Synthesis and in vitro and in vivo characterization of highly β1-Selective β-Adrenoceptor partial agonists

β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of −7.75 and −5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β1- selectivity

Association between metabolic syndrome and progression in Parkinson's disease

Background: Parkinson's disease (PD) and metabolic syndrome are separate entities that share common underlying pathophysiology. Management strategy for metabolic syndrome is clinically better characterized and finding a positive clinical correlation between the two could lead to a better understanding of Parkinson's disease progression and prognosis. Purpose: To explore the relationship between progression in PD and metabolic syndrome to characterize the underlying pathophysiology, which could then impact the clinical management of PD. Methods: Using modified NCEP (National Cholesterol Education Program) ATP III (Adult Treatment Plan) criteria, patients enrolled in STEADY-PD III (Safety, Tolerability, and Efficacy Assessment of Isradipine) were classified into one of three categories of metabolic syndrome and compared on PD progression over a period of 3 years. Results: Participants with metabolic syndrome showed a trend for more progression in terms of PD, as measured by the total Unified Parkinson's Disease Rating Scale (UPDRS), the motor EDL (Experiences of daily living) scores of the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and the Montreal Cognitive Assessment (MoCA). A significant trend for decline in MoCA was found in the group with metabolic syndrome (−0.78), compared with those without metabolic syndrome (0.14). Greater decline in MoCA signifies worse outcomes. Conclusion: The results demonstrate a trend in more clinical progression in PD in subjects with metabolic syndrome. However, results are limited by the sample size and the limited laboratory measurements available. We hope this study will encourage larger sample studies to explore this relationship further

A Novel Design of a Phase III Trial of Isradipine in Early Parkinson Disease (STEADY-PD III)

Objectives To describe the rationale for a novel study design and baseline characteristics of a disease-modifying trial of isradipine 10 mg daily in early Parkinson disease (PD). Methods STEADY-PDIII is a 36-month, Phase 3, parallel group, placebo-controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I-III score in the practically defined ON state. Secondary outcome measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed. Results The entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4). Interpretation STEADY-PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits

A Novel Design of a Phase III Trial of Isradipine in Early Parkinson Disease (STEADY-PD III)

Objectives To describe the rationale for a novel study design and baseline characteristics of a disease-modifying trial of isradipine 10 mg daily in early Parkinson disease (PD). Methods STEADY-PDIII is a 36-month, Phase 3, parallel group, placebo-controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I-III score in the practically defined ON state. Secondary outcome measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed. Results The entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4). Interpretation STEADY-PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits

Proterozoic Metamorphism of the Tobacco Root Mountains, Montana

Textures and mineral assemblages of metamorphic rocks of the Tobacco Root Mountains are consistent with metamorphism of all rocks during the Big Sky orogeny (1.77 Ga) at relatively high pressure (P \u3e1.0 GPa) followed by differential reequilibration on a clockwise P-T path at lower pressures (0.6–0.8 GPa). The highest pressures are documented by coarse-grained kyanite and orthopyroxene in aluminous orthoamphibolites, which require P ≥ 1.0 GPa. Other higher-pressure mineral assemblages of note include kyanite + orthoamphibole and kyanite + K-feldspar. Abundant textural evidence for partial melting in pelitic and basaltic rocks includes leucosomes, very large (several cm across) porphyroblasts of garnet, and an absence of primary (foliation-defining) muscovite. Partial to complete overprinting of the coarse-textured, high-pressure assemblages by lower-pressure assemblages and textures occurred across the Tobacco Root Mountains, especially where assisted by deformation and the availability of water. In aluminous rocks, sillimanite bundles typically replace kyanite, and garnet may be rimmed by cordierite + orthopyroxene symplectite or, in quartz-absent rocks, sapphirine + spinel + cordierite symplectite. Orthoamphibolites with partial pseudomorphs of garnet by cordierite are common. Garnet necklaces surround orthopyroxene in orthopyroxene-plagioclase gneisses, whereas orthopyroxene + plagioclase pseudomorphs of garnet occur in nearby hornblende amphibolites. These features appear to require nearly isobaric cooling at pressures near 0.8 GPa, followed by nearly isothermal decompression at temperatures near 700 °C. The resulting P-T path is believed to be the result of tectonic denudation late in the orogenic cycle. Quartz-plagioclase-garnet-hornblende amphibolites occur throughout the Tobacco Root Mountains. Near-rim mineral compositions from these rocks have been used to calculate Ts of 650–750 °C at Ps of 0.7–0.9 GPa across the terrane. There is no systematic variation in calculated P and T between units nor geographically within units; differences appear to reflect variations in thermometer closure possibly due to the availability of water during cooling. Field relations involving metamorphosed mafic dikes, as well as geochronological data from monazite and zircon, demonstrate that some rocks were first metamorphosed at high temperatures and pressures at 2.45 Ga. However, we have not i