Renova Menthol Sensitive Tissues Handkerchiefs (6 Packs of 9) - Extra Soft

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The application of menthol to cutaneous tissue and submucosal tissue is common in clinical practice for the alleviation of pain and to promote a cooling effect ( 54). However, there is increasing interest in the potential for menthol to exert anti-inflammatory effects when applied to the skin and associated tissues, including inflammation associated with pathological conditions and processes. Andersen et al. ( 39) reported that the application of a 40% menthol-based cream to an area of irritation and inflammation on the forearm leads to a reduction in pain, neurogenic inflammation, and hyperalgesia (high responsiveness to sensations). This study utilized topical 10% trans-cinnamaldehyde application to elicit the cutaneous symptoms, with the treatment of menthol simultaneously noted to reduce pain intensity (P<0.01), neurogenic inflammation (P<0.01), and hyperalgesia (P<0.05) compared with symptoms when menthol was not applied. Cortés-Montero E., Rodríguez-Muñoz M., Ruiz-Cantero M. D. C., Cobos E. J., Sánchez-Blázquez P., Garzón-Niño J. (2020). Calmodulin supports TRPA1 channel association with opioid receptors and glutamate NMDA receptors in the nervous tissue. Int. J. Mol. Sci. 22:229. 10.3390/ijms22010229 Ashoor A., Nordman J. C., Veltri D., Yang K. H., Shuba Y., Al Kury L., et al. (2013b). Menthol inhibits 5-HT3 receptor-mediated currents. J. Pharmacol. Exp. Ther. 347

Taken together, studies exploring the protective effects of menthol against inflammatory damage, or association with protection against chronic inflammation, are indicative of potential therapeutic applications of the compound. However, it is vital to note the limitations of the studies completed to date. One main limitation is that most of the studies are either in vitro or based on animal models of human disease, which may limit our direct application to human pathology. While menthol has been extensively used therapeutically in humans, demonstration of a clear anti-inflammatory effect should be sought and evaluated using biochemical markers or inflammation in a pathological context. Furthermore, while the evidence for the anti-inflammatory effects of menthol is compelling, additional insights may be needed to clarify the mechanisms of action and the clinical relevance of any anti-inflammatory effects. This is especially noteworthy considering the evidence for the pro-inflammatory impact of inhaled menthol when combined with cigarette smoking ( 42). Inflammatory cascades are complex and closely related to immunological function and antioxidant activity in multiple tissues; further delineation of these mechanisms and pathways is needed to truly appreciate the potential for menthol, which appears to be a molecule with multiple cellular targets, as a therapeutic anti-inflammatory compound. Author contributions Hanprasertpong T., Kor-anantakul O., Leetanaporn R., Suwanrath C., Suntharasaj T., Pruksanusak N., et al. (2015). Reducing pain and anxiety during second trimester genetic amniocentesis using aromatic therapy: A randomized trial. J. Med. Assoc. Thai. 98 Decreased perceived discomfort to a greater extent and permitted greater tetanic forces to be produced.

However, abnormal pain induced by high menthol concentration still exists experimental fact that is difficult to be explained by sensitization of TRPM8. Fan et al. (2016) demonstrated that mice showed a concentration-dependent oral aversion of menthol (>100 μg/mL or >640 mM), and that gene deletion of TRPM8 did not reduce this aversion. Lemon et al. (2019) conducted a brief-access exposure tests in mice to measure reduction in orosensory avoidance behaviors to aqueous menthol solutions and showed that oral aversion to menthol was reduced in mice deficient for TRPA1 but not TRPM8. As a naturally occurring cyclic monoterpene, menthol may utilize its chemical structure (e.g., hydroxyl groups) for its potent antioxidant effects. Several previous studies have concluded that the major monoterpenoids, particularly menthol, are responsible for the majority of the mint’s antioxidant activity ( 11, 12). In general, phytochemicals exert their antioxidant effects by scavenging free radicals, chelating divalent metals, donating hydrogen or electrons, and facilitating the decomposition of peroxyl radicals. As a result, phytochemicals can inhibit the formation of free radicals, slow or inhibit the autoxidation process (chain-breaking antioxidant), or accelerate the termination of autoxidation. Wu et al. ( 12) use in vitro chemical- and cell-based assays and in vivo tests with C. elegans model to prove that the major monoterpenoids of mint essential oil, particularly menthol, have potent antioxidant effects. Biological activity of menthol: receptor activity and signaling pathways Gong K., Jasmin L. (2017). Sustained morphine administration induces TRPM8-dependent cold hyperalgesia. J. Pain 18 Results: The decrease in pro-inflammatory cytokines and related inflammatory markers, as well as associated pathway activation, was found to play the greatest role in the protective effects of menthol against inflammatory damage or association with protection against chronic inflammation. Genome-wide association analysis have revealed that TRPM8 is associated with susceptibility to migraine without aura ( Freilinger et al., 2012), and reduced TRPM8 expression (rs10166942 carriers) helps reduce migraine risk in humans ( Gavva et al., 2019), which may provide the rationale for the topical menthol as an alternative treatment option for migraine patients. A randomized, triple-blind, placebo-controlled, crossed-over study demonstrated the efficacy, safety, and relative tolerability of cutaneous application of 10% menthol solution in the treatment of migraine without aura ( Borhani Haghighi et al., 2010). An open-label pilot study showed that 52% of subjects experienced at least one statistically significant improvement in migraine severity 2 h after using topical menthol ( St Cyr et al., 2015). Due to the limitations of these studies, larger placebo-controlled clinical trials are needed.

Colvin L. A., Bull F., Hales T. G. (2019). Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet 393 Furthermore, it has been suggested that chronic smokers may have altered sensory irritation responses as a consequence of pulmonary remodeling and inflammatory reactions that are long-standing in the respiratory tract ( 70, 73, 74). The sensitivity of TRPA1 and TRPV1 receptors has been shown to be modified in chronic smokers, which may diminish the potential for menthol to act on local receptors to reduce inflammation ( 75, 76). Additionally, a chronic state of inflammation within the respiratory tract may induce changes to receptor sensitivity and responses to stimulation, reducing the anti-inflammatory effects of menthol ( 74). Indeed, in the research by Lin et al. ( 32), sub-chronic smoke exposure in mice (less than seven days) was sufficient to promote additional inflammatory reactions with menthol exposure, while this was not observed in acute exposure (20 minutes). This suggests that shorter periods of exposure may not be linked to additive inflammatory outcomes with menthol exposure ( 32). Therefore, the chronicity of smoking and the complex biochemical pathways that occur following exposure to menthol and cigarette smoke extracts (including nicotine) may account for variations in inflammatory responses to menthol in published research. Bromm B., Scharein E., Darsow U., Ring J. (1995). Effects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett. 187, 157–160. 10.1016/0304-3940(95)11362-z [ PubMed] [ CrossRef] [ Google Scholar]Andersen H. H., Olsen R. V., Møller H. G., Eskelund P. W., Gazerani P., Arendt-Nielsen L. (2014). A review of topical high-concentration L-menthol as a translational model of cold allodynia and hyperalgesia. Eur. J. Pain 18 In conclusion, it is seemingly that menthol administration in a great variety of experimental models and settings is associated with anti-inflammatory activity. This activity is characterized by a decrease in pro-inflammatory cytokines and related inflammatory markers, including those potentially linked to chronic inflammation, as well as pathway activation that is linked to the regulation of inflammatory enzymes and proteins. Furthermore, menthol administration in pathological inflammatory contexts appears to have favorable outcomes on histopathological characteristics of lesions and wider biological effects. As menthol is considered a safe agent for humans, given the widespread use and medical indications for menthol-containing products at present, the therapeutic potential of menthol as an anti-inflammatory can justifiably be considered on the basis of this review. Except for TRPM8, there are other channels of the TRP subfamily, including TRPA1, TRPV1, and TRPV3, which can also be influenced directly or indirectly by menthol, and are seemingly involved in the process of menthol’s anti-inflammatory effect. Andersson D. A., Nash M., Bevan S. (2007). Modulation of the cold-activated channel TRPM8 by lysophospholipids and polyunsaturated fatty acids. J. Neurosci. 27 Cortellini A., Verna L., Cannita K., Napoleoni L., Parisi A., Ficorella C., et al. (2017). Topical menthol for treatment of chemotherapy-induced peripheral neuropathy. Indian J. Palliat. Care 23

Caterina M. J., Schumacher M. A., Tominaga M., Rosen T. A., Levine J. D., Julius D. (1997). The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature 389 The contrasting findings of menthol exposure on inflammatory responses in smokers may be dependent on a range of effects. For instance, it has been noted that menthol may alter the metabolism of nicotine, increasing systemic exposure to nicotine and slowing the metabolic clearance of nicotine and associated compounds in the lungs ( 35). Whether this increases the potential for more inflammation, which is associated with lung nicotine exposure, remains to be confirmed, but is one hypothesis as to why co-administration of menthol and nicotine may lead to heightened inflammation ( 70). Besides, the difference in constituents between commercial mentholated and non-mentholated cigarettes may also introduce confounding factors in the experiment. Modaressi et al. [ 39] showed that the topical application of Mentha piperita ointment at 4% and 8% accelerated the healing of infected skin wounds in mice after 4, 8, 12, and 16 days of treatment. The authors attributed the effect mainly to the modulation of the mRNA expression of the inflammation-related genes by menthol. Babamohamadi et al. [ 40] evidenced that a Mentha piperita gel (applied three times a day up to 14 days) prevented the development of pressure ulcers in hospitalized patients. In this study, we intended to prospect the effect of menthol in skin wound healing. Skin wounds were developed in rats and treated with menthol-based creams for 3, 7, or 14 days, according to previously described stages of wound healing: inflammatory, proliferative, and tissue remodeling phase [ 9]. This is the first study evaluating the in vivo wound healing potential of menthol, and we have demonstrated that, topically applied, menthol at the concentration of 0.5% accelerated the wound closure in 3, 7, and 14 days of treatment. The mechanisms potentially involved in the effect are discussed as follows.

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Fernández J. A., Skryma R., Bidaux G., Magleby K. L., Scholfield C. N., McGeown J. G., et al. (2011). Voltage- and cold-dependent gating of single TRPM8 ion channels. J. Gen. Physiol. 137 Bandell M., Story G. M., Hwang S. W., Viswanath V., Eid S. R., Petrus M. J., et al. (2004). Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41

Colvin L. A. (2019). Chemotherapy-induced peripheral neuropathy: Where are we now? Pain 160 Suppl 1 The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher’s noteBinder A., Stengel M., Klebe O., Wasner G., Baron R. (2011). Topical high-concentration (40%) menthol-somatosensory profile of a human surrogate pain model. J. Pain 12