Successful Elimination of Endemic Rubella in the WHO European Region. Is It Proper to Remove the Recommendation for Preconceptional Immunization?

BACKGROUND: Rubella is a contagious viral infection that has garnered significant attention in the field of public health due to its potential consequences, especially during pregnancy. In recent decades, it has been recommended that non-immune women receive immunization during the preconceptional and/or postpartum periods. The goal of this strategy is to prevent primary rubella infection in order to protect pregnant women against congenital rubella syndrome. In November 2022, the WHO's Regional Verification Commission declared the elimination of rubella infection in Italy. In recent years, the main migration flows to Italy have originated from regions where rubella has not yet been eliminated and where no program is in place to achieve this goal. OBJECTIVE: The aim of this study was to retrospectively assess rubella immunity in pregnant women who have attended three delivery centers in Rome over the past three years, from January 2021 to May 2023. METHODS: Data about the rubella serological status of 7937 non-consecutive pregnant women were collected. Univariate analysis was performed to verify any difference between the study groups in terms of age distribution. RESULTS: Anti-rubella IgG antibodies were found in 7224 (91%) women while 713 (9%) were susceptible to rubella (IgG negative), without differences in terms of immunity rate between Italian and non-Italian women. Age analysis showed a statistically significant older age of immune women than receptive women and of Italian immune women than non-Italian immune women. CONCLUSIONS: The National Plan for the Elimination of Measles and Congenital Rubella aimed to achieve a percentage of susceptible women of childbearing age below 5%. These data indicate the relevance of maintaining the recommendation for preconceptional rubella vaccination in Italy.

User-Centered Design of a Preference-Driven Patient Activation Tool for Optimizing Depression Treatment in Integrated Primary Care Settings (The Transform DepCare Study).

BACKGROUND: Few patient engagement tools incorporate the complex patient experiences, contexts, and workflows that limit depression treatment implementation. OBJECTIVE: Describe a user-centered design (UCD) process for operationalizing a preference-driven patient activation tool. DESIGN: Informed by UCD and behavior change/implementation science principles, we designed a preference-driven patient activation prototype for engaging patients in depression treatment. We conducted three usability cycles using different recruitment/implementation approaches: near live/live testing in primary care waiting rooms (V1-2) and lab-based think aloud testing (V3) oversampling older, low-literacy, and Spanish-speaking patients in the community and via EHR algorithms. We elicited clinician and "heuristic" expert input. MAIN MEASURES: We administered the system usability scale (SUS) all three cycles and pre-post V3, the patient activation measure, decisional conflict scale, and depression treatment barriers. We employed descriptive statistics and thematically analyzed observer notes and transcripts for usability constructs. RESULTS: Overall, 43 patients, 3 clinicians, and 5 heuristic (a usability engineering method for identifying usability problems) experts participated. Among patients, 41.9% were ≥ 65 years old, 79.1% female, 23.3% Black, 62.8% Hispanic, and 55.8% Spanish-speaking and 46.5% had ≤ high school education. We described V1-3 usability (67.2, 77.3, 81.8), treatment seeking (92.3%, 87.5%, 92.9%), likelihood/comfort discussing with clinician (76.9%, 87.5%, 100.0%), and pre vs. post decisional conflict (23.7 vs. 15.2), treatment awareness (71.4% vs. 92.9%), interest in antidepressants (7.1% vs. 14.3%), and patient activation (66.8 vs. 70.9), with fewer barriers pertaining to cost/insurance, access/coordination, and self-efficacy/stigma/treatment efficacy. Key themes included digital literacy, understandability, high acceptability for aesthetics, high usefulness of patient/clinician videos, and workflow limitations. We adapted manual entry/visibility/content; added patient activation and a personalized algorithm; and proposed flexible, care manager delivery leveraging clinic screening protocols. DISCUSSION: We provide an example of leveraging UCD to design/adapt a real-world, patient experience and workflow-aligned patient activation tool in diverse populations.

A Multifaceted Implementation Strategy to Increase Out-of-Office Blood Pressure Monitoring: The EMBRACE Cluster Randomized Clinical Trial.

Importance: Few primary care patients complete guideline-recommended out-of-office blood pressure (BP) monitoring prior to having hypertension diagnosed. Objective: To evaluate the effectiveness of a behavioral theory-informed, multifaceted implementation strategy on out-of-office BP monitoring (ambulatory BP monitoring [ABPM] or home BP monitoring [HBPM]) among patients with new hypertension. Design, Setting, and Participants: This 2-group, pre-post cluster randomized trial was conducted within a primary care network of 8 practices (4 intervention practices with 99 clinicians; 4 control practices with 55 clinicians) and 1186 patients (857 intervention; 329 control) with at least 1 visit with elevated office BP and no prior hypertension diagnosis between October 2016 and September 2017 (preimplementation period) or between April 2018 and March 2019 (postimplementation period). Data were analyzed from February to July 2023. Interventions: Usual care (control group) or a multifaceted implementation strategy consisting of an accessible ABPM service; electronic health record (EHR) tools to facilitate test ordering; clinician education, reminders, and feedback relevant to out-of-office BP monitoring; nurse training on HBPM; and patient information handouts. Main Outcomes and Measures: The primary outcome was patient completion of out-of-office BP monitoring within 6 months of an eligible visit. Secondary outcomes included clinician ordering of out-of-office BP monitoring. Blinded assessors extracted outcomes from the EHR. Results: A total of 1186 patients (857 intervention; 329 control) were included, with a mean (SD) age of 54 (16) years; 808 (68%) were female, and 549 (48%) were Spanish speaking; among those with race and ethnicity documented, 123 (10%) were Black or African American, and 368 (31%) were Hispanic. Among intervention practices, the percentage of visits resulting in completed out-of-office BP monitoring increased from 0.6% (0% ABPM; 0.6% HBPM) to 5.7% (3.7% ABPM; 2.0% HBPM) between the preimplementation and postimplementation periods (P = .009). Among control practices, the percentage of visits resulting in completed out-of-office BP monitoring changed from 5.4% (0% ABPM; 5.4% HBPM) to 4.3% (0% ABPM; 4.3% HBPM) during the corresponding period (P = .94). The ratio of relative risks (RRs) of out-of-office BP monitoring in the postimplementation vs preimplementation periods for intervention vs control practices was 10.5 (95% CI, 1.9-58.0; P = .01). The ratio of RRs of out-of-office BP monitoring being ordered was 2.2 (95% CI, 0.8-6.3; P = .12). Conclusions and Relevance: This study found that a theory-informed implementation strategy that included access to ABPM modestly increased out-of-office BP monitoring among patients with elevated office BP but no hypertension diagnosis. Trial Registration: ClinicalTrials.gov Identifier: NCT03480217.

Auto adaptation of closed-loop insulin delivery system using continuous reward functions and incremental discretization.

Several closed or hybrid loop controllers for Blood Glucose (BG) regulation, which are also known as Artificial Pancreas (AP) Systems or Automated Insulin Delivery systems (AIDs), are in development worldwide. Most AIDs are designed and evaluated for short-term performance, with a particular emphasis on the post-meal period. However, if controllers are not adapted properly to account for variations in physiology that affect Insulin Sensitivity (IS), the AIDs may perform inadequately. In this work, the performance of two Reinforcement Learning (RL) agents trained under both piecewise and continuous reward functions is evaluated in-silico for long-term adaptation of a Fully Automated Insulin Delivery (fAID) system. An automatic adaptive discretization scheme that expands the state space as needed is also implemented to avoid disproportionate state space exploration. The proposed agents are evaluated for long-term adaptation of the Automatic Regulation of Glucose (ARG) algorithm, considering variations in IS. Results show that both RL agents have improved performance compared to a rule-based decision-making approach and the baseline controller for the majority of the adult population. Moreover, the use of a continuous shaped reward function proves to enhance the performance of the agents further than a piecewise one.

Breaking Up Prolonged Sitting to Improve Cardiometabolic Risk: Dose-Response Analysis of a Randomized Crossover Trial.

PURPOSE: Sedentary time is ubiquitous in developed nations and is associated with deleterious health outcomes. Physical activity guidelines recommend reductions in sedentary time; however, quantitative guidelines that inform how often and how long sedentary time should be interrupted have not been provided. The purpose of this study was to examine the acute effects of multiple doses of a sedentary break intervention on cardiometabolic risk factors, concurrently evaluating efficacy of varying frequencies and durations of sedentary breaks. METHODS: In a randomized crossover study, middle- and older-age adults ( n = 11) completed the following 8-h conditions on five separate days: 1 uninterrupted sedentary (control) condition and four acute (experimental) trials that entailed different sedentary break frequency/duration combinations: every 30 min for 1 min, every 30 min for 5 min, every 60 min for 1 min, and every 60 min for 5 min. Sedentary breaks entailed light-intensity walking. Glucose and blood pressure (BP) were measured every 15 and 60 min, respectively. RESULTS: Compared with control, glucose incremental area under the curve was significantly attenuated only for the every 30 min for 5-min dose (-11.8[4.7]; P = 0.017). All sedentary break doses yielded significant net decreases in systolic BP from baseline compared with control ( P < 0.05). The largest reductions in systolic BP were observed for the every 60 min for 1 min (-5.2 [1.4] mm Hg) and every 30 min for 5 min (-4.3[1.4] mm Hg) doses. CONCLUSIONS: The present study provides important information concerning efficacious sedentary break doses. Higher-frequency and longer-duration breaks (every 30 min for 5 min) should be considered when targeting glycemic responses, whereas lower doses may be sufficient for BP lowering.

Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids.

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant ß-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

A theory-informed, rapid cycle approach to identifying and adapting strategies to promote sustainability: optimizing depression treatment in primary care clinics seeking to sustain collaborative care (The Transform DepCare Study).

BACKGROUND: Few real-world examples exist of how best to select and adapt implementation strategies that promote sustainability. We used a collaborative care (CC) use case to describe a novel, theory-informed, stakeholder engaged process for operationalizing strategies for sustainability using a behavioral lens. METHODS: Informed by the Dynamic Sustainability Framework, we applied the Behaviour Change Wheel to our prior mixed methods to identify key sustainability behaviors and determinants of sustainability before specifying corresponding intervention functions, behavior change techniques, and implementation strategies that would be acceptable, equitable and promote key tenets of sustainability (i.e., continued improvement, education). Drawing on user-centered design principles, we enlisted 22 national and local stakeholders to operationalize and adapt (e.g., content, functionality, workflow) a multi-level, multi-component implementation strategy to maximally target behavioral and contextual determinants of sustainability. RESULTS: After reviewing the long-term impact of early implementation strategies (i.e., external technical support, quality monitoring, and reimbursement), we identified ongoing care manager CC delivery, provider treatment optimization, and patient enrollment as key sustainability behaviors. The most acceptable, equitable, and feasible intervention functions that would facilitate ongoing improvement included environmental restructuring, education, training, modeling, persuasion, and enablement. We determined that a waiting room delivered shared decision-making and psychoeducation patient tool (DepCare), the results of which are delivered to providers, as well as ongoing problem-solving meetings/local technical assistance with care managers would be the most acceptable and equitable multi-level strategy in diverse settings seeking to sustain CC programs. Key adaptations in response to dynamic contextual factors included expanding the DepCare tool to incorporate anxiety/suicide screening, triage support, multi-modal delivery, and patient activation (vs. shared decision making) (patient); pairing summary reports with decisional support and yearly onboarding/motivational educational videos (provider); incorporating behavioral health providers into problem-solving meetings and shifting from billing support to quality improvement and triage (system). CONCLUSION: We provide a roadmap for designing behavioral theory-informed, implementation strategies that promote sustainability and employing user-centered design principles to adapt strategies to changing mental health landscapes.

First Outpatient Clinical Trial of a Full Closed-Loop Artificial Pancreas System in South America.

BACKGROUND: The first two studies of an artificial pancreas (AP) system carried out in Latin America took place in 2016 (phase 1) and 2017 (phase 2). They evaluated a hybrid algorithm from the University of Virginia (UVA) and the automatic regulation of glucose (ARG) algorithm in an inpatient setting using an AP platform developed by the UVA. The ARG algorithm does not require carbohydrate (CHO) counting and does not deliver meal priming insulin boluses. Here, the first outpatient trial of the ARG algorithm using an own AP platform and doubling the duration of previous phases is presented. METHOD: Phase 3 involved the evaluation of the ARG algorithm in five adult participants (n = 5) during 72 hours of closed-loop (CL) and 72 hours of open-loop (OL) control in an outpatient setting. This trial was performed with an own AP and remote monitoring platform developed from open-source resources, called InsuMate. The meals tested ranged its CHO content from 38 to 120 g and included challenging meals like pasta. Also, the participants performed mild exercise (3-5 km walks) daily. The clinical trial is registered in ClinicalTrials.gov with identifier: NCT04793165. RESULTS: The ARG algorithm showed an improvement in the time in hyperglycemia (52.2% [16.3%] OL vs 48.0% [15.4%] CL), time in range (46.9% [15.6%] OL vs 50.9% [14.4%] CL), and mean glucose (188.9 [25.5] mg/dl OL vs 186.2 [24.7] mg/dl CL) compared with the OL therapy. No severe hyperglycemia or hypoglycemia episodes occurred during the trial. The InsuMate platform achieved an average of more than 95% of the time in CL. CONCLUSION: The results obtained demonstrated the feasibility of outpatient full CL regulation of glucose levels involving the ARG algorithm and the InsuMate platform.

Stereospecific Effects of Benzimidazolonepiperidine Compounds on T-Type Ca2+ Channels and Pain.

T-type calcium channels activate in response to subthreshold membrane depolarizations and represent an important source of Ca2+ influx near the resting membrane potential. These channels regulate neuronal excitability and have been linked to pain. For this reason, T-type calcium channels are suitable molecular targets for the development of new non-opioid analgesics. Our previous work identified an analogue of benzimidazolonepiperidine, 5bk, that preferentially inhibited CaV3.2 channels and reversed mechanical allodynia. In this study, we synthesized and screened a small library of 47 compounds derived from 5bk. We found several compounds that inhibited the Ca2+ influx in DRG neurons of all sizes. After separating the enantiomers of each active compound, we found two compounds, 3-25-R and 3-14-3-S, that potently inhibited the Ca2+ influx. Whole-cell patch clamp recordings from small- to medium-sized DRG neurons revealed that both compounds decreased total Ca2+. Application of 3-14-3-S (but not 3-25-R) blocked transiently expressed CaV3.1-3.3 channels with a similar IC50 value. 3-14-3-S decreased T-type, but not N-type, Ca2+ currents in DRG neurons. Furthermore, intrathecal delivery of 3-14-3-S relieved tonic, neuropathic, and inflammatory pain in preclinical models. 3-14-3-S did not exhibit any activity against G protein-coupled opioid receptors. Preliminary docking studies also suggest that 3-14-3-S can bind to the central pore domain of T-type channels. Together, our chemical characterization and functional and behavioral data identify a novel T-type calcium channel blocker with in vivo efficacy in experimental models of tonic, neuropathic, and inflammatory pain.

Comparative In vitro Metabolism of Enflicoxib in Dogs, Rats, and Humans: Main Metabolites and Proposed Metabolic Pathways.

BACKGROUND: Enflicoxib is a non-steroidal anti-inflammatory drug of the coxib family characterized by a long-lasting pharmacological activity that has been attributed to its active metabolite E-6132. OBJECTIVES: The aim of this work was to explore enflicoxib biotransformation In vitro in humans, rats and dogs, and to determine its metabolic pathways. METHODS: Different In vitro test systems were used, including hepatocytes and liver and non-hepatic microsomes. The samples were incubated with enflicoxib and/or any of its metabolites at 37°C for different times depending on the test system. The analyses were performed by liquid chromatography coupled with either radioactivity detection or high-resolution mass spectrometry. RESULTS: Enflicoxib was efficiently metabolized by cytochrome P-450 into three main phase I metabolites: M8, E-6132, and M7. The non-active hydroxy-pyrazoline metabolite M8 accounted for most of the fraction metabolized in all the three species. The active pyrazol metabolite E-6132 showed a slow formation rate, especially in dogs, whereas metabolite M7 was a secondary metabolite formed by oxidation of M8. In hepatocytes, diverse phase II metabolite conjugates were formed, including enflicoxib glucuronide, M8 glucuronide, E-6132 glucuronide, M7 glucuronide, and M7 sulfate. Metabolite E-6132 was most probably eliminated by a unique glucuronidation reaction at a very low rate. CONCLUSION: The phase I metabolism of enflicoxib was qualitatively very similar among rats, humans and dogs. The low formation and glucuronidation rates of the active enflicoxib metabolite E-6132 in dogs are postulated as key factors underlying the mechanism of its long-lasting pharmacokinetics and enflicoxib's overall sustained efficacy.

Preliminary in vitro approach to evaluate the drug-drug interaction potential of EST73502, a dual µ-opioid receptor partial agonist and σ1 receptor antagonist.

The potential for drug-drug interactions (DDI) of EST73502 was preliminary explored in vitro. EST73502 is a new chemical entity intended for oral pain treatment with dual sigma-1 receptor (σ1R) antagonism and µ-opioid receptor (MOR) partial agonism, that presents a promising potent analgesic activity.Several enzymes were involved in EST73502 metabolism catalysing the formation of different metabolites, CYP3A4 and CYP2D6 being the main ones.Fraction unbound was determined due to its impact in interactions, a considerable proportion of EST73502 being available.EST73502 showed a low potential for CYP inhibition, except for CYP2D6 that showed time-dependent inhibition.No induction potential was found for CYP1A2 and 3A4, while CYP2B6 was induced at high concentration.EST73502 seemed to be a potential efflux transporter substrate (efflux ratio ≥ 2) but a negligible in vivo impact would be expected due to its high solubility and permeability in Caco-2 cells. P-gp inhibition was observed while no BCRP inhibition was detected.Preliminary in vitro interaction studies suggested that neither CYPs nor efflux transporters interactions would preclude further development of EST73502 to thoroughly assess the clinical relevance of these findings.

Preliminary in vitro assessment of pharmacokinetic drug-drug interactions of EST64401 and EST64514, two sigma-1 receptor antagonists.

EST64401 and EST64514 are two selective sigma-1 receptor ligands that showed a good profile in a lead optimization process for oral pain treatment. Their potential for pharmacokinetic-based drug-drug interactions was assessed to anticipate clinical interactions.Both compounds showed a low potential for CYP inhibition with percentages of inhibition <50% at 1 µM in recombinant human CYPs (CYP1A2, 2C9, 2C19, 2D6 and 3A4) and IC50 ≥75 µM for CYP3A4 and 2D6 in human liver microsomes.No CYP induction was observed for CYP1A2, 2B6 and 3A4 at concentrations ≤25 µM (EST64401) or ≤50 µM (EST64514) in human hepatocytes using as endpoints CYP activities and mRNA levels.More than one enzyme participated in compound metabolism. The main enzymes involved were CYP3A4 for EST64401 and CYP2D6 besides CYP3A4 for EST64514.Neither EST64401 nor EST64514 seemed to be substrates of P-gp or BCRP in Caco-2 cells (efflux ratio ≤2). Transporter inhibition was observed at concentrations ≥20 µM; EST64401 only inhibiting P-gp at higher concentrations (≥125 µM).Preliminary in vitro interaction studies suggest a similar profile for EST64401 and EST64514. Therefore, other properties will have to be considered for compound differentiation and selection for further development.

Automatic glycemic regulation for the pediatric population based on switched control and time-varying IOB constraints: an in silico study.

Artificial pancreas (AP) systems have shown to improve glucose regulation in type 1 diabetes (T1D) patients. However, full closed-loop performance remains a challenge particularly in children and adolescents, since these age groups often present the worst glycemic control. In this work, an algorithm based on switched control and time-varying IOB constraints is presented. The proposed control strategy is evaluated in silico using the FDA-approved UVA/ Padova simulator and its performance contrasted with the previously introduced Automatic Regulation of Glucose (ARG) algorithm in the pediatric population. The effect of unannounced meals is also explored. Results indicate that the proposed strategy achieves lower hypo- and hyperglycemia than the ARG for both announced and unannounced meals. Graphical Abstract Block diagram and illustrative example of insulin and glucose evolution over time for the proposed algorithm (ARGAE).

Preliminary in Vitro Assessment of the Potential of EST64454, a Sigma-1 Receptor Antagonist, for Pharmacokinetic Drug-Drug Interactions.

EST64454 is a selective sigma-1 receptor ligand intended for orally administered pain treatment that showed a promising profile in the lead optimization process. As part of the preliminary compound profiling, the potential for future drug-drug interactions was explored in vitro. Both direct and time-dependent CYP inhibition for CYP1A2, 2C9, 2C19, 2D6 and 3A4 was studied in human liver microsomes. EST64454 showed a low potential for CYP inhibition (IC50 between 100 and 1000 µM) and as time-dependent inhibitor (IC50 shift mainly around 1). CYP induction studies with HepaRG™ cells revealed no CYP induction at concentrations ≤50 µM, as shown by the CYP1A2, 3A4 and 2B6 activities measured. Reaction phenotyping was assessed after incubation with recombinant human enzymes. Although a very low metabolism was observed, several enzymes catalyzed the formation of metabolites, including CYP3A4, 2C19 and flavin monooxygenases (FMO) 1 and 3. EST64454 was not a P-glycoprotein (P-gp) substrate and was highly permeable in Caco-2 cells. P-gp inhibition was only observed at 200 µM, the highest concentration studied. Preliminary studies suggest that neither CYP nor P-gp interaction of EST64454 would be of any concern for further development. At later stages, the interaction kinetics and the clinical relevance of these findings will be thoroughly evaluated.

4-Aryl-1-oxa-4,9-diazaspiro[5.5]undecane Derivatives as Dual µ-Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain.

The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ1R) and the µ-opioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both target pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e., MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ1R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ1R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics.

The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels.

Naringenin (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one is a natural flavonoid found in fruits from the citrus family. Because (2S)-naringenin is known to racemize, its bioactivity might be related to one or both enantiomers. Computational studies predicted that (2R)-naringenin may act on voltage-gated ion channels, particularly the N-type calcium channel (CaV2.2) and the NaV1.7 sodium channel-both of which are key for pain signaling. Here we set out to identify the possible mechanism of action of naringenin. Naringenin inhibited depolarization-evoked Ca2+ influx in acetylcholine-, ATP-, and capsaicin-responding rat dorsal root ganglion (DRG) neurons. This was corroborated in electrophysiological recordings from DRG neurons. Pharmacological dissection of each of the voltage-gated Ca2+ channels subtypes could not pinpoint any selectivity of naringenin. Instead, naringenin inhibited NaV1.8-dependent and tetrodotoxin (TTX)-resistant while sparing tetrodotoxin sensitive (TTX-S) voltage-gated Na+ channels as evidenced by the lack of further inhibition by the NaV1.8 blocker A-803467. The effects of the natural flavonoid were validated ex vivo in spinal cord slices where naringenin decreased both the frequency and amplitude of sEPSC recorded in neurons within the substantia gelatinosa. The antinociceptive potential of naringenin was evaluated in male and female mice. Naringenin had no effect on the nociceptive thresholds evoked by heat. Naringenin's reversed allodynia was in mouse models of postsurgical and neuropathic pain. Here, driven by a call by the National Center for Complementary and Integrative Health's strategic plan to advance fundamental research into basic biological mechanisms of the action of natural products, we advance the antinociceptive potential of the flavonoid naringenin.

Hábitos alimentarios y estado nutricional en pacientes diabéticos con retinopatía que acuden a una Clínica Oftalmológica Privada de la ciudad de Asunción / Food habits and nutritional status in diabetic patients with retinopathy that attend a private Ophthalmological Clinic of the city of Asunción

La retinopatía diabética (RD) es una complicación microvascular crónica, específica de la diabetes. Es una causa importante de pérdida visual en adultos, con consecuencias médicas, sociales y financieras significativas. El objetivo fue evaluar los hábitos alimentarios y estado nutricional en diabéticos con retinopatía que acuden a la Clínica Vista 10 de la ciudad de Asunción entre setiembre y noviembre del año 2018. Estudio descriptivo, observacional de corte transverso que incluyó 50 pacientes, Siendo la mayor parte de ellos del sexo femenino (65%), la edad media fue de 62,8±11,3 años, el 66% (n=33) estaba casado con nivel educativo primario (n=20;40%) y vivía en Gran Asunción (n= 46; 92%). Respecto a la frecuencia de consumo de alimentos, se encontró que casi la totalidad de la población realizaba el desayuno (96%). El 70% consumía lácteos descremados menos de la cantidad recomendada. Solo un 20% consumía frutas todos los días. Un poco más de la mitad (52%) consumía verduras todos los días. El 70% consumía pescado por debajo de las recomendaciones establecidas, y el 78% consumía legumbres menos de la cantidad recomendada. Más de la mitad (58%) consumía alimentos integrales por debajo de las recomendaciones. El 54% consumía comida casera todos los días y el 56% realizaba la cena todos los días. Más de la mitad de los participantes presentó sobrepeso u obesidad. Los hábitos de la población son deficientes, en relación al consumo de frutas, lácteos según las recomendaciones de las Guías Alimentarias del Paraguay

Diabetic retinopathy (RD) is a chronic microvascular complication specific to diabetes. It is an important cause of visual loss in adults, with significant medical, social and financial consequences. The objective was to evaluate the dietary habits and nutritional status in diabetic atients with retinopathy who attend the Clínica Vista 10 in the city of Asunción between September and November of 2018. This was a descriptive, observational cross-sectional study The majority of the population studied was female (n = 33, 65%), the mean age was 62.8 ± 11.3 years, 66% (n = 33) was married and the highest percentage was presented primary education level(n = 20, 40%). According to the classification of the place of origin, most lived in Gran Asunción (n = 46, 92%). Regarding the frequency of food consumption, it was found that almost the entire population made breakfast(96%), 70% consumed low-fat dairy products less than the recommended amount. Only 20% consumed fruits every day. A little more than half(52%)consumed vegetables every day, 70% consumed fish below the established recommendations and 78% consumed legumes less than the recommended amount. More than half (58%) consumed whole food below the recommendations, 54% consumed home-cooked food every day and 56% made dinner every day. More than half of the population was overweight or obese. The habits of the population are deficient, in relation to the consumption of fruits, dairy products according to the recommendations of the Food Guides of Paraguay

Targeting the CaVα-CaVß interaction yields an antagonist of the N-type CaV2.2 channel with broad antinociceptive efficacy.

Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 channels are composed of α, ß, γ and α2δ subunits. The ß subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming α subunit of CaV. We targeted the high-affinity protein-protein interface of CaVß's pocket within the CaVα subunit. Structure-based virtual screening of 50,000 small molecule library docked to the ß subunit led to the identification of 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide (IPPQ). This small molecule bound to CaVß and inhibited its coupling with N-type voltage-gated calcium (CaV2.2) channels, leading to a reduction in CaV2.2 currents in rat dorsal root ganglion sensory neurons, decreased presynaptic localization of CaV2.2 in vivo, decreased frequency of spontaneous excitatory postsynaptic potentials and miniature excitatory postsynaptic potentials, and inhibited release of the nociceptive neurotransmitter calcitonin gene-related peptide from spinal cord. IPPQ did not target opioid receptors nor did it engage inhibitory G protein-coupled receptor signaling. IPPQ was antinociceptive in naive animals and reversed allodynia and hyperalgesia in models of acute (postsurgical) and neuropathic (spinal nerve ligation, chemotherapy- and gp120-induced peripheral neuropathy, and genome-edited neuropathy) pain. IPPQ did not cause akinesia or motor impairment, a common adverse effect of CaV2.2 targeting drugs, when injected into the brain. IPPQ, a quinazoline analog, represents a novel class of CaV2.2-targeting compounds that may serve as probes to interrogate CaVα-CaVß function and ultimately be developed as a nonopioid therapeutic for chronic pain.

Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Physalin F via Block of CaV2.3 (R-Type) and CaV2.2 (N-Type) Voltage-Gated Calcium Channels.

No universally efficacious therapy exists for chronic pain, a disease affecting one-fifth of the global population. An overreliance on the prescription of opioids for chronic pain despite their poor ability to improve function has led to a national opioid crisis. In 2018, the NIH launched a Helping to End Addiction Long-term plan to spur discovery and validation of novel targets and mechanisms to develop alternative nonaddictive treatment options. Phytochemicals with medicinal properties have long been used for various treatments worldwide. The natural product physalin F, isolated from the Physalis acutifolia (family: Solanaceae) herb, demonstrated antinociceptive effects in models of inflammatory pain, consistent with earlier reports of its anti-inflammatory and immunomodulatory activities. However, the target of action of physalin F remained unknown. Here, using whole-cell and slice electrophysiology, competition binding assays, and experimental models of neuropathic pain, we uncovered a molecular target for physalin F's antinociceptive actions. We found that physalin F (i) blocks CaV2.3 (R-type) and CaV2.2 (N-type) voltage-gated calcium channels in dorsal root ganglion (DRG) neurons, (ii) does not affect CaV3 (T-type) voltage-gated calcium channels or voltage-gated sodium or potassium channels, (iii) does not bind G-protein coupled opioid receptors, (iv) inhibits the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in spinal cord slices, and (v) reverses tactile hypersensitivity in models of paclitaxel-induced peripheral neuropathy and spinal nerve ligation. Identifying CaV2.2 as a molecular target of physalin F may spur its use as a tool for mechanistic studies and position it as a structural template for future synthetic compounds.

Synthesis and biological evaluation of the 1-arylpyrazole class of σ(1) receptor antagonists: identification of 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862).

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be necessary, in accordance with known receptor pharmacophores. A wide variety of amines and spacer lengths between the amino and pyrazole groups were tolerated, but only the ethylenoxy spacer and small cyclic amines provided compounds with sufficient selectivity for σ(1)R vs σ(2)R. The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862), which showed high activity in the mouse capsaicin model of neurogenic pain, emerged as the most interesting candidate. In addition, compound 28 exerted dose-dependent antinociceptive effects in several neuropathic pain models. This, together with its good physicochemical, safety, and ADME properties, led compound 28 to be selected as clinical candidate.