Activation of mGlu 2/3 receptors with the orthosteric agonist LY-404,039 alleviates dyskinesia in experimental parkinsonism.

LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D 2 -agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu 2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60-100 min (54%, P  < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P  < 0.01). These results provide further evidence that mGlu 2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D 2 -agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD.

Individual versus integration of multiple components of central blood pressure and aortic stiffness in predicting cardiovascular mortality in end-stage renal diseases.

Aortic stiffness, measured by carotid-femoral pulse wave velocity (PWV), is a predictor of cardiovascular (CV) mortality in patients with end-stage renal disease (ESRD). Aortic stiffness increases aortic systolic and pulse pressures (cSBP, cPP) and augmentation index adjusted for a heart rate of 75 beats per minute (AIx@75). In this study, we examined if the integration of multiple components of central blood pressure and aortic stiffness (ICPS) into risk score categories could improve CV mortality prediction in ESRD. In a prospective cohort of 311 patients with ESRD on dialysis who underwent vascular assessment at baseline, 118 CV deaths occurred after a median follow-up of 3.1 years. The relationship between hemodynamic parameters and CV mortality was analyzed through Kaplan-Meier and Cox survival analysis. ICPS risk score from 0 to 5 points were calculated from points given to tertiles, and were regrouped into three risk categories (Average, High, Very-High). A strong association was found between the ICPS risk categories and CV mortality (High risk HR = 2.20, 95% CI: 1.05-4.62, P = 0.036); Very-High risk (HR = 4.44, 95% CI: 2.21-8.92, P < 0.001) as compared to the Average risk group. The Very-High risk category remained associated with CV mortality (HR = 3.55, 95% CI: 1.37-9.21, P = 0.009) after adjustment for traditional CV risk factors as compared to the Average risk group. While higher C-statistics value of ICPS categories (C: 0.627, 95% CI: 0.578-0.676, P = 0.001) was not statistically superior to PWV, cPP or AIx@75, the use of ICPS categories resulted in a continuous net reclassification index of 0.56 (95% CI: 0.07-0.99). In conclusion, integration of multiple components of central blood pressure and aortic stiffness may potentially be useful for better prediction of CV mortality in this cohort.

Differences in Antihypertensive Medication Prescription Profiles Between 2009 and 2021: A Retrospective Cohort Study of CARTaGENE.

Background: Although blood pressure (BP) control is critical to prevent cardiovascular diseases, hypertension control rates in Canada are in decline. Objective: To assess this issue, we sought to evaluate the differences in antihypertensive medication prescription profiles in the province of Quebec between 2009 and 2021. Design: This is a retrospective cohort study. Setting: We used data from the CARTaGENE population-based cohort linked to administrative health databases. Patients: Participants with any drug claim in the 6 months prior to the end of follow-up were included. Measurements: Guideline-recommended antihypertensive drug prescription profiles were assessed at the time of enrollment (2009-2010) and end of follow-up (March 2021). Methods: Prescriptions practices from the 2 time periods were compared using Pearson's chi-square tests. A sensitivity analysis was performed by excluding participants in which antihypertensive drugs may not have been prescribed solely to treat hypertension (presence of atrial fibrillation/flutter, ischemic heart disease, heart failure, chronic kidney disease, or migraines documented prior to or during follow-up). Results: Of 8447 participants included in the study, 31.4% and 51.3% filled prescriptions for antihypertensive drugs at the beginning and end of follow-up. In both study periods, guideline-recommended monotherapy was applied in most participants with hypertension (77.9% vs 79.5%, P = .3), whereas optimal 2 and 3-drug combinations were used less frequently (62.0% vs 61.4%, P = .77, 51.9% vs 46.7%, P = .066, respectively). Only the use of long-acting thiazide-like diuretics (9.5% vs 27.7%, P < .001) and spironolactone as a fourth-line agent (8.3% vs 15.9%, P = .054) increased with time but nonetheless remained infrequent. Results were similar in the sensitivity analysis. Limitations: Specific indication of the prescribed antihypertensive medications and follow-up BP data was not available. Conclusions: Application of hypertension guidelines for the choice of antihypertensive drugs remains suboptimal, highlighting the need for education initiatives. This may be an important step to raise BP control rates in Canada.

Contexte: Bien que le contrôle de la pression artérielle (PA) soit essentiel pour prévenir les maladies cardiovasculaires, les taux de maitrise de l'hypertension artérielle sont en déclin au Canada. Objectifs: Pour traiter cette problématique, nous avons cherché à évaluer les différences dans les profils de prescription de médicaments antihypertenseurs dans la province de Québec entre 2009 et 2021. Conception: Étude de cohorte rétrospective. Cadre: Nous avons utilisé les données de la cohorte populationnelle CARTaGENE reliées aux bases de données administratives en santé. Sujets: Ont été inclus les participants qui ont présenté une demande de remboursement de médicament dans les six mois précédant la fin du suivi. Mesures: Les profils de prescription de médicaments antihypertenseurs recommandés dans les lignes directrices ont été évalués au moment de l'inclusion (2009-2010) et à la fin du suivi (mars 2021). Méthodologie: Les profils de prescription des deux périodes ont été comparés à l'aide des tests Chi-Square de Pearson. Une analyse de sensibilité a été réalisée en excluant les participants pour lesquels les antihypertenseurs n'avaient possiblement pas été prescrits uniquement pour traiter l'hypertension (présence de fibrillation auriculaire, cardiopathie ischémique, insuffisance cardiaque, insuffisance rénale chronique ou migraines documentées avant ou pendant le suivi). Résultats: Des 8 447 participants inclus dans l'étude, 31,4 % avait rempli des prescriptions de médicaments antihypertenseurs au début du suivi et 51,3 % à la fin du suivi. Dans les deux périodes à l'étude, la monothérapie recommandée par les directives a été appliquée chez la plupart des participants avec hypertension artérielle (77,9 % c. 79,5 %; P = 0,3), tandis que les combinaisons optimales de deux médicaments (62,0 % c. 61,4 %; P = 0,77) et de trois médicaments (51,9 % c. 46,7 % P = 0,066) ont été utilisées moins fréquemment. Seules les utilisations de diurétiques thiazidiques à action prolongée (9,5 % c. 27,7 %; P < 0,001) et de spironolactone en quatrième intention (8,3 % c. 15,9 %; P = 0,054) ont augmenté avec le temps, mais sont demeurées néanmoins peu fréquentes. Les résultats étaient similaires dans l'analyse de sensibilité. Limites: L'indication précise pour la prescription de médicaments antihypertenseurs et les données de suivi sur la pression artérielle n'étaient pas disponibles. Conclusion: L'application des lignes directrices sur l'hypertension artérielle pour le choix des médicaments antihypertenseurs reste sous-optimale, ce qui souligne un besoin pour des initiatives en matière d'éducation. Cela pourrait constituer une étape importante d'une stratégie visant l'augmentation des taux de contrôle de la PA au Canada.

Integrated home dialysis model: facilitating home-to-home transition.

Peritoneal dialysis (PD) and home hemodialysis (HHD) are the two home dialysis modalities offered to patients. They promote patient autonomy, enhance independence, and are generally associated with better quality of life compared to facility hemodialysis. PD offers some advantages (enhanced flexibility, ability to travel, preservation of residual kidney function, and vascular access sites) but few patients remain on PD indefinitely due to peritonitis and other complications. By contrast, HHD incurs longer and more intensive training combined with increased upfront health costs compared to PD, but is easier to sustain in the long term. As a result, the integrated home dialysis model was proposed to combine the advantages of both home-based dialysis modalities. In this paradigm, patients are encouraged to initiate dialysis on PD and transfer to HHD after PD termination. Available evidence demonstrates the feasibility and safety of this approach and some observational studies have shown that patients who undergo the PD-to-HHD transition have clinical outcomes comparable to patients who initiate dialysis directly on HHD. Nevertheless, the prevalence of PD-to-HHD transfers remains low, reflecting the multiple barriers that prevent the full uptake of home-to-home transitions, notably a lack of awareness about the model, home-care "burnout," clinical inertia after a transfer to facility HD, suboptimal integration of PD and HHD centers, and insufficient funding for home dialysis programs. In this review, we will examine the conceptual advantages and disadvantages of integrated home dialysis, present the evidence that underlies it, identify challenges that prevent its success and finally, propose solutions to increase its adoption.