Assessment of boron-containing compounds and oleoylethanolamide supplementation on the recovery trend in patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: In this study, we investigate the effect of boron-containing compounds and oleoylethanolamide supplementation on the recovery trend in patients with COVID-19. TRIAL DESIGN: The current study is a single-center, randomized, double-blind, placebo-controlled clinical trial with parallel groups. PARTICIPANTS: The inclusion criteria include male and female patients≥18 years of age, with a confirmed diagnosis of SARS-CoV-2 infection via polymerase chain reaction (PCR) and/or antibody test and with written informed consent to participate in this trial. The exclusion criteria include regular use of any other supplement, severe and critical COVID-19 pneumonia, pregnancy and breastfeeding. This study is being conducted at Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran. INTERVENTION AND COMPARATOR: Patients are randomly assigned to four groups. The first group (A) will take one capsule containing 5 mg of boron compounds twice a day for two weeks. The second group (B) will take one capsule containing 200 mg oleoylethanolamide twice a day for two weeks. The third group (C) will take one capsule containing 5 mg boron compounds with 200 mg oleoylethanolamide twice a day for two weeks, and the fourth group (D) does not receive any additional treatment other than routine treatments. Boron-containing compounds and oleoylethanolamide capsules will be synthesized at Nutrition Research Center of Tabriz University of Medical Sciences. MAIN OUTCOMES: The primary end point of this study is to investigate the recovery rate of clinical symptoms, including fever, dry cough, and fatigue, as well as preclinical features, including complete blood count (CBC), the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) profiles within two weeks of randomization. RANDOMISATION: Patients are randomized into four equal groups in a parallel design (allocation ratio 1:1). A randomized block procedure is used to divide subjects into one of four treatment blocks (A, B, C, and D) by a computer-generated allocation schedule. BLINDING (MASKING): The participants and investigators (enrolling, assessing, and analyzing) are blinded to the intervention assignments until the end of the study and data analysis. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The calculated total sample size is 40 patients, with 10 patients in each group. TRIAL STATUS: The protocol is Version 1.0, May 17, 2020. Recruitment began May 19, 2020, and is anticipated to be completed by October 19, 2020. TRIAL REGISTRATION: This clinical trial has been registered by the title of "Assessment of boron-containing compounds and oleoylethanolamide supplementation on the recovery trend in Patients with COVID-19: A double-blind randomized placebo-controlled clinical trial" in the Iranian Registry of Clinical Trials (IRCT). The registration number is " IRCT20090609002017N35 ", https://www.irct.ir/trial/48058 . The registration date is 17 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Emerging Treatments and Novel Pathways in Pruritus.

Itch treatment is a major challenge in the dermatologist's practice. We encounter patients suffering from pruritus on a regular basis, and often lack diverse treatment options to adequately respond to the patients' needs. In the last 20 years, novel pathways have been investigated that were beyond the scope of histamine. Although most did not result in a molecule available on the Canadian market, it is interesting and important as health care providers to stay up to date with new neuronal pathways involved in itch transmission and potential new therapeutic options. In this review, we will discuss pathways targeted in new topical treatments such as antagonist of proteinase-activated receptor-2, the endocannabinoid system, neurotrophins and tropomyosin-related kinase A receptor, the transient receptor potential-vanilloid or transient receptor potential-melastatine ion channels. New systemic therapies are now focusing on antagonizing the neurokinin receptor, modulating the opioidergic system, or targeting itch cytokines such as interleukin-31.

Investigation the effect of oleoylethanolamide supplementation on the abundance of Akkermansia muciniphila bacterium and the dietary intakes in people with obesity: A randomized clinical trial.

Akkermansia muciniphila bacterium is one of the inhabitant gut microbiota involving in the energy homeostasis and inhibition of the inflammations. The present study was designed to evaluate the effects of Oleoylethanolamide (OEA) supplementation on the abundance of A. muciniphila and the dietary intakes in obese people. In this randomized, double-blind, controlled clinical trial, 60 eligible obese people were selected and divided randomly into two groups including OEA group (received two capsules containing 125 mg of OEA daily) and placebo group (received two capsules containing 125 mg of starch daily). The treatment lasted for 8 weeks. Dietary intakes were evaluated according to the three -day food record and, were analyzed by the Nutritionist 4 software. In order to evaluate the changes in the abundance of A. muciniphila bacterium, faeces samples were collected at baseline and at the end of study. The targeting of the 16S rRNA gene in A. muciniphila was measured by the quantitative real-time PCR analysis. For OEA group, the energy and carbohydrate intakes decreased significantly after adjusting for baseline values and confounder factors; (p = 0.035), the amount of carbohydrate was reported as 422.25 (SD = 103.11) gr and 368.44 (SD = 99.08) gr; (p = 0.042)), before and after the treatment, respectively. The abundance of A. muciniphila bacterium increased significantly in OEA group compared to placebo group (p < 0.001). Considering the accumulating evidence identified OEA as a novel, safe, and efficacious pharmaceutical agent increasing the abundance of A. muciniphila bacterium and modifying the energy balance, therefore it is suggested to use its supplement for treatment of the obese people. However, future studies are needed to confirm the positive results obtained in this study.

Oleoylethanolamide increases the expression of PPAR-Α and reduces appetite and body weight in obese people: A clinical trial.

Obesity is a crucial public health problem worldwide and is considered as the main cause of many chronic diseases. The present study evaluated the effects of Oleoylethanolamide (OEA) supplementation on proximal proliferator-activated receptor-α (PPAR-α) gene expression, appetite sensations, and anthropometric measurements in obese people. This randomized, double-blind, placebo-controlled clinical trial was carried out on 60 healthy obese people in Tabriz, Iran, in 2016. The eligible subjects were divided into an intervention group (who received two 125 mg OEA capsules daily) and a placebo group (who received the same amount of starches) and treated for 60 days. Anthropometric measurements and body composition were assessed in a fasting state at baseline and at the end of the study. The visual analogue scales (VAS) were used to assess appetite sensations. Quantitative real-time PCR analysis targeting the 16S rRNA gene of PPAR-α was done. Analysis was done on 56 participants who continued intervention until the end of the study. A significant increase in PPAR-α gene expression was observed in the intervention group (p < 0.001). Weight, body mass index, waist circumference, and fat percent decreased significantly at the end of the study in the intervention group (all p < 0.01). Hunger, the desire to eat, and cravings for sweet foods decreased significantly and fullness increased significantly by the end of study in the intervention group at the end of study (all p < 0.01). The fullness item increased significantly by the end of study in the intervention group (p < 0.001). Use of OEA as a complementary approach could be effective in suppressing appetite and modulating energy balance in obese people.

The endocannabinoid system - a target for the treatment of LUTS?

Lower urinary tract symptoms (LUTS) are common in all age groups and both sexes, resulting in tremendous personal suffering and a substantial burden to society. Antimuscarinic drugs are the mainstay of symptom management in patients with LUTS, although their clinical utility is limited by the high prevalence of adverse effects, which often limit patients' long-term adherence to these agents. Data from controversial studies in the 1990s revealed the positive effects of marijuana-based compounds on LUTS, and sparked an interest in the possibility of treating bladder disorders with cannabis. Increased understanding of cannabinoid receptor pharmacology and the discovery of endogenous ligands of these receptors has prompted debate and further research into the clinical utility of exogenous cannabinoid receptor agonists relative to the unwanted psychotropic effects of these agents. Currently, the endocannabinoid system is considered as a potential drug target for pharmacological management of LUTS, with a more favourable adverse event profile than antimuscarinic agents.

Fatty acid amide supplementation decreases impulsivity in young adult heavy drinkers.

Compromised dopamine signaling in the striatum has been associated with the expression of impulsive behaviors in addiction, obesity and alcoholism. In rodents, intragastric infusion of the fatty acid amide oleoylethanolamide increases striatal extracellular dopamine levels via vagal afferent signaling. Here we tested whether supplementation with PhosphoLean™, a dietary supplement that contains the precursor of the fatty acid amide oleoylethanolamide (N-oleyl-phosphatidylethanolamine), would reduce impulsive responding and alcohol use in heavy drinking young adults. Twenty-two individuals were assigned to a three-week supplementation regimen with PhosphoLean™ or placebo. Impulsivity was assessed with self-report questionnaires and behavioral tasks pre- and post-supplementation. Although self-report measures of impulsivity did not change, supplementation with PhosphoLean™, but not placebo, significantly reduced false alarm rate on a Go/No-Go task. In addition, an association was found between improved sensitivity on the Go/No-Go task and reduced alcohol intake. These findings provide preliminary evidence that promoting fatty acid derived gut-brain dopamine communication may have therapeutic potential for reducing impulsivity in heavy drinkers.

Diet-induced changes in n-3- and n-6-derived endocannabinoids and reductions in headache pain and psychological distress.

UNLABELLED: Omega-3 and omega-6 fatty acids are biosynthetic precursors of endocannabinoids with antinociceptive, anxiolytic, and neurogenic properties. We recently reported that targeted dietary manipulation-increasing omega-3 fatty acids while reducing omega-6 linoleic acid (the H3-L6 intervention)-reduced headache pain and psychological distress among chronic headache patients. It is not yet known whether these clinical improvements were due to changes in endocannabinoids and related mediators derived from omega-3 and omega-6 fatty acids. We therefore used data from this trial (N = 55) to investigate 1) whether the H3-L6 intervention altered omega-3- and omega-6-derived endocannabinoids in plasma and 2) whether diet-induced changes in these bioactive lipids were associated with clinical improvements. The H3-L6 intervention significantly increased the omega-3 docosahexaenoic acid derivatives 2-docosahexaenoylglycerol (+65%, P < .001) and docosahexaenoylethanolamine (+99%, P < .001) and reduced the omega-6 arachidonic acid derivative 2-arachidonoylglycerol (-25%, P = .001). Diet-induced changes in these endocannabinoid derivatives of omega-3 docosahexaenoic acid, but not omega-6 arachidonic acid, correlated with reductions in physical pain and psychological distress. These findings demonstrate that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids in humans and suggest that 2-docosahexaenoylglycerol and docosahexaenoylethanolamine could have physical and/or psychological pain modulating properties. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01157208) PERSPECTIVE: This article demonstrates that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids and that these changes are related to reductions in headache pain and psychological distress. These findings suggest that dietary interventions could provide an effective, complementary approach for managing chronic pain and related conditions.

Retrospective observational study to investigate Sinerga, a multifactorial nutritional product, and bacterial extracts in the prevention of recurrent respiratory infections in children.

In this retrospective observational clinical study, 167 children, aged 3 to 7 years, of both sexes, with a clinical history of recurrent respiratory infections, administered with bacterial extracts of first and second generation or Sinerga a nutritional product containing palmitoylethanolamide, bovine colostrum, phenylethylamine and the new generation of probiotic kluyveromyces FM B0399, were observed. The goal of the study was to compare the supplementation with Sinerga with the supplementation with bacterial extracts, for the effect on the frequency of episodes of respiratory infection that had resulted in a prescription for antibiotics. The study focused retrospectively on the months from March 2013 to November 2012. The results showed a greater reduction in the frequency of respiratory infections with antibiotic therapy in the group of children supplemented with Sinerga than in the group treated with bacterial extracts. In particular, it was observed that 49.3% of the children supplemented with Sinerga, against 5% of those supplemented with extracts, had no infectious episodes requiring the administration of an antibiotic. 100% of subjects supplemented with Sinerga have had no more than two episodes of respiratory infection, while this condition, in the cohort treated with bacterial extracts, was observed in only 51% of cases.

N-Palmitoylethanolamine depot injection increased its tissue levels and those of other acylethanolamide lipids.

N-Palmitoylethanolamine (NAE 16:0) is an endogenous lipid signaling molecule that has limited water solubility, and its action is short-lived due to its rapid metabolism. This poses a problem for use in vivo as oral administration requires a high concentration for significant levels to reach target tissues, and injection of the compound in a dimethyl sulfoxide- or ethanol-based vehicle is usually not desirable during long-term treatment. A depot injection of NAE 16:0 was successfully emulsified in sterile corn oil (10 mg/kg) and administered in young DBA/2 mice in order to elevate baseline levels of NAE 16:0 in target tissues. NAE 16:0 levels were increased in various tissues, particularly in the retina, 24 and 48 hours following injections. Increases ranged between 22% and 215% (above basal levels) in blood serum, heart, brain, and retina and induced an entourage effect by increasing levels of other 18 carbon N-Acylethanolamines (NAEs), which ranged between 31% and 117% above baseline. These results indicate that NAE 16:0 can be used as a depot preparation, avoiding the use of inadequate vehicles, and can provide the basis for designing tissue-specific dosing regimens for therapies involving NAEs and related compounds.

2-AG into the lateral hypothalamus increases REM sleep and cFos expression in melanin concentrating hormone neurons in rats.

Orexins/hypocretins (OX) and melanin-concentrating hormone (MCH) neurons located in the lateral hypothalamus seem to modulate different stages of the sleep-wake cycle. OX are necessary for wakefulness and MCH appears to regulate rapid eye movement sleep (REMS). Likewise, endocannabinoids, the endogenous ligands for cannabinoid receptors 1 and 2 (CB1R, CB2R), also modulate REMS in rats. Moreover, it has been shown that the activation of the CB1R in the lateral hypothalamus of rats excites MCH neurons while inhibiting OX neurons in in vitro preparations. Hence, we assessed the effects of 2-arachidonoylglicerol (2-AG, an endocannabinoid) in the lateral hypothalamus on the sleep-wake cycle of rats. We also utilized the CB1R inverse agonist AM251 to further support the involvement of this receptor, and we performed double immunofluorescence experiments to detect c-Fos, as a marker of neural activation, in OX and in MCH neurons to determine which neurons were activated. Our results indicate that 2-AG increases REMS through CB1R activation, and increases c-Fos expression in MCH neurons. These results suggest that endocannabinoid activation of the CB1R in the lateral hypothalamus, which activates MCH neurons, is one mechanism by which REMS is triggered.

Vestibulodynia: synergy between palmitoylethanolamide + transpolydatin and transcutaneous electrical nerve stimulation.

OBJECTIVE: The study aimed to assess the effect of palmitoylethanolamide + transpolydatin combination in patients with vestibulodynia undergoing transcutaneous electrical nerve stimulation (TENS) therapy and to confirm the effectiveness of TENS also in a domiciliary protocol. The study is based on the premise that palmitoylethanolamide + transpolydatin combination may contribute to a down-regulation of mast cell hyperactivity, which is believed to be responsible for the proliferation and sprouting of vestibular pain fibers and the associated hyperalgesia and allodynia. MATERIALS AND METHODS: Twenty women with vestibulodynia were randomly assigned to receive oral palmitoylethanolamide (PEA) 400 mg and transpolydatin 40 mg or placebo, twice daily for 60 days. All patients underwent TENS therapy in a self-administered home protocol. Visual analogue scale (VAS), Marinoff score for dyspareunia, and current perception threshold obtained from the vulvar vestibule were assessed at baseline and at the end of treatment. RESULTS: The patients received a mean of 26.7 TENS sessions. All scores in the 2 groups improved significantly, although the level of improvement was similar between the groups (VAS, p < .57; dyspareunia, p < .38). Nevertheless, the analysis of regression of symptoms related to the duration of disease revealed the therapy to be more effective when PEA + transpolydatin is included in cases with more recent disease onset, as compared with the placebo group (PEA: VAS, p < .01; dyspareunia, p < .01) (placebo: VAS, p = nonsignificant; dyspareunia, p = nonsignificant). CONCLUSIONS: This study confirms that TENS is of significant benefit in the management of vestibulodynia, also in a home environment. PEA + transpolydatin can be a value-added treatment adjunct when the onset of vestibulodynia is more recent or when the disease relapses.

Amyotrophic lateral sclerosis treatment with ultramicronized palmitoylethanolamide: a case report.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons which leads to muscular atrophy, paralysis and death in 3-5 years from starting symptoms. This disorder is accompanied by noteworthy spinal inflammation mediated in particular by microglia and mast cells. No effective therapy is available. This report describes the effects of administering the anti-inflammatory agent palmitoylethanolamide in a case of sporadic amyotrophic lateral sclerosis. Palmitoylethanolamide treatment led to an improved clinical picture, as evidenced by electromyographic analysis and pulmonary function. Conceivably, the action of palmitoylethanolamide could result, in part, from its ability to dampen mast cell and microglia activation.