Antinociceptive Effect of a p-Cymene/ß-Cyclodextrin Inclusion Complex in a Murine Cancer Pain Model: Characterization Aided through a Docking Study.

Pain is one of the most prevalent and difficult to manage symptoms in cancer patients, and conventional drugs present a range of adverse reactions. The development of ß-cyclodextrins (ß-CD) complexes has been used to avoid physicochemical and pharmacological limitations due to the lipophilicity of compounds such as p-Cymene (PC), a monoterpene with antinociceptive effects. Our aim was to obtain, characterize, and measure the effect of the complex of p-cymene and ß-cyclodextrin (PC/ß-CD) in a cancer pain model. Initially, molecular docking was performed to predict the viability of complex formation. Afterward, PC/ß-CD was obtained by slurry complexation, characterized by HPLC and NMR. Finally, PC/ß-CD was tested in a Sarcoma 180 (S180)-induced pain model. Molecular docking indicated that the occurrence of interaction between PC and ß-CD is favorable. PC/ß-CD showed complexation efficiency of 82.61%, and NMR demonstrated PC complexation in the ß-CD cavity. In the S180 cancer pain model, PC/ß-CD significantly reduced the mechanical hyperalgesia, spontaneous nociception, and nociception induced by non-noxious palpation at the doses tested (p < 0.05) when compared to vehicle differently from free PC (p > 0.05). Therefore, the complexation of PC in ß-CD was shown to improve the pharmacological effect of the drug as well as reducing the required dose.

Antinociceptive and anti-inflammatory activities of the ethanolic extract of Annona vepretorum Mart. (Annonaceae) in rodents.

BACKGROUND: Annona vepretorum Mart. (Annonaceae) is a native tree from Caatinga (Brazilian Northeastern savanna biome), popularly known as "araticum" and "pinha da Caatinga". In this study, we investigated the effects of the crude ethanolic extract (Av-EtOH) in models of pain and inflammation in rodents. METHODS: The evaluation of antinociceptive activity was carried out by the acetic acid-induced writhing, formalin, hot plate and tail flick tests, while paw edema induced by carrageenan or histamine, and leukocyte migration to the peritoneal cavity were used for anti-inflammatory profile. Histological analyses also were carried out. RESULTS: Av-EtOH (25, 50 and 100 mg/kg, p.o) significantly reduced the number of writhing (P < 0.01) and decreased (P < 0.01) the paw licking time in both phases of the formalin test. In the hot plate and tail flick tests, this extract increased the reaction time, consequently reduced painful behavior. The effects in the formalin and hot plate tests were antagonized by naloxone. Av-EtOH inhibited significantly (P < 0.01) the increase in the edema volume after administration of carrageenan and histamine. In the peritonitis test, acute pre-treatment with Av-EtOH inhibited leukocyte migration. Histological analysis showed less inflammation in the groups treated with the extract when the inflammation was induced by carrageenan or histamine. CONCLUSION: Thus, Av-EtOH has significant antinociceptive and anti-inflammatory properties, which are related probably with the activation of opioid receptors and inhibition of release of mediators of the inflammatory process. This specie is a potential target for drug discovery.

Antihyperalgesic effect of γ-terpinene complexed in ß-cyclodextrin on neuropathic pain model induced by tumor cells.

Neuropathic pain is a high-intensity pain that can be caused by compression, transection, injury, nerve infiltration and drug treatment of cancer. Furthermore, drug therapy has low clinical efficacy, many adverse effects and remission of painful symptoms. In this way, natural products derived from plants constitute a promising therapeutic alternative. Therefore, the aim of this study was to evaluate the antihyperalgesic effect of γ-terpinene (γ-TPN) e γ-terpinene in ß-cyclodextrin inclusion complexes (TPN/CD) on neuropathic pain induced by tumor cells. Complexation extended the effect time for another 5 h and daily treatment for six days with γ-TPN (50 mg/kg, p.o.) and γ-TPN/ß-CD (50 mg/kg, p.o.) significantly reduced (p < 0.001) the mechanical hyperalgesia induced by the administration of 2x106 sarcoma cells 180 in the around the sciatic nerve. In addition, the Grip and Rota-rod techniques demonstrated that there was no interference on the muscle strength and motor coordination of the animals, suggesting that the compound under study does not have central nervous system depressant effects at the doses used. Molecular docking studies demonstrate favorable binding energies between γ-TPN and ß-CD, and alpha-2 adrenergic, glutamatergic, opioid and cholinergic receptors. Thus, this study demonstrates the potential of terpinene complexation in controlling neuropathic pain induced by tumor cells.

Monoterpenes with analgesic activity--a systematic review.

There is still the need for efficacious therapies for pain. In the search for new therapeutic options, plants are a major source of novel biomolecules. Monoterpenes constitute 90% of essential oils, and there is a growing interest in understanding the mechanisms underlying their pharmacological activity. This systematic review reports what is so far known about the analgesic activity of monoterpenes and also provides an overview of their mechanisms of action. The search terms analgesia, anti-inflammatory, anaesthetic and antioxidant were used to retrieve English language articles in SCOPUS, PUBMED and EMBASE published between 1990 and 2012. Forty-five papers were found concerning the potential analgesic activity of 27 monoterpenes. The data reviewed here suggest these compounds are possible candidates for the treatment of painful conditions.

Corrigendum to "Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities" [Heliyon 8 (11) (November 2022) Article e11368].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e11368.].

Orofacial analgesic-like activity of carvacrol in rodents.

Carvacrol (CARV) is a phenolic monoterpene present in the essential oil of several aromatic spices. The purpose of the present study was to evaluate the antinociceptive effect of CARV on formalin-, capsaicin-, and glutamate-induced orofacial nociception in mice. Male mice were pretreated with CARV [25, 50, and 100 mg/kg body weight (BW), intraperitoneal (i.p.)], morphine (5 mg/kg BW, i.p.), or vehicle (distilled water + one drop of 0.3% cremophor in distilled water), before formalin (20 microl, 2%), capsaicin (20 microl, 2.5 microg), or glutamate (40 microl, 25 microM) was injected into the right upper lip. Our results revealed that i.p. pretreatment with CARV was effective in reducing the nociceptive face-rubbing behaviour in both phases of the formalin test and also produced a significant antinociceptive effect at all doses in the capsaicin and glutamate tests. Further, we showed that the action of CARV on the central nervous system (CNS) did not affect these results, since this compound did not exert a significant CNS-depressant effect, as shown by the pentobarbital-induced hypnosis. Our results suggest that CARV might represent an important tool for the treatment of orofacial pain.

Evaluation of the anti-inflammatory and antinociceptive properties of p-cymene in mice.

We attempted to identify the antinociceptive and anti-inflammatory actions of the monoterpene p-cymene. Firstly, behavioural screening was carried out to verify the influence of p-cymene [25, 50, and 100 mg/kg intraperitoneal (i.p.)] on the central nervous system (CNS) activity. The antinociceptive activity of p-cymene was evaluated by the acetic acid-induced writhing response, formalin, and hot-plate test, respectively. The leukocyte migration induced by injection of carrageenan was used to assess the anti-inflammatory activity. p-Cymene showed depressant activity on CNS after 4 h of treatment and also a possible action on the autonomous nervous system (ANS), mainly at the dose of 100 mg/kg (i.p.). It was found that p-cymene (50 and 100 mg/kg, i.p.) significantly (p < 0.05) reduced the writhing responses induced by acetic acid. p-Cymene also decreased the licking time in the first and second phase, respectively, of the formalin test. The results of the hot-plate test showed that all doses of p-cymene increased significantly the latency time of the response to the thermal stimulus in both licking and jumping parameters. In addition, there was a significantly (p < 0.05) decreased leukocyte migration at all doses of p-cymene. The experimental data demonstrate that p-cymene possesses antinociceptive and anti-inflammatory activities.

Carvone and its pharmacological activities: A systematic review.

Natural products from plants have gained prominence in the search for therapeutic alternatives. Monoterpenes, such as carvone, are suggested as candidates for the treatment of several diseases. Therefore, the objective of this study is to review the pharmacological activities of carvone in experimental models in vitro and in vivo. For this, the searches were carried out in May 2020 (upgraded in July 2021) in the databases of PubMed, Web of Science and Scopus and gathered studies on the pharmacological activities of carvone. Two independent reviewers performed the selection of articles using the Rayyan application, extracted the relevant data and assessed the methodological quality of the selected studies using Syrcle's risk of bias tool. Ninety-one articles were selected that described 10 pharmacological activities of carvone, such as antimicrobial, antispasmodic, anti-inflammatory, antioxidant, antinociceptive, anticonvulsant, among others. The evaluation of the methodological quality presented an uncertain risk of bias for most studies. In light of that, carvone stands out as a viable and promising alternative in the treatment of several pathological conditions. However, carrying out studies to evaluate possible mechanisms of action and the safety of this monoterpene is recommended.

Citrus Extract as a Perspective for the Control of Dyslipidemia: A Systematic Review With Meta-Analysis From Animal Models to Human Studies.

This study aims to obtain scientific evidence on the use of Citrus to control dyslipidemia. The surveys were carried out in 2020 and updated in March 2021, in the PubMed, Scopus, LILACS, and SciELO databases, using the following descriptors: Citrus, dyslipidemias, hypercholesterolemia, hyperlipidemias, lipoproteins, and cholesterol. The risk of bias was assessed according to the Cochrane methodology for clinical trials and ARRIVE for preclinical trials. A meta-analysis was performed using the application of R software. A total of 958 articles were identified and 26 studies demonstrating the effectiveness of the Citrus genus in controlling dyslipidemia were selected, of which 25 were included in the meta-analysis. The effects of Citrus products on dyslipidemia appear consistently robust, acting to reduce total cholesterol, LDL, and triglycerides, in addition to increasing HDL. These effects are associated with the composition of the extracts, extremely rich in antioxidant, as flavonoids, and that act on biochemical targets involved in lipogenesis and beta-oxidation. The risk of bias over all of the included studies was considered critically low to moderate. The meta-analysis demonstrated results favorable to control dyslipidemia by Citrus products. On the other hand, high heterogeneity values were identified, weakening the evidence presented. From this study, one can suggest that Citrus species extracts are potential candidates for dyslipidemia control, but more studies are needed to increase the strength of this occurrence.

New approaches to the effectiveness of inhalation aromatherapy in controlling painful conditions: A systematic review with meta-analysis.

OBJECTIVE: Gather scientific evidence on the application of inhalation aromatherapy for pain relief and estimate the effect measure of this practice on pain reduction. METHODS: Searches were performed in 2021 in the Pubmed, Scopus, Web of Science, Cochrane, Science direct, Lilacs, Scielo databases. We selected 44 articles demonstrating the effect of aromatherapy on different painful conditions, of which 17 were inserted in the meta-analysis. The risk of bias was assessed according to Cochrane methodology. RESULTS: In 35 (79.55%) studies was observed a significant reduction in pain, especially pain labor and postoperative pain. Through the meta-analysis, it was found that inhalation aromatherapy reduces by up to -1.73 points of the visual analog scale (VAS), indicating that this practice contributes to the reduction of pain perception in different painful conditions. In addition, the meta-analysis indicated that the time after inhalation, the type of oil used and the type of pain treated are important variables that interfere with the magnitude of the effect. These effects are attributed to the ability of essential oils to modulate nerve control centers and neurotransmission systems involved in pain control. CONCLUSION: From the gathering of articles on aromatherapy, it can be noted that aromatherapy appears to be helpful in alleviating acute pain, however there is an imminent need to improve aromatherapy studies to reduce the risk of bias and increase the power of its clinical evidence. PROSPERO: CRD42019121665.

γ-Terpinene complexed with ß-cyclodextrin attenuates spinal neuroactivity in animals with cancer pain by Ca2+ channel block.

OBJECTIVES: Considering that γ-terpinene (γ-TPN) is a monoterpene found in Cannabis oil, with high lipophilicity and limited pharmacokinetics, our objective was to evaluate whether its complexation in ß-cyclodextrin (γ-TPN/ß-CD) could improve its physicochemical properties and action on cancer pain, as well as verify the mechanisms of action involved. METHODS: The γ-TPN/ß-CD was prepared and submitted to physicochemical characterization. Animals with sarcoma 180 were treated (vehicle, γ-TPN 50 mg/kg, γ-TPN/ß-CD 5 mg/kg or morphine) and assessed for hyperalgesia, TNF-α and IL-1ß levels, iNOS and c-Fos activity. The effects of γ-TPN on calcium channels were studied by patch-clamp and molecular docking. RESULTS: ß-CD improved the physicochemical properties and prolonged the anti-hyperalgesic effect of γ-TPN. This compound also reduced the levels of IL-1ß, TNF-α and iNOS in the tumour, and c-Fos protein in the spinal cord. In addition, it reduced Ca2+ current, presenting favourable chemical interactions with different voltage-dependent calcium channels. CONCLUSION: These results indicate that the complexation of γ-TPN into ß-CD increases its stability and time effect, reducing spinal neuroactivity and inflammation by blocking calcium channels.

Cross-sectional analysis of students and school workers reveals a high number of asymptomatic SARS-CoV-2 infections during school reopening in Brazilian cities.

Brazil experienced one of the most prolonged periods of school closures, and reopening could have exposed students to high rates of SARS-CoV-2 infection. However, the infection status of students and school workers at the time of the reopening of schools located in Brazilian cities is unknown. Here we evaluated viral carriage by RT-PCR and seroprevalence of anti-SARS-CoV-2 antibodies (IgM and IgG) by immunochromatography in 2259 individuals (1139 students and 1120 school workers) from 28 schools in 28 Brazilian cities. We collected the samples within 30 days after public schools reopened and before the start of vaccination campaigns. Most students (n = 421) and school workers (n = 446) had active (qRT-PCR + IgM- IgG- or qRT-PCR + IgM + IgG-/+) SARS-CoV-2 infection. Regression analysis indicated a strong association between the infection status of students and school workers. Furthermore, while 45% (n = 515) of the students and 37% (n = 415) of the school workers were neither antigen nor antibody positive in laboratory tests, 16% of the participants (169 students and 193 school workers) were oligosymptomatic, including those reinfected. These individuals presented mild symptoms such as headache, sore throat, and cough. Notably, most of the individuals were asymptomatic (83.9%). These results indicate that many SARS-CoV-2 infections in Brazilian cities during school reopening were asymptomatic. Thus, our study highlights the need to promote a coordinated public health effort to guarantee a safe educational environment while avoiding exacerbating pre-existent social inequalities in Brazil, reducing social, mental, and economic losses for students, school workers, and their families.

Anti-inflammatory and redox-protective activities of citronellal.

The anti-inflammatory and redox protective effects of the citronellal (CT) were evaluated using in vivo and in vitro tests. Intraperitoneal (i.p.) administration of CT (50, 100, and 200 mg/kg) inhibited (p < 0.05) the carrageenan-induced leukocyte migration to the peritoneal cavity. Additionally, the carrageenan- and arachidonic acid-induced rat hind paw edema was significantly inhibited (p < 0.05) by i.p. administration of 100 and 200 mg/kg of the compound. When the redox activity was evaluated, CT (200 mg/kg) significantly reduced hepatic lipoperoxidation (p < 0.001), as well as oxidation of plasmatic (p < 0.05) and hepatic (p < 0.01) proteins. The results of the present study support the hypothesis that CT possesses anti-inflammatory and redox protective activities. It is suggested that its effects are associated with the inhibition of the enzymes in the arachidonic acid pathway, which prevent cell migration by inhibiting leukotriene production, edema formation and the increase of reactive oxygen species in tissues. Therefore, CT is of potential benefit to manage inflammatory disorders and correlated damages caused by oxidant agents.

Bioassay-guided evaluation of antinociceptive properties and chemical variability of the essential oil of Hyptis fruticosa.

The composition of three samples of essential oil (EO) extracted from the leaves and flowers of Hyptis fruticosa (Lamiaceae) were investigated by GC/MS and GC-FID. The variability of the constituents and biological activity were evaluated in the oil samples. Acetic acid-induced abdominal constrictions and formalin-induced pain tests in mice were used for screening the antinociceptive activity. The possible antagonism of the essential oils or morphine (MOR) antinociceptive effects by pretreatment with naloxone, showed no influence on the antinociceptive action of the oils in the acetic acid-induced writhing test. All examined oil samples presented antinociceptive activity. The oil sample obtained from the leaves collected during the vegetative growth stage, near São Cristóvão at Sítio Tujubeba exhibited the highest effect. The same oil sample had a main percentage of 1,8-cineole (18.70%). Nevertheless, the oil obtained from flowers collected at the same location, showed a significant difference (p < 0.05) in the response intensity in the first phase of paw licking (100 mg/kg) possibly due to the higher contents of α-pinene (20.51%) and ß-pinene (13.64%). The results provide evidence for the use of H. fruticosa by traditional medicine practitioners in the management of pain.

α-Terpineol reduces nociceptive behavior in mice.

CONTEXT: α-Terpineol (TPN) is a monoterpenoid alcohol present in the essential oils of several species of the Eucalyptus genus (Myrtaceae). OBJECTIVE: TPN was assessed for its antinociceptive activity in rodents. MATERIALS AND METHODS: The antinociceptive effect of TPN was examined using the acetic acid writhing reflex, formalin, glutamate, and capsaicin-induced nociception tests. RESULTS: TPN produced a significant (P < 0.01 or P < 0.001) analgesic effect by reduction at the early and late phases of paw licking and reduced the writhing reflex in mice (formalin and writhing tests, respectively). In the glutamate test, all doses of TPN produced significant (P < 0.01) nociceptive protection. When the capsaicin-induced nociception test was conducted, TPN produced dose-related inhibition of the nociceptive behavior. In addition, the results of a hot plate test showed central analgesic properties for TPN (P < 0.01 or P < 0.001). Such results were unlikely to be provoked by motor abnormality. CONCLUSION: Our results suggest that TPN might represent an important tool for management and/or treatment of painful conditions.

Monoterpenes as a perspective for the treatment of seizures: A Systematic Review.

BACKGROUND: Epilepsy affects more than 65 million people worldwide. Treatment for epileptic seizures is ineffective and has many adverse effects. For this reason, the search for new therapeutic options capable of filling these limitations is necessary. HYPOTHESIS/PURPOSE: In this sense, natural products, such as monoterpenes, have been indicated as a new option to control neurological disorders such as epilepsy. STUDY DESIGN: Therefore, the objective of this study was to review the monoterpenes that have anticonvulsive activity in animal models. METHODS: The searches were performed in the PubMed, Web of Science and Scopus databases in September, 2020 and compiled studies using monoterpenes as an alternative to seizure. Two independent reviewers performed the study selection, data extraction and methodological quality assessment using the Syrcle tool. RESULTS: 51 articles that described the anticonvulsant activity of 35 monoterpenes were selected with action on the main pharmacological target, including GABAA receptors, glutamate, calcium channels, sodium and potassium. In addition, these compounds are capable of reducing neuronal inflammation and oxidative stress caused by seizure. CONCLUSION: These compounds stand out as a promising alternative for acting through different pharmacological mechanisms, which may not only reduce seizure, but also promote neuroprotective effect by reducing toxicity in brain regions. However, further studies are needed to determine the mechanism of action and safety assessment of these compounds.

Estimated SARS-CoV-2 Infection and Seroprevalence in Firefighters from a Northeastern Brazilian State: A Cross-Sectional Study.

The new coronavirus has been affecting health worldwide and essential service workers are continually exposed to this infectious agent, increasing the chance of infection and the development of the disease. Thus, this study aimed to estimate the frequency of infection and seroprevalence for SARS-CoV-2 in military firefighters in a city in Northeastern Brazil in January 2021. An observational cross-sectional study was carried out with 123 firefighters who answered a brief questionnaire to collect socio-epidemiological data and underwent RT-PCR and immunofluorescence test (IgM and IgG). The results found reveal a positive seroprevalence, with a high rate of infection in this class of workers, since they are essential service professionals who are exposed to risk due to their working hours, in addition to sharing some spaces and work materials. Besides, there were significant associations between positivity for IgG and IgM, as well as for positive RT-PCR prior to the study and the presence of IgG, with odd ratios of 3.04 and 4.9, respectively. These findings reinforce the need for immunization in this category, whose line of service hinders the adoption of distancing measures, since in many situations physical contact is inevitable.

Terpenes as possible drugs for the mitigation of arthritic symptoms - A systematic review.

BACKGROUND: Arthritis is a syndrome associated with exacerbated inflammation, joint destruction and chronic pain and disability. Chronic treatment of arthritis is associated with several side effects and high abandonment. Therefore, there has been an ongoing search for alternative treatments to overcome these problems. PURPOSE: Natural products, which are already widely used for their biological, cosmetic and pharmacotechnic properties, are a possible source for new drugs. Terpenes, a large class of organic compounds produced mainly by plants and trees, are a promising natural product and have already been shown to be effective in treating chronic pain, particularly of an inflammatory origin. STUDY DESIGN AND METHODS: This review identifies the main terpenes with anti-arthritic activity reported in the last 10 years. A survey was conducted between December 2017 and June 2018 in the PUBMED, SCOPUS and Science Direct databases using combinations of the descriptors terpenes, arthritis and inflammation. RESULTS: The results showed that terpenes have promising biological effects in relation to the treatment of arthritis, with the 24 terpenes identified in our survey being effective in the modulation of inflammatory mediators important to the physiopathology of arthritis, such as IL-6, IL-17, TNF-α, NFκB, and COX-2, among others. It is important to note that most of the studies used animal models, which limits, at least in part, the direct translation to humans of the experimental evidence produced by the studies. CONCLUSION: Together, our finds suggest that terpenes can modulate the immuno-regulatory and destructive tissue events that underlie the clinical presentation and the progression of arthritis and are worthy of further clinical investigation.

The use of terpenes and derivatives as a new perspective for cardiovascular disease treatment: a patent review (2008-2018).

INTRODUCTION: Terpenes are a class of secondary metabolites that can be found in a variety of animal and plants species. They are considered the most structurally diversified and abundant of all natural compounds. Several studies have shown the application of terpenes, such as carvacrol, linalool, and limonene in many pharmaceutical and medicinal fields, including cardiovascular disorders, the leading cause of death worldwide. AREAS COVERED: In this review, the authors outlined patents from the last 10 years relating to the therapeutic application of terpenes for the treatment and/or prevention of cardiovascular diseases found in different databases, emphasizing the possibility of these compounds becoming new drugs that may help to decrease the burden of these disorders. EXPERT OPINION: There has been a growing awareness over recent years of the therapeutic use of terpenes and their derivatives as new pharmaceutical products. Patents involving the use of terpenes have been especially important in the technological development of new strategies for the treatment of cardiovascular diseases by bringing new scientific knowledge into the pharmaceutical industry. Therefore, the development of biotechnologies using natural products should be encouraged in order to increase the variety of drugs available for the treatment of cardiovascular diseases.

Alcoholic monoterpenes found in essential oil of aromatic spices reduce allergic inflammation by the modulation of inflammatory cytokines.

Allergic inflammation is a response of the body against pathogens by cytokine release and leucocyte recruitment. Recently, there was an increase in morbimortality associated with allergic inflammation, especially asthma. The treatment has many adverse effects, requiring the search for new therapies. Monoterpenes are natural products with anti-inflammatory activity demonstrated in several studies and can be an option to inflammation management. Thus, we investigated the effects of citronellol, α-terpineol and carvacrol on allergic inflammation. The model of asthma was established by OVA induction in male Swiss mice. The monoterpenes were administered (25, 50 or 100 mg/kg, i.p.) 1 h before induction. After 24hs, the animals were sacrificed to leucocytes and TNF-α quantification. Monoterpenes significantly decrease leucocyte migration and TNF-α levels, possibly by modulation of COX, PGE2 and H1 receptor, as demonstrated by molecular docking. These findings indicate that alcoholic monoterpenes can be an alternative for treatment of allergic inflammation and asthma.