Administration of VP025 (Vasogen Inc.), a novel drug formulation based on phospholipid nanoparticles incorporating phosphatidylglycerol, has previously been shown to have a neuroprotective effect in the brain. We examined the effect of VP025 in a rat model of Parkinson's disease, the 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. VP025 or phosphate-buffered saline (PBS) was administered to rats 14 days, 13 days and 1 day before the unilateral 6-OHDA lesion. Functional integrity of nigrostriatal dopaminergic neurons was assessed 7 and 21 days later by amphetamine-induced rotational testing and we observed that rotational counts were significantly less in rats that were pretreated with VP025 compared with PBS-pretreated 6-OHDA-lesioned rats. Neurochemical analysis at 10 and 28 days after lesion revealed that VP025 protected against a 6-OHDA-induced decrease in concentrations of striatal dopamine and its metabolites. Immunocytochemical studies of the ipsilateral substantia nigra showed that VP025 significantly inhibited 6-OHDA-induced loss of dopaminergic neurons. We also observed that increases in immunostaining for activated microglia and for activated p38 in dopaminergic neurons of 6-OHDA-lesioned rats were prevented by VP025. This study shows that VP025 has significant protective effects on the 6-OHDA-lesioned nigrostriatal pathway and may therefore have potential for the treatment of Parkinson's disease.

ImportanceUltrasound renal denervation (uRDN) was shown to lower blood pressure (BP) in patients with uncontrolled hypertension (HTN). Establishing the magnitude and consistency of the uRDN effect across the HTN spectrum is clinically important.ObjectiveTo characterize the effectiveness and safety of uRDN vs a sham procedure from individual patient-level pooled data across uRDN trials including either patients with mild to moderate HTN on a background of no medications or with HTN resistant to standardized triple-combination therapy.Data SourcesA Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN SOLO and TRIO) and A Study of the ReCor Medical Paradise System in Stage II Hypertension (RADIANCE II) trials.Study SelectionTrials with similar designs, standardized operational implementation (medication standardization and blinding of both patients and physicians to treatment assignment), and follow-up.Data Extraction and SynthesisPooled analysis using individual patient-level data using linear regression models to compare uRDN with sham across the trials.Main Outcomes and MeasuresThe primary outcome was baseline-adjusted change in 2-month daytime ambulatory systolic BP (dASBP) between groups.ResultsA total of 506 patients were randomized in the 3 studies (uRDN, 293; sham, 213; mean [SD] age, 54.1 [9.3]; 354 male [70.0%]). After a 1-month medication stabilization period, dASBP was similar between the groups (mean [SD], uRDN, 150.3 [9.2] mm Hg; sham, 150.8 [10.5] mm Hg). At 2 months, dASBP decreased by 8.5 mm Hg to mean (SD) 141.8 (13.8) mm Hg among patients treated with uRDN and by 2.9 mm Hg to 147.9 (14.6) mm Hg among patients treated with a sham procedure (mean difference, −5.9; 95% CI, −8.1 to −3.8 mm Hg; P < .001 in favor of uRDN). BP decreases from baseline with uRDN vs sham were consistent across trials and across BP parameters (office SBP: −10.4 mm Hg vs −3.4 mm Hg; mean difference, −6.4 mm Hg; 95% CI, −9.1 to –3.6 mm Hg; home SBP: −8.4 mm Hg vs −1.4 mm Hg; mean difference, −6.8 mm Hg; 95% CI, −8.7 to −4.9 mm Hg, respectively). The BP reductions with uRDN vs sham were consistent across prespecified subgroups. Independent predictors of a larger BP response to uRDN were higher baseline BP and heart rate and the presence of orthostatic hypertension. No differences in early safety end points were observed between groups.Conclusions and RelevanceResults of this patient-level pooled analysis suggest that BP reductions with uRDN were consistent across HTN severity in sham-controlled trials designed with a 2-month primary end point to standardize medications across randomized groups.Trial RegistrationClinicalTrials.gov Identifier: NCT02649426 and NCT03614260

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In 1948, Paton and Zaimis reported on a series of polymethylene bistrimethyl ammonium compounds with unusual properties; the decamethonium (C10) member of this series exhibited marked curariform activity, while the penta-and hexamethonium (C5 and C6) compounds revealed ganglionic blocking action (1, 2). Since this report, a number of clinical studies have called attention to the favorable effects of C5 and C6 in hypertension (3-6), peptic ulcer (7) and peripheral vascular diseases (4,8,9). Investigations in this laboratory indicated that in a cool environment C6 produced a greater elevation of skin temperature of the digits than either tetraethylammonium salts or Priscoline (9). In addition, C6 caused less side effects and had a longer duration of action than either of the other blocking agents.These results suggested that the increase in peripheral blood flow after administration of C6 was greater than was produced by previously known compounds and might, in fact, approach that achieved following complete blockade of the sympathetic vasoconstrictor outflow. Since the changes in skin temperature provide at best only approximate estimations of variations in peripheral blood flow, it was decided to measure quantitatively the increase of blood flow in the foot after C6, using the plethysmographic method, and to compare this increase with the presumably maximum flow obtained from, regional block of the sympathetic nerves to the lower extremities. Blood flow was measured in the left foot using the venous occlusion plethysmograph described by Abramson (10), but with certain modifications. These changes were introduced because of the necessity of removing the foot from the plethysmograph at the time of the regional block and then replacing it rapidly to avoid delaying the determinations of blood flow. Therefore, instead of cementing the edge of a thick rubber sheeting to the ankle, a thin rubber boot was prepared, the edges of which were everted and sealed permanently to the inlet of the plethysmograph in a manner similar to that described by Krogh, Landis and Turner (11) for use with the limb segment plethysmograph. The boot was made of rubber thin and pliable enough for the pressure of the water filling the plethysmograph to press the rubber membrane snugly against the contours of the foot.4 Since an air pocket usually formed at the upper end of the boot, the air was removed by means of small-bore plastic tubing leading from the toe of the boot to one of the two outlets of the plethysmograph. The trapped air could then be removed by applying suction to the plastic tube with a syringe. By means of this device, the foot could be sealed quickly within the plethysmograph, and valid blood flows recorded within 15 minutes after the block had been completed. The smoked drum method of recording was replaced by an electrically heated writing point attached to the Brodie's bellows and the recordings made on heat-sensitive paper.5Digital pulse volumfe and blood flow were measured in the first toe of the opposite foot with a ...

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