Are levodopa preparationas with benserazide and carbidopa clinically equivalent?

Parkinson’s disease is the only neurodegenerative disease that can be effectively treated symptomatically. Treatment of motor symptoms is based primarily on the use of drugs that increase the activity of the nigrostriatal dopaminergic system and compensate for dopamine deficiency. Levodopa remains the gold standard of dopaminergic therapy. It is the most effective and best tolerated anti-parkinsonian drug, it causes the fewest side effects, also in the elderly patients. Oral preparations of levodopa additionally contain one of the aromatic L-amino acid decarboxylase inhibitors: benserazide or carbidopa. Inhibitors have a beneficial effect on the bioavailability of levodopa in the central nervous system, its clinical efficacy and tolerability. In practice, according to common opinion, the preparations of levodopa with carbidopa and levodopa with benserazide are clinically equivalent and can be used interchangeably. The case of a 69-year-old patient treated for 6 years for Parkinson’s disease is presented. The patient presented motor symptoms of advanced Parkinson’s disease: wearing-off motor fluctuations and peak dose dyskinesia. The was treated with levodopa in a dose of 5 × 200 mg (preparation of levodopa with benserazide) as a monotherapy. Due to the worsening availability of the drug used so far in pharmacies, it was changed to a preparation containing levodopa and carbidopa, while maintaining the same dose of levodopa. During the next visit, the patient reported that the change of the formulation had a beneficial effect in the form of a slight but significant reduction in the incidence and severity of peak dose dyskinesia. Pharmacokinetic studies showed that the mean maximum concentration of levodopa after administration of levodopa + benserazide was significantly higher than after administration of levodopa + carbidopa. The preparation containing benserazide caused a rapid increase and then a rapid decrease of the lewodopa plasma concentration. When levodopa was combined with carbidopa, the concentration of levodopa increased and decreased slowly. The results of these pharmacokinetic studies may explain the patient’s observation of the amelioration of peak dose dyskinesia after switching from a levodopa + benserazide formulation to a levodopa + carbidopa combination.

Abstract 12727: Microvascular Coronary Dysfunction Affects Global Longitudinal Strain After Dipyridamole Stress Echocardiography

Introduction: Coronary microvascular dysfunction (CMD) is a potential cause of myocardial ischemia and may affect myocardial function. CMD can be identified, in patients with non-obstructive coronary artery disease (CAD), by a reduced transthoracic Doppler-derived coronary flow reserve (CFR), which is an index of coronary arterial reactivity. Hypothesis: The aim of this study was to investigate the dipyridamole-induced changes of global longitudinal strain (GLS) in patients with CMD. Methods: fiftythree patients (35M, 18F; mean age 67±8 years) without obstructive CAD, assessed by invasive coronary angiogram, underwent dipyridamole stress echocardiography. CFR were determined as the ratio of hyperaemic to baseline diastolic coronary flow velocity. CMD was defined as CFR < 2. GLS was visualized as a bull’s-eye map in a quick and feasible manner. In each patient, we used a frame rate of 70 frames/sec for adequate 2D strain analysis. We analyzed GLS at each step of stress test and compared peak-dose values with baseline. Results: Sixteen patients (30%) among the overall population showed CMD. There were no significant differences in baseline characteristics between patients with or without CMD. GLS, at baseline, was significantly lower in patients with CMD (-16.7±3.77 vs. -17.9±3.75 - p<0.01). We observed a different response to dipyridamole stress echocardiography, between the two groups: GLS significantly increased up to peak dose in patients without CMD (from -17.9±3.75 to -19.5±4.12 - p<0.01), whereas on the other hand, a significant decrease from rest to peak dose was observed in patients with CMD (from -16.7±3.77 to -15.4±4.21- p<0.01). There was a significant inverse correlation between CFR and delta GLS measured at rest and after dipyridamole peak dose (r = -0.83 - p<0.01). Conclusions: GLS analysis, performed by comparing dipyridamole peak-dose with baseline values, shows that in patients with CMD there is a different response of left ventricular myocardiim to stress test. It could be assumed that the inverse correlation between CFR and delta GLS reflects a progressive subclinical worsening of left ventricular myocardial function in these patients. Larger studies could confirm our data.

Inverse response of global longitudinal strain after dipyridamole stress echocardiography in patients with microvascular coronary dysfunction

Background Coronary microvascular dysfunction (CMD) is a potential cause of myocardial ischemia and may affect myocardial function at rest and during stress. CMD can be identified, in patients with non-obstructive coronary artery disease (CAD), by a reduced transthoracic Doppler-derived coronary flow reserve (CFR), which is an index of coronary arterial reactivity, and can be impaired in both obstructive CAD and CMD. The aim of this study was to investigate the dipyridamole-induced changes of global longitudinal strain (GLS) in patients with CMD. Methods 43 patients (29M, 14F; mean age 68±7 years) without obstructive CAD, assessed by invasive coronary angiogram, underwent dipyridamole stress echocardiography. Coronary flow was assessed in the left anterior descending coronary artery (LAD) and was identified as the colour signal directed from the base to the apex of the left ventricle, containing the characteristic biphasic pulsed-Doppler flow signals. CFR were determined as the ratio of hyperaemic to baseline diastolic coronary flow velocity. CMD was defined as CFR &lt;2. GLS was measured using automated function imaging, through the positioning of three endocardial markers (two markers at the mitral annulus and one at the apex) in each apical view. Subsequently, the obtained segmental values of GLS were visualized as a bull's-eye map in a quick and feasible manner. We had optimal left ventricular endocardial tracking in the overall population. In each patient, we used a frame rate of 70 frames/sec for adequate 2D strain analysis. We analyzed GLS at each step of stress test and compared peak-dose values with baseline. Results Thirteen patients (30%) among the overall population showed CMD. There were no significant differences in baseline characteristics between patients with or without CMD. GLS, at baseline, was significantly lower in patients with CMD (−16.9±3.78 vs. −17.8±3.77 – p&lt;0.01). We observed a different response to dipyridamole stress echocardiography, between the two groups: GLS significantly increased up to peak dose in patients without CMD (from −17.8±3.77 to −19.3±4.09 – p&lt;0.01), whereas on the other hand, a significant decrease from rest to peak dose was observed in patients with CMD (from −16.9±3.78 to −15.5±4.18 – p&lt;0.01). There was a significant inverse correlation between CFR and delta GLS measured at rest and after dipyridamole peak dose (r=−0.82 – p&lt;0.01). Conclusions GLS analysis, particularly performed by comparing dipyridamole peak-dose with baseline values, shows that in patients with CMD there is a different response of left ventricular myocardiim to stress test. It could be assumed that the inverse correlation between CFR and delta GLS reflects a progressive subclinical worsening of left ventricular myocardial function in these patients. Larger studies could confirm our data. Funding Acknowledgement Type of funding source: None

Complete Remission of Mouse Melanoma after Temporally Fractionated Microbeam Radiotherapy

Background: Synchrotron Microbeam Radiotherapy (MRT) significantly improves local tumour control with minimal normal tissue toxicity. MRT delivers orthovoltage X-rays at an ultra-high “FLASH” dose rate in spatially fractionated beams, typically only few tens of micrometres wide. One of the biggest challenges in translating MRT to the clinic is its use of high peak doses, of around 300–600 Gy, which can currently only be delivered by synchrotron facilities. Therefore, in an effort to improve the translation of MRT to the clinic, this work studied whether the temporal fractionation of traditional MRT into several sessions with lower, more clinically feasible, peak doses could still maintain local tumour control. Methods: Two groups of twelve C57Bl/6J female mice harbouring B16-F10 melanomas in their ears were treated with microbeams of 50 µm in width spaced by 200 µm from their centres. The treatment modality was either (i) a single MRT session of 401.23 Gy peak dose (7.40 Gy valley dose, i.e., dose between beams), or (ii) three MRT sessions of 133.41 Gy peak dose (2.46 Gy valley dose) delivered over 3 days in different anatomical planes, which intersected at 45 degrees. The mean dose rate was 12,750 Gy/s, with exposure times between 34.2 and 11.4 ms, respectively. Results: Temporally fractionated MRT ablated 50% of B16-F10 mouse melanomas, preventing organ metastases and local tumour recurrence for 18 months. In the rest of the animals, the median survival increased by 2.5-fold in comparison to the single MRT session and by 4.1-fold with respect to untreated mice. Conclusions: Temporally fractionating MRT with lower peak doses not only maintained tumour control, but also increased the efficacy of this technique. These results demonstrate that the solution to making MRT more clinically feasible is to irradiate with several fractions of intersecting arrays with lower peak doses. This provides alternatives to synchrotron sources where future microbeam radiotherapy could be delivered with less intense radiation sources.

Conventional dose rate spatially-fractionated radiation therapy (SFRT) treatment response and its association with dosimetric parameters – A preclinical study in a Fisher 344 rat model

PurposeTo identify key dosimetric parameters that have close associations with tumor treatment response and body weight change in SFRT treatments with a large range of spatial-fractionation scale at dose rates of several Gy/min.MethodsSix study arms using uniform tumor radiation, half-tumor radiation, 2mm beam array radiation, 0.3mm minibeam radiation, and an untreated arm were used. All treatments were delivered on a 320kV x-ray irradiator. Forty-two female Fischer 344 rats with fibrosarcoma tumor allografts were used. Dosimetric parameters studied are peak dose and width, valley dose and width, peak-to-valley-dose-ratio, volumetric average dose, percentage volume directly irradiated, and tumor- and normal-tissue EUD. Animal survival, tumor volume change, and body weight change (indicative of treatment toxicity) are tested for association with the dosimetric parameters using linear regression and Cox Proportional Hazards models.ResultsThe dosimetric parameters most closely associated with tumor response are tumor EUD (R2=0.7923, F-stat=15.26*; z-test=−4.07***), valley/minimum dose (R2=0.7636, F-stat=12.92*; z-test=−4.338***), and percentage tumor directly irradiated (R2=0.7153, F-stat=10.05*; z-test=−3.837***) per the linear regression and Cox Proportional Hazards models, respectively. Tumor response is linearly proportional to valley/minimum doses and tumor EUD. Average dose (R2=0.2745, F-stat=1.514 (no sig.); z-test=−2.811**) and peak dose (R2=0.04472, F-stat=0.6874 (not sig.); z-test=−0.786 (not sig.)) show the weakest associations to tumor response. Only the uniform radiation arm did not gain body weight post-radiation, indicative of treatment toxicity; however, body weight change in general shows weak association with all dosimetric parameters except for valley/min dose (R2=0.3814, F-stat=13.56**), valley width (R2=0.2853, F-stat=8.783**), and peak width (R2=0.2759, F-stat=8.382**).ConclusionsFor a single-fraction SFRT at conventional dose rates, valley, not peak, dose is closely associated with tumor treatment response and thus should be used for treatment prescription. Tumor EUD, valley/min dose, and percentage tumor directly irradiated are the top three dosimetric parameters that exhibited close associations with tumor response.