Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19.

In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.

Efficacy of broccoli and glucoraphanin in COVID-19: From hypothesis to proof-of-concept with three experimental clinical cases.

COVID-19 is described in a clinical case involving a patient who proposed the hypothesis that Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-interacting nutrients may help to prevent severe COVID-19 symptoms. Capsules of broccoli seeds containing glucoraphanin were being taken before the onset of SARS-CoV-2 infection and were continued daily for over a month after the first COVID-19 symptoms. They were found to reduce many of the symptoms rapidly and for a duration of 6-12 h by repeated dosing. When the patient was stable but still suffering from cough and nasal obstruction when not taking the broccoli capsules, a double-blind induced cough challenge confirmed the speed of onset of the capsules (less than 10 min). A second clinical case with lower broccoli doses carried out during the cytokine storm confirmed the clinical benefits already observed. A third clinical case showed similar effects at the onset of symptoms. In the first clinical trial, we used a dose of under 600 µmol per day of glucoraphanin. However, such a high dose may induce pharmacologic effects that require careful examination before the performance of any study. It is likely that the fast onset of action is mediated through the TRPA1 channel. These experimental clinical cases represent a proof-of-concept confirming the hypothesis that Nrf2-interacting nutrients are effective in COVID-19. However, this cannot be used in practice before the availability of further safety data, and confirmation is necessary through proper trials on efficacy and safety.

Spices to Control COVID-19 Symptoms: Yes, but Not Only .

There are large country variations in COVID-19 death rates that may be partly explained by diet. Many countries with low COVID-19 death rates have a common feature of eating large quantities of fermented vegetables such as cabbage and, in some continents, various spices. Fermented vegetables and spices are agonists of the antioxidant transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and spices are transient receptor potential ankyrin 1 and vanillin 1 (TRPA1/V1) agonists. These mechanisms may explain many COVID-19 symptoms and severity. It appears that there is a synergy between Nrf2 and TRPA1/V1 foods that may explain the role of diet in COVID-19. One of the mechanisms of COVID-19 appears to be an oxygen species (ROS)-mediated process in synergy with TRP channels, modulated by Nrf2 pathways. Spicy foods are likely to desensitize TRP channels and act in synergy with exogenous antioxidants that activate the Nrf2 pathway.

Estudios controlados en humanos de éxtasis / Controlled trials of ecstasy administration in humans

Objetivo: recopilar y analizar la información sobre los efectos de la MDMA obtenida en estudios controlados en humanos. Método: la mayoría de ensayos analizados han sido de diseño enmascarado a doble ciego, cruzados, con asignación aleatoria a la secuencia de tratamientos, y controlados con placebo y/o fármaco patrón. Resultados: además del incremento de la presión y frecuencia cardíaca, la MDMA incrementa el consumo miocárdico de oxígeno sin efectos inotrópicos y puede incrementar el intervalo QTc en el ECG. El aumento de temperatura no fue significativo frente a placebo. Produce euforia, bienestar y activación. No se han descrito ni alucinaciones ni ilusiones. En el EEG aumenta la actividad beta y disminuye la alfa. Aumenta de forma dosis-dependiente las concentraciones de ACTH, cortisol, prolactina, dihidroepiandrosterona y vasopresina. Inmunológicamente su efecto parece ser inmunosupresor. Su farmacocinética parece ser no-lineal con tendencia a la acumulación a dosis alta. Conclusiones: los estudios controlados han permitido conocer mejor la MDMA, profundizando en sus efectos subjetivos, y aportando datos originales en cuanto a cambios hormonales e inmunológicos. Se necesitan más estudios para determinar científicamente los efectos y toxicidad de la MDMA (AU)

Objective: to compile and analyse knowledge about the pharmacodynamics and pharmacokinetics of MDMA from controlled clinical trials in humans. Methods: the typical design of the trials was masked (double blind), randomized, cross-over, and controlled with placebo and/or an active drug. Results: MDMA increases the heart rate, arterial blood pressure, oxygen consumption by the heart and produced an enlargement of the QTC interval in the ECG. No statistical differences were found with placebo in the increase of body temperature. MDMA induce euphoria, wellbeing and activation. Neither ilusions nor hallucinations were described. An increase of beta activity and a decrease of alpha activity in the EEG was seen. A dose-dependent increase in the plasma levels of ACTH, cortisol, prolactin, dehydroepiandrosterone and vasopresine was observed. Immunogically, MDMA posses an immunosupresor effect. Its pharmacokinetic properties seems to be non-lineal, with a tendency to accumulation at high doses. Conclusion: the results obtained in these controlled clinical trials increase our previous knowledge on MDMA and add new data related to its hormonal and immunological effects. Further studies are needed in order to better understand the effects and toxicity of MDMA (AU)