The dopamine precursor levodopa has shown some, albeit relatively weak, promise in treating cocaine dependence. This study sought to identify the most appropriate behavioral therapy platform for levodopa pharmacotherapy by evaluating its effect when administered in combination with behavioral platforms of varying intensities.
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Single unit discharge characteristics of neurons in the PPN region were analysed in four patients and PPN local field potentials (LFP) in one patient, recorded during the course of DBS implantation. Two patients had Parkinson disease, and two had non-sinemet responsive parkinsonism. Cell locations were plotted in the coordinate system of a human brainstem atlas.