Latest Insights into the In Vivo Studies in Murine Regarding the Role of TRP Channels in Wound Healing-A Review.

Wound healing involves physical, chemical and immunological processes. Transient receptor potential (TRP) and other ion channels are implicated in epidermal re-epithelization. Ion movement across ion channels can induce transmembrane potential that leads to transepithelial potential (TEP) changes. TEP is present in epidermis surrounding the lesion decreases and induces an endogenous direct current generating an epithelial electric field (EF) that could be implicated in wound re-epithelialization. TRP channels are involved in the activation of immune cells during mainly the inflammatory phase of wound healing. The aim of the study was to review the mechanisms of ion channel involvement in wound healing in in vivo experiments in murine (mice, rats) and how can this process be influenced. This review used the latest results published in scientific journals over the last year and this year to date (1 January 2023-31 December 3000) in order to include the in-press articles. Some types of TRP channels, such as TRPV1, TRPV3 and TRPA1, are expressed in immune cells and can be activated by inflammatory mediators. The most beneficial effects in wound healing are produced using agonists of TRPV1, TRPV4 and TRPA1 channels or by inhibiting with antagonists, antisense oligonucleotides or knocking down TRPV3 and TRPM8 channels.

A Systematic Review of Clinical Studies on the Effect of Psychoactive Cannabinoids in Psychiatric Conditions in Alzheimer Dementia.

BACKGROUND: The systematic reviews and meta-analyses performed until now did not provide the adequate picture of actual knowledge in the field of neuropsychiatric symptoms treatment using psychotropic cannabinoids in patients with Alzheimer disease (AD). THE STUDY QUESTION: Which is the level of evidence, from quantitative and qualitative point of view, concerning the efficacy and safety of the treatment with psychotropic cannabinoids of neuropsychiatric symptoms in AD? STUDY DESIGN: PubMed, EMBASE, Cochrane Database of Systematic Reviews, Google Scholar Data, and Clinicaltrials.gov were searched for randomized clinical trials with cannabinoids in Alzheimer dementia agitation and aggression. MEASURES AND OUTCOMES: The rationale, the objectives, and the methods used for searching the trials have been established according to PRISMA Criteria 2009. RESULTS: The total number of patients in the 9 publications evaluated in this study, which included data from 6 clinical trials, was 422 patients-treatments, where treatment was a psychoactive cannabinoid or placebo, some of them obtained by multiplying selected patients with the number of cannabinoid treatments in the crossover studies. There are multiple sources of bias in the analyzed studies; 2 elements have prevented conclusive results. One element was polypragmazia, a major role being played by the use of psychotropic drugs other than cannabinoids, in an effort to reduce agitation and aggressive behavior. The second one was the large number of concomitant symptoms, for example, pain (commonly causing anxiety and agitation). CONCLUSIONS: No clear conclusion can be drawn on the effectiveness of psychoactive cannabinoids in the treatment of psychiatric manifestations, in particular agitation and aggression, in AD. In the future, large randomized controlled trial with adequate designs, without crossover and for longer duration, adapted to cannabinoid pharmacokinetics, is required to establish the real efficacy and safety of these drugs in aggressive and/or agitated patients with AD.

The Complex Role of Botulinum Toxin in Enhancing Goal Achievement for Post-Stroke Patients.

INTRODUCTION: The rehabilitation medical team is responsible for the therapeutic management of post-stroke patients and, therefore, for the complex therapeutic approach of spasticity. Considering the generous arsenal at our disposal in terms of both pharmacological treatment, through the possibility of administering botulinum toxin to combat spasticity, and in terms of accurate assessment through developed functional scales such as the GAS (Goal Attainment Scale), one of our purposes is to monitor the parameters that influence the achievement of functional goals set by patients together with the medical team in order to render the patients as close as possible to achieving their proposed functional goals, thus enhancing their quality of life. By assessing and establishing statistical and clinical correlations between the GAS and quantifiable parameters related to the affected post-stroke upper limb, namely degree of spasticity, motor control, pain level and evolution of pain under treatment with BoNT-A (abobotulinum toxin A), and patients' overall response to BoNT-A treatment, we aim to quantify the improvement of the therapeutic management of post-stroke patients with spasticity and develop a more personalized and effective approach to their disability and impairment. RESULTS AND DISCUSSIONS: The analysis concluded that there were two independent predictors of the Achieved GAS-T score (the study's endpoint parameter) motor control at any level of the upper limb and number of prior BoNT-A injections. The number of prior BoNT-A injections was an independent predictor of Achieved GAS-T score improvement but had no significant influence over Baseline GAS-T score. Enhancement in proximal and intermediate motor control showed a GAS score improvement of 3.3 points and a 0.93-point GAS score improvement for wrist motor control progress. From a separate viewpoint, patients with motor deficit on the left side have shown significantly greater improvement in Changed GAS-T scores by 2.5 points compared to patients with deficits on the right side; however, we note as a study limitation the fact that there was no statistical analysis over the dominant cerebral hemisphere of each patient. CONCLUSIONS: Improvement in the Achieved GAS-T score means better achievement of patients' goals. Thus, after the BoNT- A intervention, at follow-up evaluation, GAS was found to be directly correlated with improvement in motor control of the affected upper limb. Mobility of the corresponding limb was enhanced by pain decrease during p-ROM (passive range of motion) and by amelioration of spasticity. MATERIALS AND METHODS: We conducted an observational, non-randomized clinical study on 52 stroke patients, a representative sample of patients with post-stroke spasticity and disability from our neurological rehabilitation clinic, who have been treated and undergone a specific rehabilitation program in our tertiary diagnostic and treatment medical center, including BoNT-A focal treatment for spasticity in the affected upper limb. The primary objective of the study was to assess the influence of abobotulinum toxin A treatment on the Goal Attainment Scale. Secondary objectives of the study included the assessment of BoNT-A treatment efficacy on spasticity with the MAS (Modified Ashworth Scale), pain with the NRS (Numerical Rating Scale), and joint passive range of motion (p-ROM), identifying demographic, clinical, and pharmacological factors that influence the response to BoNT-A treatment, as well as to conduct a descriptive and exploratory analysis of the studied variables.

The Effect of Topical Celecoxib as an Anti-Psoriasis Agent.

Our previous research showed that, in a mice tail model for psoriasis, topical celecoxib might have an antipsoriatic effect in vivo by increasing granular layer development. The aim of the present study is to assess the effect of three celecoxib concentrations using a mice model for psoriasis. Topical application of celecoxib (2%, 4% and 8%), with two negative controls (untreated and white soft paraffin as ointment base) and one positive control (tretinoin 0.05%), was performed for two weeks. The effect on granular layer development and epidermal thickness was measured on hematoxylin-eosin staining. The morphometric assessment was made by using mean orthokeratosis degree and mean epidermal thickness as main parameters. All celecoxib concentrations have significantly increased the mean orthokeratosis degree as a marker of an anti-psoriatic effect. Celecoxib 8% and 4% lead to a statistically significant increase in orthokeratosis degree when compared with celecoxib 2% and tretinoin 0.05%. Along with cyclo-oxygenase inhibition, other mechanisms of action of celecoxib are discussed. This study offers valuable information for future clinical trials with celecoxib as a topical anti-psoriasis agent.

Non-Insulin Novel Antidiabetic Drugs Mechanisms in the Pathogenesis of COVID-19.

The present study aimed to analyse the published data and to realize an update about the use and pathogenesis of the novel antidiabetic drugs, respectively, dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 Ra), and sodium-glucose co-transporter-2 inhibitors (SGLT-2i), in patients with type 2 diabetes mellitus (T2DM) and coronavirus disease (COVID-19). Literature research in the PubMed and Web of Science database was performed in order to identify relevant published clinical trials and meta-analyses that include information about the treatment with novel antidiabetic agents in patients with T2DM and COVID-19. A total of seven articles were included, and their primary and secondary outcomes were reported and analysed. DPP-4i has mixed results on mortality in T2DM patients with COVID-19 but with an overall slightly favourable or neutral effect, whereas GLP-1 Ra seems to have a rather beneficial impact, while SGLT-2i may be useful in acute illness. Even if there are limited data, they seem to have favourable efficacy and safety profiles. The available evidence is heterogenous and insufficient to evaluate if the benefits of non-insulin novel antidiabetic drugs in COVID-19 treatment are due to the improvement of glycaemic control or to their intrinsic anti-inflammatory effects but highlights their beneficial effects in the pathogenesis and evolution of the disease.

Anti-Psoriasis Effect of Diclofenac and Celecoxib Using the Tail Model for Psoriasis.

Non-steroidal anti-inflammatory drugs (NSAIDs) showed effects in some hyperproliferative dermatologic pathologies. The aim of the study is the assessment of anti-psoriasis effect of diclofenac and celecoxib using a mice tail model. The topical application of substances on the proximal mice tails was performed for two weeks. The effects on the epidermal granular layer and mean epidermal thickness (excluding the stratum corneum) were evaluated using hematoxylin-eosin staining. Orthokeratosis degree and percentual drug activity were calculated. A positive control group treated with tretinoin and two negative controls (white soft paraffin and untreated mice) were used. Orthokeratosis degree significantly increased in all the NSAIDs groups (celecoxib 1%, 2% and diclofenac 1%, 2%) and in the tretinoin 0.05% group, versus negative controls. Celecoxib 1% and 2%, tretinoin 0.05% and white soft paraffin significantly increased mean epidermal thickness, versus untreated mice. The values obtained in the case of celecoxib 2% ointment regarding the orthokeratosis degree and percentual drug activity are providing premises for further investigations regarding this effect and the mechanisms of action involved. Celecoxib 2% had the greatest percentual drug activity and is a promising substance for the anti-psoriasis topical treatment. Along with the COX-2 inhibition, celecoxib might have an anti-psoriasis effect by other independent mechanisms.

Association between Liver Cirrhosis and Diabetes Mellitus: A Review on Hepatic Outcomes.

BACKGROUND: Liver cirrhosis (LC) is largely associated with diabetes mellitus (DM). More than 80% of patients with LC manifest glucose intolerance and about 30% have type 2 DM. A particular and yet unrecognized entity is hepatogenous diabetes (HD), defined as impaired glucose regulation caused by altered liver function following LC. Numerous studies have shown that DM could negatively influence liver-related outcomes. AIM: We aimed to investigate whether patients with LC and DM are at higher risk for hepatic encephalopathy (HE), variceal hemorrhage (VH), infections and hepatocellular carcinoma (HCC). The impact of DM on liver transplant (LT) outcomes was also addressed. METHODS: Literature search was performed in PubMed, Ovid, and Elsevier databases. Population-based observational studies reporting liver outcomes in patients with LC were included. RESULTS: Diabetics are at higher risk for HE, including post-transjugular intrahepatic portosystemic shunt HE. DM also increases the risk of VH and contributes to elevated portal pressure and variceal re-bleeding, while uncontrolled DM is associated with increased risk of bacterial infections. DM also increases the risk of HCC and contributes to adverse LT outcomes. CONCLUSIONS: Patients with DM and LC may benefit from close follow-up in order to reduce readmissions and mortality. Due to the heterogeneity of available research, prospective multicenter clinical trials are needed to further validate these findings.

Comprehensive analysis of drugs to treat SARS­CoV­2 infection: Mechanistic insights into current COVID­19 therapies (Review).

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.

The histaminergic control of the iridal vascular tone in rats and its influencing by topical administration of olopatadine and ranitidine.

Objective. We evaluated the histamine's role in regulating the iris vasomotricity in rats, using as a research tool topical olopatadine, a selective H1 blocker, which is indicated for the treatment of allergic conjunctivitis and ranitidine, a selective H2 blocker mainly used for the treatment of peptic ulcer disease. Methods. Two groups of six Wistar rats anesthetized with ketamine 200 mg/kg body weight were used. They received distilled water in conjunctival instillations, initially and after 5 minutes, olopatadine 2.5 mmol/ l for the first group, respectively ranitidine 2.5 mmol/ l for the second group. The changes of the iris arteriolar and venular diameters were recorded. Results. Both olopatadine and ranitidine produced statistically significant iridal arteriolar vasoconstriction and ranitidine determined statistically significant venuloconstriction, while distilled water did not produce any statistically significant effect. Conclusions. There is a vasodilator histaminergic tone exerted through the histaminergic H1 and H2 receptors in the iris arterioles and, respectively, through the H2 receptors in the iridal venules. Olopatadine, a topical H1 antagonist used in the treatment of ocular allergies, may interfere with the humoral regulation of the iris arteriolar tone. Ranitidine, an H2 antagonist, decreased the diameter of the iris arterioles and venules, when administered topically in rats.

Antidepressant effect of the interaction of fluoxetine with granisetron.

Selective serotonin reuptake inhibitors (SSRIs) may produce digestive side effects such as nausea and vomiting, diarrhoea and decreased appetite. These side effects are determined by the increase in serotonin availability at 5-HT3 receptors. Granisetron, a serotonin 5-HT3 receptor antagonist, is expected to antagonize the digestive adverse effects of serotonin reuptake inhibitors, but the question is to what extent granisetron influences the antidepressant effect of these substances. The aim of this study was to determine the dose of fluoxetine that has an antidepressant effect in the Porsolt test, and the interaction between fluoxetine and granisetron with respect to the antidepressant effect in this test. In experiment 1, fluoxetine was antidepressant only at 20 mg/kg body weight (bw). In experiment 2, granisetron 1 mg/kg bw had a statistically significant antidepressant effect vs. control. Fluoxetine 20 mg/kg bw associated with a small dose of granisetron (0.1 mg/kg bw) produced a significant antidepressant effect vs. control. This shows that low doses of granisetron associated to fluoxetine might produce a significant antidepressant effect, suggesting a potentiation between these two drugs used in sub-effective antidepressant doses. In conclusion, in our experimental conditions, we can assume that granisetron in low doses could be used to combat intestinal transit disorders produced by SSRI antidepressants. These low doses are preferred, because they increase the antidepressant effect of these SSRIs.

Topical administration of Metamizole and its implications on vascular reactivity in Wistar rats- Experimental research.

Aim: The aim of this paper was to describe the possible implications of topical (ocular) administration of Metamizole on vascular reactivity of the iris in Wistar rats. No other study regarding its topical use was found. Methods: Male adult Wistar rats were anaesthetized with Ketamine 100 mg /kg body weight - injected intraperitoneally - while maintaining spontaneous respiration and the blink reflex. After selecting the area of interest (long posterior ciliary artery - LPCA), manual adjustments of the image magnitude, clarity, and brightness were made, and the experiment began. The image recording lasted 10 minutes. Results: Metamizole induced a slight vasoconstriction that started with the initial moment for all the doses used. After the topical administration of Metamizole, we did not observe an increase of the vascular diameter of LPCA in a dose dependent manner. The saline solution used as a negative control did not modify the vessel diameter. Conclusions: Metamizole (dipyrone) is a non-opioid drug, which is commonly used in human and veterinary medicine. It is the most popular first-line analgesic in various populations. In some cases, this agent is still incorrectly classified as a non-steroidal anti-inflammatory drug. The high analgesic efficacy of metamizole, as well as its spasmolytic effect, makes it a very important pharmaceutical agent that could be used in the therapy of various eye disorders in humans and in animals. Abbreviations: COX = Cyclooxygenase; LPCA = Long Posterior Ciliary Artery; PRP = panretinal photocoagulation; PDR = proliferative diabetic retinopathy; Sec = second(s); VSPR = very severe non proliferative diabetic retinopathy.

Recent data on cannabinoids and their pharmacological implications in neuropathic pain.

Natural cannabinoids have been used for centuries for their psychotropic properties, but their possible therapeutic implications in analgesia have been recently documented. The present review intended to make an analysis of the neuroanatomy and physiology of the cannabinoid system (receptors, functions, agents acting on these receptors) and of its implications in neuropathic pain. There were also described the complex phenomena implicated in the generation and maintenance of neuropathic pain, by high lightening the implications of endogenous cannabinoids in this complex of painful conditions. The pharmacological analgesia test proves of cannabinoid implication in neuropathic pain was sustained by many studies presented in this paper. Therapeutic approaches using natural and synthetic cannabinoid receptor agonists were reviewed. Therapeutic perspectives in neuropathic pain might involve the development of new agents that influence the cannabinoid system. Thus, peripheral acting cannabinoid 1 receptors agonists, selective cannabinoid 2 receptor agonists and also modulators of endocannabinoids metabolism might be a way to success in the treatment of this complex entity called neuropathic pain.