Spinal NKCC1 blockade inhibits TRPV1-dependent referred allodynia

Background The Na+, K+, 2Cl- type I cotransporter (NKCC1) and TRPV1 receptors, at the level of the dorsal horn, have been implicated in mediating allodynia in response to an inflammatory insult. The NKCC1 cotransporter regulates intracellular [Cl-] and thus the magnitude and polarity of GABAA receptor responses in neurons. TRPV1 receptors transduce diverse chemical and natural stimuli in nociceptors and are critical for inflammatory hyperalgesia.Results Here we have tested the role of spinal NKCC1 cotransporters and TRPV1 receptors in referred allodynia in a model of visceral hyperalgesia in mice. Intrathecal (IT) injection of the NKCC1 inhibitor bumetanide (BUM, 1 nmol) inhibited referred, abdominal allodynia evoked by an intracolonic capsaicin injection. BUM was effective when injected IT either before or up to 4 hrs after the establishment of referred allodynia. The TRPV1 antagonist AMG 9810 (1 nmol) also inhibited referred allodynia in this model suggesting the involvement of an endogenous TRPV1 agonist in the dorsal horn in referred allodynia. In support of this suggestion, the endovanilloid TRPV1 agonist, narachidonoyl- dopamine (NADA, 1 or 10 nmol, IT) evoked stroking allodynia in the hindpaw that was blocked by co-treatment with AMG 9810 (1 nmol). The TRPV1-dependent stroking allodynia caused by NADA appeared to be functionally linked to NKCC1 because BUM (1 nmol) also inhibited NADA-evoked stroking allodynia.Conclusion Our findings indicate that spinal NKCC1 and TRPV1 are critical for referred allodynia mediated by a painful visceral stimulus. Moreover, they suggest that endogenous TRPV1 agonists, released in the CNS in painful conditions, might stimulate TRPV1 receptors on primary afferents that, in turn, play a role in increasing NKCC1 activity leading to allodynia.This work was supported by the National Institutes for Neurological Disorders and Stroke (NINDS, DA19959, to TJP), the American Pain Society (to TJP), the Spanish Secretaria de Estado de Educacion y Universidades: Formacion de Profesorado Universitario Grant (to JME), the Canadian Foundation for Innovation (CFI, to FC), the Canadian Institutes of Health Research (CIHR, to FC) and the Fonds de la recherche en santé du Québec (FRSQ, to FC)

Los nuevos retos de la industria farmacéutica

Diverse challenges of the modern pharmaceutical industry are analysed in this papero High competitiveness in the pharmaceutical sector and new regulations dictated by the different governments or organizations in charge of watching over public health have generated the need to devise new ways in the discovery of new drugs. On one hand, the rational drug design has acquired a leading role and on the other, the development of robotics has prompted the development of combinatorial chemistry and high production screening. The pharmaceutical industry of the future must be more dynamic and innovating. One of the observed phenomena has been the merging of a number of pharmaceutical fusions faced to the necessity of reducing production costs.En este trabajo se analizan los distintos retos de la industria farmacéutica moderna. La elevada competitividad del sector farmacéutico y las nuevas regulaciones dictadas por los diferentes gobiernos u organismos encargados de velar por la salud pública han generado la necesidad de idear nuevas vías en el descubrimiento de nuevos medicamentos. Por una parte, el diseño racional de fármacos ha adquirido un enorme protagonismo y, por otra, el desarrollo de la robótica han potenciado el desarrollo de la química combinatoria y del tamizado de alta producción. La futura industria farmacéutica debe ser más dinámica e innovadora. Uno de sus fenómenos observados ha sido el elevado número de fusiones de empresas farmacéuticas, ante la necesidad de reducir los costes de los productos

Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin.

Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception

Soluble epoxide hydrolase inhibitors: design, synthesis, in vitro profiling and in vivo evaluation in murine models of pain

Trabajo presentado en el ASPET Annual Meeting at Experimental Biology 2022, celebrado en Philadelphia, PA (Estados Unidos), del 2 al 5 de abril de 2022This research by the Grant PID2020-118127RB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” to S.V. Financial support from Fundació Bosch i Gimpera, Universitat de Barcelona (F2I grant), to S.V., and from the Xunta de Galicia (ED431G 2019/02 and ED431C 2018/21) to M.I.L. are acknowledged. Partial support was provided by NIH-NIEHS River Award R35 ES03443, NIH-NIEHS Superfund Program P42 ES004699, NINDS R01 DK107767, and NIDDK R01 DK103616 to B.D.H. S.C. acknowledges a PhD fellowship from the Universitat de Barcelona (APIF grant)

Synthesis, in Vitro Profiling, and in Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field

Seroprevalence of Toxoplasma gondii in Gallus domesticus in Havana, Cuba

El estudio tuvo como objetivo determinar la seroprevalencia de T. gondii en Gallus domesticus en La Habana, Cuba. Se colectaron 300 muestras de sueros de pollitas White Leghorn L33 en fase de desarrollo en 2015, distribuidas a razón de 100 aves por cada lote incorporado a la unidad avícola desde procedencias diferentes. Las muestras fueron analizadas mediante un ELISA de inhibición y se utilizaron las pruebas Chi-cuadrado y Dócima de Duncan para comparar las proporciones de aves positivas entre los lotes estudiados. Se encontró una relativa baja seroprevalencia de T. gondii (9.6%), similar a otros hallazgos reportados a nivel internacional. Se evidenciaron diferencias significativas (p=0.0001) en la prevalencia de T. gondii entre los tres lotes de aves. Se concluye que la seroprevalencia de T. gondii en Gallus domesticus en La Habana es baja, aunque esta constituye un riesgo de infección para las poblaciones humanas y animales susceptibles.The aim of this study was to determine the seroprevalence of T. gondii in Gallus domesticus in Havana, Cuba. Three hundred serum samples were collected from White Leghorn pullets L33 in growing stage in 2015. Samples represented 100 birds per batch incorporated into the poultry unit from different origins. Samples were evaluated by an ELISA inhibition test and data was analyzed by the Chi-square and Duncan tests to compare proportions of positive birds among batches. A relatively low seroprevalence of T. gondii was found (9.6%), similar to other findings reported internationally. Significant differences (p=0.0001) in the prevalence of T. gondii among the three bird batches were found. It is concluded that the seroprevalence of T. gondii in Gallus domesticus in Havana is low, though this constitutes a risk of infection for susceptible human and animal populations

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design