Capsaicin: Emerging Pharmacological and Therapeutic Insights

Abstract

Keywords: capsaicin, bioavailability, physiopathology, anti-cancer effects, local effects, adverse effects

1. Introduction

The most prominent pungent principle in the hot peppers (Capsicum annuum) of the genus Capsicum [1] is capsaicin (8-methyl-N-vanillyl-6-nonenamide), an organic nitrogenous compound within the lipid group [2]. It must be noted that the name capsaicin was originally used to refer to a multitude of substances originally isolated from C. oleoresin; these compounds are now known as capsaicinoids [3], a distinction made after the 1960s [4].

Interestingly, it has been discovered that the cultivation of chilli peppers began around the 5th millennium BC [5], thus rendering them amongst the oldest cultivated plants; their origin is estimated to be somewhere in Bolivia [6]. Chilli peppers came to Europe only after the discovery of the New World and the subsequent Columbian Exchange, which had far-reaching consequences [7]; this is hardly surprising as numerous foodstuffs followed this historical process [8,9,10]. Subsequently, chilli peppers were swiftly adopted by many cultures and, as such, are ingredients in many local and traditional dishes [11]. It is believed that the synthesis of capsaicin within the plant is part of a defence mechanism developed against consumption by herbivores and micro-organism infestations [12]; however, not all chillies are pungent [13].

Extracted initially as an impure formulation by C.F. Bucholz (1770–1818), it was termed “capsicin” [14,15]. The original compound, isolated almost completely in 1876 by J.C. Thresh (1850–1932) [16,17,18], was a colourless substance of a crystalline structure—though purified in the 1870s, the first description of its structure is recorded in 1919 [19]—this is not surprising given that the complete isolation of the compound was achieved only in 1898 by K. Micko [20,21]. Based on the original isolation of capsaicin and the identification of its chemical and physical properties, capsaicinoids, of which capsaicin is a member, are defined as chemical compounds which have similar structures and properties as capsaicin [22].

Regarding capsaicin in particular, in its pure form, it is a solid, colourless, hydrophobic, highly volatile and highly pungent substance [23]; if heated to decomposition (80–140 °C), the fumes emitted are toxic nitrogen oxides [24]. Its chemical formula is C₁₈H₂₇NO₃ [25]. Capsaicin naturally occurs in its trans form, although a cis-isomer also exists [26].

The biosynthetic path of capsaicin, as described in research [27], involves a chemical reaction between vanillylamine and 7-methyloct-5-ene-1-carboxylic acid chloride; this reaction takes place in the fleshy parts of the fruits. In the seeds of these fruits, no capsaicin is produced; however, the white part of their inner wall contains the highest capsaicin concentration, and it is where the seeds are attached [26]. It is interesting to note that under stress conditions, the capsaicin production of the plant increases [28,29]. Currently, artificial synthesis of capsaicin is possible using a number of different methods [30]. The first artificial synthesis of capsaicin was recorded in 1930 [31]; a number of methods have been developed lately to enhance its production [32,33,34,35], given its high demand for research and applications.

The most oft-used scale to measure capsaicin’s, or indeed any other compound’s, pungency is the Scoville Heat Unit (SHU) scale, proposed in the early 1990s [36]; this is based on the subjective pungency perception of people consuming pungent substances and foods. It is a linear scale, and it can exceed even 10⁶ SHU for the hottest peppers containing the highest amounts of capsaicinoids [37].

Due to its properties, capsaicin has a number of already established clinical and industrial uses (Table 1), while a number of novel clinical applications are under discussion. Outside of medical applications, the very potent irritative effect of capsaicin on mucosae [38] means that it constitutes an important component in pepper spray products [39,40,41,42].

In this review, we will present a comprehensive analysis of the pharmacodynamics and pharmacokinetics of capsaicin and elaborate on its pharmacotoxicity. Given that our study focuses on the pharmacological properties of capsaicin, the most prominent local, systemic and anticarcinogenic applications of capsaicin will be presented in detail. The applications of capsaicin in traditional medicine will also be addressed, and current evidence of the most promising avenues of future research will be reported.

2. Materials and Methods

This review was conducted by systematically searching major electronic databases, including PubMed, Scopus, and Web of Science. The search strategy was developed using a combination of Medical Subject Headings (MeSH) and keywords. MeSH terms included “Capsaicin”, “Biochemical Properties”, “Therapeutic Applications”, and “Pharmacology”. Keywords related to these terms, such as “pain management”, “analgesic effect”, and “TRPV1 receptor”, were also used to ensure comprehensive coverage.

Inclusion Criteria: Peer-reviewed articles and studies focused on the biochemical properties, therapeutic applications, or pharmacological insights of capsaicin.

Exclusion Criteria: Studies not specifically addressing capsaicin, non-peer-reviewed literature, such as abstracts, conference proceedings, and grey literature.

The search strategy aimed to capture a wide array of relevant studies to provide an updated and comprehensive overview of capsaicin. Each database was searched using tailored strategies to maximise the retrieval of pertinent studies. The selection process involved screening titles and abstracts, followed by a full-text review to ascertain eligibility based on the predefined inclusion and exclusion criteria.

3. Pharmacokinetics and Pharmacodynamics of Capsaicin

Being liposoluble, capsaicin is well absorbed orally, as well as at the digestive tract level; internal administration means that it will also reach systemic circulation, while systemic administration itself is also possible [76]. The absorption of capsaicin takes place at the level of the stomach and the intestine, varying between 50% and 90%; at any rate, it is invariably a passive process [77]. The intestinal epithelial cells can metabolise a small percentage of the absorbed capsaicin [78]. Despite its lipophilicity, which correlates with good skin absorption [79], capsaicin does not reach sufficiently high levels in the plasma following local or transdermal administration to exert its effects systemically [80].

Following its internal (oral) administration, capsaicin is hepatically metabolised [78], with the small aforementioned exception. Based on in vitro studies, it has been established that, following its rapid metabolisation, the three most important metabolites are 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin; vanillin is a minor metabolite [81,82]. Based on a subsequent study [83], another metabolite of capsaicin was identified, which corresponds to a compound occurring after phase I demethylation and dehydrogenation. A glycine and a glutathione conjugate were also identified. At any rate, a small percentage of capsaicin is fecally excreted, while most of the elimination is renal for the glucuronide metabolites of capsaicin [84].

While it may be assumed that cytochrome P₄₅₀ enzymes are, most probably, involved in capsaicin metabolism [85,86], in human skin cell studies, the biotransformation process has been found to be slow, and most of the administered capsaicin did not undergo any changes [87]—this last fact has important implications for medicinal capsaicin applications. The half-life of capsaicin in the human body was determined to be 25 min [87]; conversely, the local application of a 3% capsaicin solution yielded a value of 24 h [88,89]. More recent research [90] has identified a novel metabolic pathway in the human body, resulting in macrocyclic diene and imide metabolites.

The first physiological action of capsaicin is observed when it binds to the TRPV1 (transient receptor potential cation channel subfamily V member 1) [91]; capsaicin is a potent TRPV1 receptor agonist [92]. Such is the physiological importance of this receptor, and of temperature and mechanically activated channels in general, that research on them resulted in the awarding of the 2021 Nobel Prize in Physiology or Medicine to David Julius and Ardem Patapoutian [93,94,95] based on their previous research (e.g., [96,97,98,99,100,101]).

This receptor, which is also called capsaicin or vanilloid receptor 1 [102], can be activated, apart from its agonists, by a temperature higher than 43 °C and a pH lower than 5.2. Some examples of endogenous agonists are bradykinin and prostaglandins [103]. The receptor function is associated either with protein kinase A or protein kinase C [104,105]. The activation of this receptor enables it to exert its modulatory activity; its principal role is body temperature regulation [106,107]. The heat perception properties of TRPV1 have also been proposed by Tominaga et al. [108] who have also noted that TRPV1 is instrumental in peripheral nociception. The nerve signals resulting from its activation reach all up to the spinal cord and eventually the brain.

TRPV1 was identified in the central nervous system as well as in the sensory neurons of the dorsal root ganglion [109]. At the level of the cardiovascular system, it can also be found in vascular smooth muscle cells and endothelial cells [110]; of course, neural TRPV1 activation will also have cardiovascular-related effects [111]. It must be noted that TRPV1 does not seem to be expressed in cardiomyocytes [112], but there is a report indicating that it is possibly expressed in the nerve fibres of the epicardium [113]. At the level of the respiratory system, TRPV1 is found in the airway epithelial cells and in the T cells of the upper and lower airways [114]; interestingly, the expression of TRPV1 in the respiratory system seems to vary in different pathological situations [115,116]. At the level of the gastrointestinal tract (GIT), TRPV1 can be found in the submucosal nerve plexus, myenteric nerve plexus, gastrointestinal mucosal cells, parietal and antral G cells [117].

At the level of the integumentary system, TRPV1 can be found in a number of different cell types, namely unmyelinated type C and thin myelinated A_δ sensory nerve fibres, keratinocytes, sebocytes, dermal blood vessels, mast cells, fibroblasts, hair follicles, and vascular smooth muscle cells [118,119,120]. In the eyes, TRPV1 is present in corneal cells [121] and retinal ganglion cells [122].

Capsaicin induces a variety of TRPV1-mediated sensations with different intensities, from warming and tingling up to burning [123,124]. Another aspect that must be considered is that capsaicin-induced activation of TRPV1 is more persistent compared to the effect of other natural agonists. In fact, capsaicin is a more potent agonist compared to any endogenous TRPV1 agonists—which have been analysed in detail in recent studies [125]—and, although being the most characteristic exogenous TRPV1 agonist [126], there are some more potent such agonists, like resiniferatoxin [127,128] and a number of recently researched compounds [129]. The capsaicin-induced activation of TRPV1 is associated, at least in a number of cases, with a relative desensitisation [130].

Capsaicin exerts a host of different effects at cellular [131,132,133,134,135] and subcellular levels [136,137]. Two pathways are thought to exist via which capsaicin may inhibit nociception: a TRPV1-dependent one and a TRPV1-independent one. The TRPV1-independent effects are associated with changes in the lipid membrane properties, the modulation of voltage-gated ion channels and direct binding to other enzymes and transporters [138,139,140]. The TRPV-1-dependent pathway implies activation of the receptor and subsequent desensitisation, which can be modulated by various factors, including cAMP/PKA-dependent activation [141,142]. Both the dependent and independent effects are most possibly associated with the reduced nociception caused by capsaicin [138].

The aforementioned blockade of nociceptors, when coupled with the capacity of reducing the inflammation-associated substance P [143], renders capsaicin a good candidate for a non-narcotic analgesic [144,145]; indeed, the new technologies available render the design of pharmacological capsaicin analogues a possible and potent eventuality [126]. In the manifestation of analgesic effects, the indirect blockage of voltage-gated Na⁺ channels may also play a role [146,147]. In addition, some other associated capsaicin-induced actions comprise the degeneration of epidermal nerve fibres after prolonged local administration [148]. A number of researchers have presented the most recent developments regarding the novel analgesic capsaicin applications [149,150,151,152]. A general outline of the TRPV1-mediated activation by capsaicin is presented in Figure 1.

Figure 1 Capsaicin activation of TRPV1. Capsaicin induces sensory neuronal depolarization and local sensitisation to activation by heat, acidosis, and endogenous agonists. Topical application of capsaicin induces sensations of heat, burning, stinging, or itching. When high concentrations of capsaicin are used, or there are repeated applications in cutaneous nociceptors, a de-functionalization process is induced. (Figure not reproduced here; see the original article.)

4. Indications and Therapeutical Uses of Capsaicin

In general, the uses of capsaicin are numerous and varied, ranging from medicine, either human or veterinary, to uses in agriculture, the food industry, and fragrances. In human medicine, we distinguish between local and systemic applications (Table 2 and Table 3).

4.1. Capsaicin as a Local Agent

As discussed above, capsaicin is lipophilic and can hence be absorbed readily, reaching and activating the TRPV1 receptor, which can be found both in nociceptive and non-nociceptive structures. The binding of capsaicin leads to receptor activation, upon which a prolonged desensitisation state prevails; this second state renders the use of capsaicin very promising in chronic pain syndromes, as well as against hyperplasias, inflammation and inflammatory skin diseases, various dermatoses, as well as chemotherapy-induced and radiotherapy-induced mucositis [153].

For local applications, a variety of capsaicin preparations are available, such as creams, gels, liquids and patches [154], while novel formulations comprise nanolipid carriers [155,156,157], flexible membrane vesicles [158] and alginate microcapsules [159]. These last formulations can be considered better in that they improve the pain threshold in a dose-dependent manner, compared to the older locally-administered drugs; the positive effect is exerted through the reduction of tissue prostaglandin E2 levels, while skin irritation is also reduced [160]. The most prominent local capsaicin applications are presented in Table 2.

Most, if not all, of the local applications mentioned in Table 2 can be combined with anti-inflammatory drugs; this enables augmentation of their effects, thus leading to dose reduction, which diminishes their systemic side effects [230]. It may be observed that an abundance of these applications is associated with the inhibition and/or depletion of substance P; substance P, a bioactive peptide of the tachykinin family [231], is secreted by nerve cells and a host of inflammatory cells [232]. Substance P is associated with neurogenic inflammation [233,234] both systemically and at the level of the skin [235,236,237], the cardiovascular system [238,239], the respiratory [240,241,242], gastrointestinal [243,244,245] and genitourinary [246,247] tracts and also in the cerebral arteries [248,249]. The relative ubiquity of substance P in the human body renders it a prime target for pharmacological interventions in inflammatory diseases [250]. Notably, substance P is associated with infection-induced inflammation, a fact proven in both human and animal models [251,252,253,254]; taking into account the already proven antimicrobial properties of capsaicin, this could prove an interesting research avenue. In an experimental setting, capsaicin has also been used locally to demonstrate the effects of psychological triggers on vascular responses [255]—this could be a useful future experimental avenue.

4.2. Systemic Applications of Capsaicin

In the recent relevant literature, the tissue-specific and systemic side effects of capsaicin have been rigorously studied. Despite its lipophilicity, local capsaicin administration does not result in any systemic bioavailability, a fact correlating with its poor aqueous solubility properties [256]. Here, it must be remarked again that systemic capsaicin administration correlates with a number of dose-dependent side effects [257]. Since most of these effects are usually GIT-related, they can now be mostly obviated by employing liposomal carriers, which release capsaicin directly into the blood flow [258,259]. In Table 3, based on selected scientific publications, the most notable systemic effects of capsaicin are presented.

In addition to all the aforementioned, in a recent experimental study, it was shown that capsaicin inhibits a series of proteins associated with the Warburg effect in sepsis and also downregulates cyclo-oxygenase 2 (COX-2) in a TRPV-1-independent manner [277]. This is important for a number of reasons; to start with, the Warburg effect, originally proposed in the 1920s [278,279], is essential for the metabolism of cancer cells [280], and its inhibition might provide an avenue for novel therapeutic strategies [268,281,282]. Secondly, the inhibition of COX-2, which is already the target of a number of drugs (e.g., [283,284,285]), means that capsaicin can be used in conjunction with them to enhance their effect. Finally, in the presence of TRPV-1 agonists other than capsaicin (e.g., [286,287,288]) or antagonists (e.g., [289,290,291,292]), this approach will, theoretically, still be functional.

4.3. Capsaicin as an Anti-Cancer Agent

The anticarcinogenic effect of capsaicin is mainly associated with the activation of TRPV1, which can be considered a probable link between inflammatory, immune and carcinogenic processes, as seen in Table 4.

There are several events in the anti-cancer trajectory of capsaicin that were documented: antimutagenic activity, anti-oxidative action, anti-inflammatory action, cell cycle regulation and clear involvement in cancer cell death [328]. Out of all the mentioned molecular events associated with capsaicin’s anti-cancer action, the induction of cancer cell death is the most important, as capsaicin acts on multiple targets. As outlined in Figure 2, besides TRPV1, another member of the TRPV family involved in the anti-cancer action of capsaicin is TRPV6. Comparable to TRPV1, TRPV6 regulates calcium homeostasis. In in vitro studies, it was shown that capsaicin increases TRPV6 expression and increased levels of intracellular calcium ions that activate the calpain pathway for apoptosis [329]. Moreover, TRPV6 overexpression increased mitochondria permeability through the activation of Bax and p53 through C-jun N-terminal kinase (JNK) activation. Apoptosis can thus be induced by capsaicin in a TRPV1-dependent and independent manner. In the TRPV1 independent pathway, capsaicin activates adenosine 5-monophosphate-activated protein kinase (AMPK), p53 and JNK. When capsaicin binds to the mitochondrial complex I and II in the electron transport chain, the mitochondrial membrane potential is disrupted, and the membrane permeability is increased. Capsaicin increases ROS levels and increases the expression of pro-apoptotic Bcl-2 (Bax), as it was found in the case of neuroendocrine melanoma, a very aggressive and fatal tumour by Jun et al. [294,330,331]. This decreases the anti-apoptotic Bcl-2 and CytC release and induces apoptosis [317].

Figure 2 Apoptotic network triggered by capsaicin via TRPV 1 and TRPV6. (Figure not reproduced here; see the original article.)

Some other anticarcinogenic applications of capsaicin should be mentioned here. It is possible to use capsaicin as a radio-sensitising agent in patients with prostate cancer; this particular use takes advantage of capsaicin-induced inhibition of NFκB signalling [332], resulting in angiogenesis inhibition [333]. More generally, recent studies explore the potential of combining capsaicin with conventional chemotherapeutic agents [334,335,336,337]. Other carcinogenesis-related signalling pathways may represent potential targets for future studies [338].

Another aspect we should consider is the increase of serum somatostatin induced by systemic capsaicin administration, which has already been noted by Thán et al. [260] and Szolcsányi et al. [339]. The release of somatostatin is associated with anti-inflammatory [340] and anti-nociceptive effects [341] in rats. The research of [342] has also focused on the somatostatin-induced inhibition of inflammation and nociception.

It is known that somatostatin is linked with such effects in humans [342,343], and somatostatin and its analogues have already been explored as targets for anti-cancer therapies [344,345,346,347,348,349,350,351,352,353]. The use of capsaicin in such a manner appears to be a promising avenue in cancer therapy research—a particular application could be in the case of hepatocellular cell carcinoma (HCC) where somatostatin and capsaicin application could be, in theory, effectively combined—the application of capsaicin in the pathogenesis of HCC specifically is explored by Scheau et al. [124].

The anticarcinogenic activity of capsaicin has also been a subject of in vivo studies, where chronic exposure to capsaicin seems to actually promote neoplasia by increasing collagen and elastin deposition [354] and by inhibiting NK cell function [355]. Capsaicin also exhibits a carcinogenic potential when combined with 9, 10-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate [356]. Finally, long-term capsaicin consumption favours metastasis because it modifies the microbiome of the gut, thus promoting the translocation of bacteria to the liver and altering bile acid metabolism, which ultimately inhibits NK cell function [357]; therefore, it must be examined in detail if and under which circumstances, the use of capsaicin may actually have detrimental effects in human health.

5. Capsaicin in Traditional Medicine Therapies

Originally, the capsaicin-containing plants of the genus Capsicum were native to Central and South America [358,359]. However, after the discovery of the Americas in the 16th century, it was quickly exported, as already mentioned, and gradually became a staple of many different culinary traditions [360].

While this genus comprises about 25 species, only five of them have been domesticated [361,362,363] and are commonly cultivated [364]; although the species is typically a perennial plant, it can be cultivated as an annual crop in areas with low temperatures [365,366]. Chile peppers, along with a number of other parts, were integral in the Mesoamerican civilisation’s agriculture [367] and even later in the formation of traditional Mexican cuisine [368]—the same has happened in a number of other localities, such as Pueblo in Colorado [369].

The traditional medical and even culinary usage of chilli peppers, and therefore capsaicin, is quite diverse [370]. While the domestication of the plant is estimated to have taken place somewhen before the 5th millennium BC [366], it may be assumed that they were also consumed sometime before [371] since the agriculture of many pre-colonial communities was pretty advanced ([372]; and references therein); the domestication process seems to have begun independently in a number of different areas [358]. Its significance is readily apparent from archaeological finds of the pre-Ceramic (ca. 9500–900 BC) and Formative (900 BC–250 AD) periods in South America [373,374] (time frames based on Lanning [375]). The millennia of chilli consumption must have given rise to a number of medicinal applications. In addition, a number of different civilisations that occupied pre-Columbian America, such as the Incas [376], Mayas [377], and Aztecs [378], used chilli peppers as war-related artefacts and for ritualistic purposes [6]. While these last two uses of chilli may be seen as atypical, on the one hand, it must be remarked that the absence of a monetary economy led to natural goods and materials having a more prominent role, a typical example being that of obsidian and other rocks and minerals [379,380]; on the other, a significant number of civilisations have used plants in ritualistic purposes [381,382,383].

It is known that capsaicin content differs between different Capsicum species [384]. Different foodstuffs also have, as expected, differing capsaicin contents [385], and this presumably influences their various uses to some extent. In fact, it is even possible to conceive the use of chilli peppers as a food-medicine continuum in the minds of the locals [386,387]. Perhaps the most diverse uses are recorded in Mexico, where chile is native, as is seen in Table 5; interestingly, the increased capsaicin consumption in parts of Mexico seems to correlate positively with adiposity and fat markers [388]. The complete spectrum of the local ethnobotanical use of chilli peppers is provided in a recent study [387]; various uses of different parts of the chilli plants are provided by Meghvansi et al. [389]. Miscellaneous or unverified uses of peppers, and thus capsaicin, also exist, such as those reported by Saleh et al. [390].

In addition, chilli is used along with other herbs and plants for a number of diseases or ailments related to the metaphysical concept of soul and evil energy [397,403,406,409,410,411]. It is possible that a number of medical applications of chilli peppers in traditional medical practice, especially for Native Americans, have been lost to time or have not yet been discovered. It must not be forgotten that Inca medicine, for example, was relatively advanced and possibly superior to contemporary European practises in some fields like surgery [412,413], as evidenced by a variety of findings and mentions in Spanish chronicles [414]. It is, therefore, entirely possible that a number of useful and effective applications of chilli extracts, as well as those of other plants, existed. In order to elucidate the full extent of the intertwining of food, medicine and culture in a local and traditional context, further research and novel practices are required [415,416].

On another note, we would like to point out that, as presented in the tables of the previous sections, based on previous research [63,64,65], capsaicin cream was applied to acupuncture point P6 or K-D2, which is the Korean equivalent, and also in LI4 [197] and ST36 [194]. Most, if not all, of the effects in these cases, are associated with some form of inhibition of the synthesis, transport and/or action of substance P; indeed, substance P is integral in the modern interpretation of the action of acupuncture in many pain states [417]. Traditional Chinese Medicine (TCM) is one of the most widely used traditional medicine systems in the world, and although it does not incorporate capsaicin-containing plants in its original, ancient phytochemical tradition [418,419], it is interesting to note this, apparently, as of yet, successful combination with capsaicin.

6. Side Effects of Capsaicin

Extensive research has revealed a variety of physiological and pathological effects of capsaicin (Table 6); most but not all of capsaicin’s side effects are exerted by the activation of TRPV1. When applied locally, at the level of the skin or other external mucous membranes, it will induce skin erythema, neurogenic inflammation [420], non-blistering associated burning [421], marked lacrimation, blepharospasm and even conjunctivitis [422]. It must be noted here that a specific form of contact dermatitis, the so-called “Hunan hand” was first diagnosed in individuals who handled peppers daily due to their occupation. This is considered a clear and reliable marker of dermal capsaicin toxicity [423,424].

At the level of the CNS, capsaicin toxicity is associated with convulsions, excitement [425,426], disorientation and fear [427]; a host of other generalised symptoms, such as loss of body motor control, including diminished hand-eye coordination, have been reported [427].

In the cardiovascular system, capsaicin causes blood pressure increase and heart rate increase, and, in highly toxic levels, these effects may progress respectively to hypertension and tachycardia, with even ventricular fibrillation having been reported [427]. The blood pressure increase is associated both with the heart rate elevation and with the increased vascular contractility [428], leading to vasoconstriction. A summary of all the hypotheses and determined effects and side effects of capsaicin in the cardiovascular system in different modes of application has been provided in recent research [111]. Particular features of the cardiovascular system might predispose to or aggravate these responses [429,430,431,432].

At the level of the respiratory system, it causes bronchoconstriction and coughing [433], while in increased doses, it may even cause oedema of the larynx and the lungs, chemical pneumonitis and even respiratory arrest [434]; these data for capsaicin toxicity are derived from in vitro experiments with capsaicin analogues [434]. Systemic capsaicin toxicity has also been associated with pulmonary oedema and hyperventilation. A particular mechanism of neurogenic toxicity may be beneficial in controlling the neurogenic inflammation associated with nasal polyps, at least in some cases [182].

At the level of the gastrointestinal tract, an increased dose of capsaicin causes a general irritation, ranging from a local warmth sensation to a painful burning sensation [435]. It is also known that capsaicin influences gastric activity [436]. Despite capsaicin having some gastroprotective effects, it also has the potential to induce ulcers [275,437].

From a medical standpoint, in cases of capsaicin overexposure, common adverse effects are painful skin reactions and systemic effects, like nausea, vomiting, abdominal pain and diarrhoea accompanied by a burning sensation [438]; capsaicin is toxic in far lower doses in children compared to adults. In the case of eye exposure, following contact with pepper sprays, marked lacrimation, pain, conjunctivitis, and blepharospasm are common and may be aggravated by the presence of risk factors [439,440]. For local toxic reactions, a thorough decontamination of the skin and mucous membranes is recommended [441], involving water and antiacids [442]; furthermore, the treatment of systemic toxicity is based on the management of symptoms until capsaicin excretion [443].

Finally, a few fringe cases of capsaicin toxicity are reported in the medical literature, namely an acute polyneuropathy, presenting as Guillain-Barre syndrome following pepper spray exposure [444], the death of an infant after a capsaicin-containing traditional medicine was orally administered [445], and an acute MI in a patient with a transdermal capsaicin patch [446].

7. Discussion and Future Research Perspectives

Currently, as a phytomedical compound, capsaicin has been demonstrated to have analgesic, antioxidant, anti-inflammatory, anti-cancer, cardio-protective, and metabolic modulation effects. Capsaicin analogues are also currently evaluated for such properties [447]. A recent study even documented capsaicin-induced inhibition of cell senescence [448], while another proposed that capsaicin may even be a viable management option in cases of schizophrenia [449]; regarding the cardio-protective effects of capsaicin, it might even be possible to use it to alleviate acute myocardial injury [450]. Considering that the majority of such mechanisms are caused by the activation and subsequent inactivation of the TRPV1 receptor, further studies of the role of this receptor may yield useful results regarding both diagnostic and treatment methods. Notably, TRPV1 belongs to a category of receptors recently characterised as extra-oral taste receptors, i.e., oral receptors not found in the oral cavity [451,452]. Outside of the oral cavity, these receptors appear to have immune system-related and bronchorelaxation-associated properties [453,454]; it is known that taste receptors and their associated effector biomolecules are expressed in tuft-1 cells [455,456,457,458]. The characteristic morphology of these cells has been described in detail by Hendel et al. [459]; their localisation is quite diverse [455,460,461]. Moreover, it seems that they are also involved in the regulation of the immune system [462].

A significant challenge of using capsaicin for its potent therapeutic properties is its poor bioavailability due to its quick metabolisation [463]. It is believed that in vivo capsaicin concentrations achieved through conventional routes of administration are inferior to the levels that demonstrated effectiveness in vitro [464]. This is due to variations and limitations in absorption, distribution, and excretion, which limit the permeation of capsaicin to the desired action site. Therefore, in vivo, replication of the effects observed in vitro is an increasing focus of interest, and effective methods are being researched in this regard [465,466,467]. Furthermore, systemic capsaicin administration is associated with a number of side effects, and so in order to produce the maximum possible therapeutic effect in the target tissue while, at the same time, minimising side effects, it is desirable to control its delivery with precision. This can be performed, as previously alluded to, by employing novel delivery systems, namely liposomes, micelles, micro-emulsions and nano-emulsions [468,469], colloidal capsules and solid nanoparticles [470]; another avenue concerning implant-associated infections [471] would be the integration of capsaicin into 3D printed biomaterials [472]. These improve oral bioavailability for targeted applications, including anti-cancer endeavours [473,474]. Combination of capsaicin with bioenhancing substances such as piperine can prevent its degradation and increase its systemic concentration [475,476]. A number of nanostructured lipid carriers can also be incorporated into transdermal patches to reduce local side effects, such as skin irritation and erythema [477]—the use of capsaicin in the management and treatment of skin pathologies is a promising and rapidly developing field [118]. A future perspective on increasing capsaicin concentration for anti-cancer effects is also its integration into a delivery system that responds to physiologic triggers such as temperature or local pH, therefore optimising its clinical use and expanding its potential as an anti-cancer therapeutic agent [156,478,479]. Capsaicin, as well as other phytochemicals with promising medicinal properties [480], may benefit from such novel delivery methods. A novel way for capsaicin delivery for a particular case of colorectal cancer has recently been explored by Rajput et al. [481].

In cases of inflammation, either local or systemic, capsaicin may offer a good alternative if the common anti-inflammatory drugs are not tolerated due to their side effects. The combination of capsaicin with acupuncture may also be useful in that regard, given that acupuncture is already quite effective in the treatment of pain (e.g., [482,483,484,485]) and other inflammatory states (e.g., [486,487,488]), and the relevant research interest is increasing [489].

Of particular interest is the emerging research on the antibacterial (e.g., [490,491,492]), antifungal (e.g., [493,494]), antiviral (e.g., [495]) and antiparasitic (e.g., [496]) properties of capsaicin. Already, a number of different phytomedical compounds and their derivatives are being researched for their antimicrobial/antiviral potential, such as kaempferol [497,498,499,500], quercetin [501,502,503], curcumin [504,505,506,507], coumarin [508,509,510], and allicin [511,512,513]. This is especially important when considering the increasing antimicrobial resistance (e.g., [514,515,516,517,518,519,520]) and the occasional severe side-effects like allergies to antimicrobial drugs (e.g., antibiotics [521,522]) and especially some antiparasitic drugs ([523] and references therein).

Furthermore, other research directions could involve capsaicin’s role in modulating intestinal microbiota, of whose diversity it increases; this opens new possibilities in combating the complications of various GIT-related illnesses [524,525] through the modulation of the gut-brain axis and immune system interaction [526]. Potential applications of capsaicin in pulmonary and gastrointestinal cancers have also been concisely summarised in recent papers [527,528]. An interesting research direction could also involve the application of capsaicin at acupuncture points, aside from the aforementioned combination of capsaicin and acupuncture; indeed, based on the positive results of three clinical trials [63,64,65] where capsaicin was applied locally at acupuncture points, larger-scale research for a number of conditions can be undertaken, following the same principle—similar positive research results were also reported by Kim et al. [194,197]. When considering the proposed special properties of meridians in interstitial fluid—or generally fluid—circulation [529,530,531,532], it is compelling to consider the potential for applying specialised cutaneous treatment schemes, using capsaicin or even other bioactive compounds, in this manner.

8. Conclusions

Capsaicin is a potent phytochemical substance that has numerous health benefits. It can be used medicinally both in systemic and local administration. At the same time, the potential toxicity of capsaicin poses an important constraint on its medicinal use, especially in certain sensitive tissues such as the eyes. Already, capsaicin forms part of a number of medical traditions, and such proposed medicinal uses warrant further research. The association between capsaicin and acupuncture must also be explored more thoroughly. Based on the data presented in this paper, we conclude that capsaicin may be used as a monotherapy or adjunct therapy in the treatment or management of a number of pathologies.

Author Contributions

Conceptualization, E.M.P. and A.P.; methodology, C.C. (Constantin Caruntu) and C.S.; formal analysis, L.T., A.-T.P., A.-E.S., I.A.B., A.C., I.S.-F., D.C., C.C. (Carolina Constantin), and C.S.; investigation, E.M.P. and A.P.; resources, E.M.P., A.P., C.C. (Carolina Constantin), and M.N.; data curation, I.A.B., K.P., A.C., I.S.-F., D.C., C.C. (Carolina Constantin), M.N., C.C. (Constantin Caruntu), and C.S.; writing—original draft preparation, E.M.P., A.P., L.T., A.-T.P., A.-E.S., I.A.B., K.P., A.C., I.S.-F., R.-M.S., D.C., C.C. (Carolina Constantin), M.N., C.C. (Constantin Caruntu), and C.S.; writing—review and editing, D.C., C.C. (Constantin Caruntu), and C.S.; visualisation, C.C. (Carolina Constantin) and M.N.; supervision, C.C. (Constantin Caruntu) and C.S. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Funding Statement

This work was partially supported by a grant from the Ministry of Research, Innovation, and Digitization, CCCDI—UEFISCDI, project number PN-III-P2-2.1-PED-2021-2243, within PNCDI III.

Footnotes

References

Associated Data

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

References

1. Cordell G.A., Araujo O.E. Capsaicin: Identification, nomenclature, and pharmacotherapy. Ann. Pharmacother. 1993;27:330–336. doi: 10.1177/106002809302700316.
2. Srinivasan K. Biological Activities of Red Pepper (Capsicum annuum) and Its Pungent Principle Capsaicin: A Review. Crit. Rev. Food Sci. Nutr. 2016;56:1488–1500. doi: 10.1080/10408398.2013.772090.
3. Naves E.R., de Ávila Silva L., Sulpice R., Araújo W.L., Nunes-Nesi A., Peres L.E.P., Zsögön A. Capsaicinoids: Pungency beyond Capsicum. Trends Plant Sci. 2019;24:109–120. doi: 10.1016/j.tplants.2018.11.001.
4. Chen K., Feng L., Feng S., Yan Y., Ge Z., Li Z., Chen Z. Multiple quantitative structure-pungency correlations of capsaicinoids. Food Chem. 2019;283:611–620. doi: 10.1016/j.foodchem.2019.01.078.
5. Mózsik G., Past T., Abdel Salam O.M., Kuzma M., Perjési P. Interdisciplinary review for correlation between the plant origin capsaicinoids, non-steroidal antiinflammatory drugs, gastrointestinal mucosal damage and prevention in animals and human beings. Inflammopharmacology. 2009;17:113–150. doi: 10.1007/s10787-009-0002-3.
6. Chiou K.L., Hastorf C.A., Bonavia D., Dillehay T.D. Documenting Cultural Selection Pressure Changes on Chile Pepper (Capsicum baccatum L.) Seed Size Through Time in Coastal Peru (7,600 B.P.–Present) Econ. Bot. 2014;68:190–202. doi: 10.1007/s12231-014-9270-y.
7. Nunn N., Qian N. The Columbian exchange: A history of disease, food, and ideas. J. Econ. Perspect. 2010;24:163–188. doi: 10.1257/jep.24.2.163.
8. Cumo C. The Ongoing Columbian Exchange: Stories of Biological and Economic Transfer in World History: Stories of Biological and Economic Transfer in World History. ABC-CLIO; New York, NY, USA: 2015.
9. Williams D.E. Routledge Handbook of Agricultural Biodiversity. Routledge; Oxfordshire, UK: 2017. Agricultural Biodiversity and the Columbian Exchange; pp. 192–212.
10. Herniter I.A., Muñoz-Amatriaín M., Close T.J. Genetic, textual, and archeological evidence of the historical global spread of cowpea (Vigna unguiculata [L.] Walp.) Legume Sci. 2020;2:e57. doi: 10.1002/leg3.57.
11. Basith S., Cui M., Hong S., Choi S. Harnessing the Therapeutic Potential of Capsaicin and Its Analogues in Pain and Other Diseases. Molecules. 2016;21:966. doi: 10.3390/molecules21080966.
12. Tewksbury J.J., Manchego C., Haak D.C., Levey D.J. Where did the chili get its spice? Biogeography of capsaicinoid production in ancestral wild chili species. J. Chem. Ecol. 2006;32:547–564. doi: 10.1007/s10886-005-9017-4.
13. Haak D.C., McGinnis L.A., Levey D.J., Tewksbury J.J. Why are not all chilies hot? A trade-off limits pungency. Proc. Biol. Sci. 2012;279:2012–2017. doi: 10.1098/rspb.2011.2091.
14. Bucholz C. Chemische Untersuchung der trockenen reifen spanischen Pfeffers. Alm. Oder Taschenb. Scheidekünstler Apoth. 1816;37:1–30.
15. King J., Felter H.W. King’s American Dispensatory. Volume 1 Ohio Valley Company; Cincinnati, OH, USA: 1909.
16. Thresh J.C. Isolation of capsaicin. Pharm. J. Trans. 1876;6:941–947.
17. Thresh J.C. Capsaicin, the active principle of capsicum fruits. Pharm. J. Trans. 1876;7:259–260.
18. Thresh J.C. Capsaicin—The active principle of cayenne pepper. Analyst. 1877;2:108. doi: 10.1039/AN8770200108.
19. Nelson E. The constitution of capsaicin, the pungent principle of capsicum. J. Am. Chem. Soc. 1919;41:1115–1121. doi: 10.1021/ja02228a011.
20. Micko K. Zur Kenntniss des Capsaïcins. Z. Unters. Nahr.-Und Genußmittel Sowie Gebrauchsgegenstände. 1898;1:818–829. doi: 10.1007/BF02529190.
21. Micko K. Ueber den wirksamen Bestandtheil des Cayennepfeffers. Z. Unters. Nahr.-Und Genußmittel Sowie Gebrauchsgegenstände. 1899;2:411–412. doi: 10.1007/BF02529197.
22. Kosuge S., Furuta M., Oda T. Studies on the Pungent Principles of Red Pepper. Part XIII On the pungent principles contents of Japanese red pepper. Nippon. Shokuhin Kogyo Gakkaishi. 1967;14:407–410. doi: 10.3136/nskkk1962.14.407.
23. Gradinaru T.C., Petran M., Dragos D., Gilca M. PlantMolecularTasteDB: A Database of Taste Active Phytochemicals. Front. Pharmacol. 2021;12:751712. doi: 10.3389/fphar.2021.751712.
24. Wachtel R.E. Capsaicin. Reg. Anesth. Pain. Med. 1999;24:361–363. doi: 10.1097/00115550-199924040-00015.
25. Alberti A., Galasso V., Kovac B., Modelli A., Pichierri F. Probing the molecular and electronic structure of capsaicin: A spectroscopic and quantum mechanical study. J. Phys. Chem. A. 2008;112:5700–5711. doi: 10.1021/jp801890g.
26. Reyes-Escogido Mde L., Gonzalez-Mondragon E.G., Vazquez-Tzompantzi E. Chemical and pharmacological aspects of capsaicin. Molecules. 2011;16:1253–1270. doi: 10.3390/molecules16021253.
27. Lu M., Chen C., Lan Y., Xiao J., Li R., Huang J., Huang Q., Cao Y., Ho C.T. Capsaicin-the major bioactive ingredient of chili peppers: Bio-efficacy and delivery systems. Food Funct. 2020;11:2848–2860. doi: 10.1039/D0FO00351D.
28. Sung Y., Chang Y.-Y., Ni-Lun T. Capsaicin biosynthesis in water-stressed hot pepper fruits. Bot. Bull. Acad. Sin. 2005;46:35–42.
29. Arora R., Gill N., Chauhan G., Rana A. An overview about versatile molecule capsaicin. Int. J. Pharm. Sci. Drug Res. 2011;3:280–286.
30. Katsuragi H., Shimoda K., Yamamoto R., Ohara T., Hamada H. Enzymatic synthesis of capsaicin 4-O-β-xylooligosaccharides by β-xylosidase from Aspergillus sp. Acta Biol. Hung. 2011;62:151–155. doi: 10.1556/ABiol.62.2011.2.5.
31. Späth E., Darling S.F. Synthese des capsaicins. Berichte Dtsch. Chem. Ges. (A B Ser.) 1930;63:737–743. doi: 10.1002/cber.19300630331.
32. Ochoa-Alejo N., Ramirez-Malagon R. In vitro chili pepper biotechnology. Vitr. Cell. Dev. Biol.-Plant. 2001;37:701–729. doi: 10.1007/s11627-001-0121-z.
33. Castillo E., López-González I., De Regil-Hernández R., Reyes-Duarte D., Sánchez-Herrera D., López-Munguía A., Darszon A. Enzymatic synthesis of capsaicin analogs and their effect on the T-type Ca2+ channels. Biochem. Biophys. Res. Commun. 2007;356:424–430. doi: 10.1016/j.bbrc.2007.02.144.
34. Pandhair V., Gosal S. Capsaicin production in cell suspension cultures derived from placenta of Capsicum annuum L. fruit. Indian J. Agric. Biochem. 2009;22:78–82.
35. Akhtar F., Muhammad Sharif H., Arshad Mallick M., Zahoor F., Abdulmalik A., Baig W., Shujaat N., Gul S., Bibi G., Ramzan R., et al. Capsaicin: Its Biological Activities and In Silico Target Fishing. Acta Pol. Pharm. 2017;74:321–329.
36. Moirangthem S.S., Gogoi S., Thongbam P.D., Ramya K.T., Fiyaz R.A., Pandey D.S. Effect of sowing time and crop geometry on the Capsaicinoid content in Bhoot Jolokia (Capsicum chinense Jacq.) J. Food Sci. Technol. 2014;51:1974–1981. doi: 10.1007/s13197-012-0684-1.
37. Maurya V.K., Gothandam K.M., Ranjan V., Shakya A., Pareek S. Effect of drying methods (microwave vacuum, freeze, hot air and sun drying) on physical, chemical and nutritional attributes of five pepper (Capsicum annuum var. annuum) cultivars. J. Sci. Food Agric. 2018;98:3492–3500. doi: 10.1002/jsfa.8868.
38. Krishnatreyya H., Hazarika H., Saha A., Chattopadhyay P. Capsaicin, the primary constituent of pepper sprays and its pharmacological effects on mammalian ocular tissues. Eur. J. Pharmacol. 2018;819:114–121. doi: 10.1016/j.ejphar.2017.11.042.
39. Busker R.W., van Helden H.P. Toxicologic evaluation of pepper spray as a possible weapon for the Dutch police force: Risk assessment and efficacy. Am. J. Forensic Med. Pathol. 1998;19:309–316. doi: 10.1097/00000433-199812000-00003.
40. Kim Y.J., Payal A.R., Daly M.K. Effects of tear gases on the eye. Surv. Ophthalmol. 2016;61:434–442. doi: 10.1016/j.survophthal.2016.01.002.
41. Tidwell R.D., Wills B.K. StatPearls. StatPearls Publishing LLC.; Treasure Island, FL, USA: 2023. Tear Gas and Pepper Spray Toxicity.
42. Quiroga-Garza M.E., Ruiz-Lozano R.E., Azar N.S., Mousa H.M., Komai S., Sevilla-Llorca J.L., Perez V.L. Noxious effects of riot control agents on the ocular surface: Pathogenic mechanisms and management. Front. Toxicol. 2023;5:1118731. doi: 10.3389/ftox.2023.1118731.
43. Cowles R.S., Keller J.E., Miller J.R. Pungent spices, ground red pepper, and synthetic capsaicin as onion fly ovipositional deterrents. J. Chem. Ecol. 1989;15:719–730. doi: 10.1007/BF01014714.
44. Sterner R.T., Shumake S.A., Gaddis S.E., Bourassa J.B. Capsicum oleoresin: Development of an in-soil repellent for pocket gophers. Pest. Manag. Sci. 2005;61:1202–1208. doi: 10.1002/ps.1118.
45. Kimball B.A., Taylor J., Perry K.R., Capelli C. Deer responses to repellent stimuli. J. Chem. Ecol. 2009;35:1461–1470. doi: 10.1007/s10886-009-9721-6.
46. Stock B., Haag-Wackernagel D. Effectiveness of Gel Repellents on Feral Pigeons. Animals. 2013;4:1–15. doi: 10.3390/ani4010001.
47. Yang N., Galves C., Racioni Goncalves A.C., Chen J., Fisk I. Impact of capsaicin on aroma release: In vitro and in vivo analysis. Food Res. Int. 2020;133:109197. doi: 10.1016/j.foodres.2020.109197.
48. Hu X., Ayed C., Chen J., Fisk I., Yang N. The role of capsaicin stimulation on the physicochemical properties of saliva and aroma release in model aqueous and oil systems. Food Chem. 2022;386:132824. doi: 10.1016/j.foodchem.2022.132824.
49. Yang N., Yang Q., Chen J., Fisk I. Impact of capsaicin on aroma release and perception from flavoured solutions. LWT. 2021;138:110613. doi: 10.1016/j.lwt.2020.110613.
50. Maliszewska J., Wyszkowska J., Kletkiewicz H., Rogalska J. Capsaicin-induced dysregulation of acid-base status in the American cockroach. J. Environ. Sci. Health B. 2019;54:676–680. doi: 10.1080/03601234.2019.1632642.
51. Li Y., Bai P., Wei L., Kang R., Chen L., Zhang M., Tan E.K., Liu W. Capsaicin Functions as Drosophila Ovipositional Repellent and Causes Intestinal Dysplasia. Sci. Rep. 2020;10:9963. doi: 10.1038/s41598-020-66900-2.
52. Xie D., Yang Z., Hu X., Wen Y. Synthesis, Antibacterial and Insecticidal Activities of Novel Capsaicin Derivatives Containing a Sulfonic Acid Esters Moiety. Front. Chem. 2022;10:929050. doi: 10.3389/fchem.2022.929050.
53. Cui S.-F., Wang J.-W., Li H.-F., Fang R., Yu X., Lu Y.-J. Microencapsulation of Capsaicin in Chitosan Microcapsules: Characterization, Release Behavior, and Pesticidal Properties against Tribolium castaneum (Herbst) Insects. 2023;14:27. doi: 10.3390/insects14010027.
54. Hsu Y.J., Huang W.C., Chiu C.C., Liu Y.L., Chiu W.C., Chiu C.H., Chiu Y.S., Huang C.C. Capsaicin Supplementation Reduces Physical Fatigue and Improves Exercise Performance in Mice. Nutrients. 2016;8:648. doi: 10.3390/nu8100648.
55. Adaszek Ł., Gadomska D., Mazurek Ł., Łyp P., Madany J., Winiarczyk S. Properties of capsaicin and its utility in veterinary and human medicine. Res. Vet. Sci. 2019;123:14–19. doi: 10.1016/j.rvsc.2018.12.002.
56. Mohammad S., Mustofa Helmi E., Faisal F., Muhammad Thohawi Elziyad P. Role of Capsaicin in the Repair of Cellular Activity in Mice Liver. Pharmacogn. J. 2021;13:1573–1576.
57. Watson P.N.C., Evans R.J. The postmastectomy pain syndrome and topical capsaicin: A randomized trial. Pain. 1992;51:375–379. doi: 10.1016/0304-3959(92)90223-X.
58. McCleane G. The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in painful osteoarthritis: A randomized, double blind, placebo controlled study. Eur. J. Pain. 2000;4:355–360. doi: 10.1053/eujp.2000.0200.
59. Grushka M., Epstein J.B., Gorsky M. Burning mouth syndrome. Am. Fam. Physician. 2002;65:615–620.
60. Mason L., Moore R.A., Derry S., Edwards J.E., McQuay H.J. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328:991. doi: 10.1136/bmj.38042.506748.EE.
61. Saguil A., Kane S., Mercado M., Lauters R. Herpes Zoster and Postherpetic Neuralgia: Prevention and Management. Am. Fam. Physician. 2017;96:656–663.
62. Hayman M., Kam P.C.A. Capsaicin: A review of its pharmacology and clinical applications. Curr. Anaesth. Crit. Care. 2008;19:338–343. doi: 10.1016/j.cacc.2008.07.003.
63. Agarwal A., Dhiraaj S., Tandon M., Singh P.K., Singh U., Pawar S. Evaluation of capsaicin ointment at the Korean hand acupressure point K-D2 for prevention of postoperative nausea and vomiting. Anaesthesia. 2005;60:1185–1188. doi: 10.1111/j.1365-2044.2005.04402.x.
64. Kim K.S., Koo M.S., Jeon J.W., Park H.S., Seung I.S. Capsicum plaster at the korean hand acupuncture point reduces postoperative nausea and vomiting after abdominal hysterectomy. Anesth. Analg. 2002;95:1103–1107. doi: 10.1213/00000539-200210000-00059.
65. Misra M.N., Pullani A.J., Mohamed Z.U. Prevention of PONV by acustimulation with capsicum plaster is comparable to ondansetron after middle ear surgery. Can. J. Anaesth. 2005;52:485–489. doi: 10.1007/BF03016527.
66. Park H.S., Kim K.S., Min H.K., Kim D.W. Prevention of postoperative sore throat using capsicum plaster applied at the Korean hand acupuncture point. Anaesthesia. 2004;59:647–651. doi: 10.1111/j.1365-2044.2004.03739.x.
67. Breneman D.L., Cardone J.S., Blumsack R.F., Lather R.M., Searle E.A., Pollack V.E. Topical capsaicin for treatment of hemodialysis-related pruritus. J. Am. Acad. Dermatol. 1992;26:91–94. doi: 10.1016/0190-9622(92)70013-6.
68. Tarng D.C., Cho Y.L., Liu H.N., Huang T.P. Hemodialysis-related pruritus: A double-blind, placebo-controlled, crossover study of capsaicin 0.025% cream. Nephron. 1996;72:617–622. doi: 10.1159/000188949.
69. Lysy J., Sistiery-Ittah M., Israelit Y., Shmueli A., Strauss-Liviatan N., Mindrul V., Keret D., Goldin E. Topical capsaicin--a novel and effective treatment for idiopathic intractable pruritus ani: A randomised, placebo controlled, crossover study. Gut. 2003;52:1323–1326. doi: 10.1136/gut.52.9.1323.
70. Makhlough A., Ala S., Haj-Heydari Z., Kashi Z., Bari A. Topical capsaicin therapy for uremic pruritus in patients on hemodialysis. Iran. J. Kidney Dis. 2010;4:137–140.
71. Gooding S.M., Canter P.H., Coelho H.F., Boddy K., Ernst E. Systematic review of topical capsaicin in the treatment of pruritus. Int. J. Dermatol. 2010;49:858–865. doi: 10.1111/j.1365-4632.2010.04537.x.
72. Cruz F. Mechanisms involved in new therapies for overactive bladder. Urology. 2004;63:65–73. doi: 10.1016/j.urology.2003.11.001.
73. de Sèze M., Wiart L., de Sèze M.P., Soyeur L., Dosque J.P., Blajezewski S., Moore N., Brochet B., Mazaux J.M., Barat M., et al. Intravesical capsaicin versus resiniferatoxin for the treatment of detrusor hyperreflexia in spinal cord injured patients: A double-blind, randomized, controlled study. J. Urol. 2004;171:251–255. doi: 10.1097/01.ju.0000100385.93801.d4.
74. Botonis P.G., Miliotis P.G., Kounalakis S.N., Koskolou M.D., Geladas N.D. Effects of capsaicin application on the skin during resting exposure to temperate and warm conditions. Scand. J. Med. Sci. Sports. 2019;29:171–179. doi: 10.1111/sms.13317.
75. Rothenberger J., Wittwer M., Tschumi C., Constantinescu M.A., Daigeler A., Olariu R. Quantitative impact analysis of remote ischemic conditioning and capsaicin application on human skin microcirculation. Clin. Hemorheol. Microcirc. 2019;71:291–298. doi: 10.3233/CH-180373.
76. Kawada T., Suzuki T., Takahashi M., Iwai K. Gastrointestinal absorption and metabolism of capsaicin and dihydrocapsaicin in rats. Toxicol. Appl. Pharmacol. 1984;72:449–456. doi: 10.1016/0041-008X(84)90121-2.
77. Sharma S.K., Vij A.S., Sharma M. Mechanisms and clinical uses of capsaicin. Eur. J. Pharmacol. 2013;720:55–62. doi: 10.1016/j.ejphar.2013.10.053.
78. Reilly C.A., Crouch D.J., Yost G.S., Fatah A.A. Determination of capsaicin, nonivamide, and dihydrocapsaicin in blood and tissue by liquid chromatography-tandem mass spectrometry. J. Anal. Toxicol. 2002;26:313–319. doi: 10.1093/jat/26.6.313.
79. Ilie M.A., Caruntu C., Tampa M., Georgescu S.R., Matei C., Negrei C., Ion R.M., Constantin C., Neagu M., Boda D. Capsaicin: Physicochemical properties, cutaneous reactions and potential applications in painful and inflammatory conditions. Exp. Ther. Med. 2019;18:916–925. doi: 10.3892/etm.2019.7513.
80. Zhang S., Wang D., Huang J., Hu Y., Xu Y. Application of capsaicin as a potential new therapeutic drug in human cancers. J. Clin. Pharm. Ther. 2020;45:16–28. doi: 10.1111/jcpt.13039.
81. Qin L., Wang Y., Gong Y., Chen J., Xu B., Tang L., Guo L., Xie J. Capsaicin metabolites and GSH-associated detoxification and biotransformation pathways in human liver microsomes revealed by LC-HRMS/MS with data-mining tools. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2019;1133:121843. doi: 10.1016/j.jchromb.2019.121843.
82. Chanda S., Bashir M., Babbar S., Koganti A., Bley K. In vitro hepatic and skin metabolism of capsaicin. Drug Metab. Dispos. 2008;36:670–675. doi: 10.1124/dmd.107.019240.
83. Oyagbemi A.A., Saba A.B., Azeez O.I. Capsaicin: A novel chemopreventive molecule and its underlying molecular mechanisms of action. Indian J. Cancer. 2010;47:53–58. doi: 10.4103/0019-509X.58860.
84. Suresh D., Srinivasan K. Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats. Indian J. Med. Res. 2010;131:682–691.
85. Reilly C.A., Yost G.S. Metabolism of capsaicinoids by P450 enzymes: A review of recent findings on reaction mechanisms, bio-activation, and detoxification processes. Drug Metab. Rev. 2006;38:685–706. doi: 10.1080/03602530600959557.
86. van Eijl S., Zhu Z., Cupitt J., Gierula M., Götz C., Fritsche E., Edwards R.J. Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling. PLoS ONE. 2012;7:e41721. doi: 10.1371/journal.pone.0041721.
87. Rollyson W.D., Stover C.A., Brown K.C., Perry H.E., Stevenson C.D., McNees C.A., Ball J.G., Valentovic M.A., Dasgupta P. Bioavailability of capsaicin and its implications for drug delivery. J. Control Release. 2014;196:96–105. doi: 10.1016/j.jconrel.2014.09.027.
88. Babbar S., Marier J.F., Mouksassi M.S., Beliveau M., Vanhove G.F., Chanda S., Bley K. Pharmacokinetic analysis of capsaicin after topical administration of a high-concentration capsaicin patch to patients with peripheral neuropathic pain. Ther. Drug Monit. 2009;31:502–510. doi: 10.1097/FTD.0b013e3181a8b200.
89. Zak A., Siwinska N., Slowikowska M., Borowicz H., Szpot P., Zawadzki M., Niedzwiedz A. The detection of capsaicin and dihydrocapsaicin in horse serum following long-term local administration. BMC Vet. Res. 2018;14:193. doi: 10.1186/s12917-018-1518-9.
90. Tian K., Zhu J., Li M., Qiu X. Capsaicin is efficiently transformed by multiple cytochrome P450s from Capsicum fruit-feeding Helicoverpa armigera. Pestic. Biochem. Physiol. 2019;156:145–151. doi: 10.1016/j.pestbp.2019.02.015.
91. Hanson S.M., Newstead S., Swartz K.J., Sansom M.S.P. Capsaicin interaction with TRPV1 channels in a lipid bilayer: Molecular dynamics simulation. Biophys. J. 2015;108:1425–1434. doi: 10.1016/j.bpj.2015.02.013.
92. Yang F., Zheng J. Understand spiciness: Mechanism of TRPV1 channel activation by capsaicin. Protein Cell. 2017;8:169–177. doi: 10.1007/s13238-016-0353-7.
93. Cheng Y. TRPV1 and Piezo: The 2021 Nobel Prize in Physiology or Medicine. IUCrJ. 2022;9:4–5. doi: 10.1107/S2052252521013488.
94. Earley S., Santana L.F., Lederer W.J. The physiological sensor channels TRP and piezo: Nobel Prize in Physiology or Medicine 2021. Physiol. Rev. 2022;102:1153–1158. doi: 10.1152/physrev.00057.2021.
95. Reeh P.W., Fischer M.J. Nobel somatosensations and pain. Pflügers Arch.-Eur. J. Physiol. 2022;474:405–420. doi: 10.1007/s00424-022-02667-x.
96. Caterina M.J., Schumacher M.A., Tominaga M., Rosen T.A., Levine J.D., Julius D. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature. 1997;389:816–824. doi: 10.1038/39807.
97. Tominaga M., Caterina M.J., Malmberg A.B., Rosen T.A., Gilbert H., Skinner K., Raumann B.E., Basbaum A.I., Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998;21:531–543. doi: 10.1016/S0896-6273(00)80564-4.
98. Caterina M.J., Leffler A., Malmberg A.B., Martin W., Trafton J., Petersen-Zeitz K., Koltzenburg M., Basbaum A., Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000;288:306–313. doi: 10.1126/science.288.5464.306.
99. McKemy D.D., Neuhausser W.M., Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416:52–58. doi: 10.1038/nature719.
100. Peier A.M., Moqrich A., Hergarden A.C., Reeve A.J., Andersson D.A., Story G.M., Earley T.J., Dragoni I., McIntyre P., Bevan S. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108:705–715. doi: 10.1016/S0092-8674(02)00652-9.
101. Coste B., Mathur J., Schmidt M., Earley T.J., Ranade S., Petrus M.J., Dubin A.E., Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science. 2010;330:55–60. doi: 10.1126/science.1193270.
102. Frias B., Merighi A. Capsaicin, Nociception and Pain. Molecules. 2016;21:797. doi: 10.3390/molecules21060797.
103. Aghazadeh Tabrizi M., Baraldi P.G., Baraldi S., Gessi S., Merighi S., Borea P.A. Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists. Med. Res. Rev. 2017;37:936–983. doi: 10.1002/med.21427.
104. Frey E., Karney-Grobe S., Krolak T., Milbrandt J., DiAntonio A. TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca(2+)/PKA Signaling. eNeuro. 2018;5:ENEURO.0095-18.2018. doi: 10.1523/ENEURO.0095-18.2018.
105. Zhou Y., Zhou Z.S., Zhao Z.Q. PKC regulates capsaicin-induced currents of dorsal root ganglion neurons in rats. Neuropharmacology. 2001;41:601–608. doi: 10.1016/S0028-3908(01)00106-X.
106. Lee T.H., Lee J.W., Osaka T., Kobayashi A., Namba Y., Inoue S., Kimura S. Lack of integrative control of body temperature after capsaicin administration. Korean J. Intern. Med. 2000;15:103–108. doi: 10.3904/kjim.2000.15.2.103.
107. Rosenberger D.C., Binzen U., Treede R.-D., Greffrath W. The capsaicin receptor TRPV1 is the first line defense protecting from acute non damaging heat: A translational approach. J. Transl. Med. 2020;18:28. doi: 10.1186/s12967-019-02200-2.
108. Tominaga M., Tominaga T. Structure and function of TRPV1. Pflug. Arch. 2005;451:143–150. doi: 10.1007/s00424-005-1457-8.
109. Hwang M.K., Bode A.M., Byun S., Song N.R., Lee H.J., Lee K.W., Dong Z. Cocarcinogenic effect of capsaicin involves activation of EGFR signaling but not TRPV1. Cancer Res. 2010;70:6859–6869. doi: 10.1158/0008-5472.CAN-09-4393.
110. Zhang C., Ye L., Zhang Q., Wu F., Wang L. The role of TRPV1 channels in atherosclerosis. Channels. 2020;14:141–150. doi: 10.1080/19336950.2020.1747803.
111. Munjuluri S., Wilkerson D.A., Sooch G., Chen X., White F.A., Obukhov A.G. Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation. Cells. 2021;11:18. doi: 10.3390/cells11010018.
112. Hoebart C., Rojas-Galvan N.S., Ciotu C.I., Aykac I., Reissig L.F., Weninger W.J., Kiss A., Podesser B.K., Fischer M.J.M., Heber S. No functional TRPA1 in cardiomyocytes. Acta Physiol. 2021;232:e13659. doi: 10.1111/apha.13659.
113. Yoshie K., Rajendran P.S., Massoud L., Mistry J., Swid M.A., Wu X., Sallam T., Zhang R., Goldhaber J.I., Salavatian S., et al. Cardiac TRPV1 afferent signaling promotes arrhythmogenic ventricular remodeling after myocardial infarction. JCI Insight. 2020;5:e124477. doi: 10.1172/jci.insight.124477.
114. Kim J.H. The Emerging Role of TRPV1 in Airway Inflammation. Allergy Asthma Immunol. Res. 2018;10:187–188. doi: 10.4168/aair.2018.10.3.187.
115. Baxter M., Eltom S., Dekkak B., Yew-Booth L., Dubuis E.D., Maher S.A., Belvisi M.G., Birrell M.A. Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung. Thorax. 2014;69:1080–1089. doi: 10.1136/thoraxjnl-2014-205467.
116. McGarvey L.P., Butler C.A., Stokesberry S., Polley L., McQuaid S., Abdullah H., Ashraf S., McGahon M.K., Curtis T.M., Arron J., et al. Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma. J. Allergy Clin. Immunol. 2014;133:704–712.e4. doi: 10.1016/j.jaci.2013.09.016.
117. Du Q., Liao Q., Chen C., Yang X., Xie R., Xu J. The Role of Transient Receptor Potential Vanilloid 1 in Common Diseases of the Digestive Tract and the Cardiovascular and Respiratory System. Front. Physiol. 2019;10:1064. doi: 10.3389/fphys.2019.01064.
118. Caruntu C., Negrei C., Ilie Ghita M., Caruntu A., Badarau B., ioan Buraga I.B., Boda D., Albu A., Brănişteanu D. Capsaicin, a hot topic in skin pharmacology and physiology. Farmacia. 2015;63:487–491.
119. Inoue K., Koizumi S., Fuziwara S., Denda S., Inoue K., Denda M. Functional vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem. Biophys. Res. Commun. 2002;291:124–129. doi: 10.1006/bbrc.2002.6393.
120. Ständer S., Moormann C., Schumacher M., Buddenkotte J., Artuc M., Shpacovitch V., Brzoska T., Lippert U., Henz B.M., Luger T.A., et al. Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp. Dermatol. 2004;13:129–139. doi: 10.1111/j.0906-6705.2004.0178.x.
121. Yang T.J., Yu Y., Yang J.Y., Li J.J., Zhu J.Y., Vieira J.A.C., Jiang Q. Involvement of transient receptor potential channels in ocular diseases: A narrative review. Ann. Transl. Med. 2022;10:839. doi: 10.21037/atm-21-6145.
122. Sappington R.M., Sidorova T., Long D.J., Calkins D.J. TRPV1: Contribution to retinal ganglion cell apoptosis and increased intracellular Ca2+ with exposure to hydrostatic pressure. Investig. Ophthalmol. Vis. Sci. 2009;50:717–728. doi: 10.1167/iovs.08-2321.
123. Wang F., Xue Y., Fu L., Wang Y., He M., Zhao L., Liao X. Extraction, purification, bioactivity and pharmacological effects of capsaicin: A review. Crit. Rev. Food Sci. Nutr. 2022;62:5322–5348. doi: 10.1080/10408398.2021.1884840.
124. Scheau C., Badarau I.A., Caruntu C., Mihai G.L., Didilescu A.C., Constantin C., Neagu M. Capsaicin: Effects on the Pathogenesis of Hepatocellular Carcinoma. Molecules. 2019;24:2350. doi: 10.3390/molecules24132350.
125. Benítez-Angeles M., Morales-Lázaro S.L., Juárez-González E., Rosenbaum T. TRPV1: Structure, Endogenous Agonists, and Mechanisms. Int. J. Mol. Sci. 2020;21:3421. doi: 10.3390/ijms21103421.
126. Caballero J. A new era for the design of TRPV1 antagonists and agonists with the use of structural information and molecular docking of capsaicin-like compounds. J. Enzym. Inhib. Med. Chem. 2022;37:2169–2178. doi: 10.1080/14756366.2022.2110089.
127. Szallasi A., Blumberg P.M. Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper. Neuroscience. 1989;30:515–520. doi: 10.1016/0306-4522(89)90269-8.
128. Raisinghani M., Pabbidi R.M., Premkumar L.S. Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin. J. Physiol. 2005;567:771–786. doi: 10.1113/jphysiol.2005.087874.
129. Duarte Y., Cáceres J., Sepúlveda R.V., Arriagada D., Olivares P., Díaz-Franulic I., Stehberg J., González-Nilo F. Novel TRPV1 Channel Agonists with Faster and More Potent Analgesic Properties Than Capsaicin. Front. Pharmacol. 2020;11:1040. doi: 10.3389/fphar.2020.01040.
130. Căruntu C., Boda D. Evaluation through in vivo reflectance confocal microscopy of the cutaneous neurogenic inflammatory reaction induced by capsaicin in human subjects. J. Biomed. Opt. 2012;17:085003. doi: 10.1117/1.JBO.17.8.085003.
131. Jung M.Y., Kang H.J., Moon A. Capsaicin-induced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 downregulation and caspase-3 activation. Cancer Lett. 2001;165:139–145. doi: 10.1016/S0304-3835(01)00426-8.
132. Hail N., Jr., Lotan R. Examining the role of mitochondrial respiration in vanilloid-induced apoptosis. J. Natl. Cancer Inst. 2002;94:1281–1292. doi: 10.1093/jnci/94.17.1281.
133. Kim C.S., Park W.H., Park J.Y., Kang J.H., Kim M.O., Kawada T., Yoo H., Han I.S., Yu R. Capsaicin, a spicy component of hot pepper, induces apoptosis by activation of the peroxisome proliferator-activated receptor gamma in HT-29 human colon cancer cells. J. Med. Food. 2004;7:267–273. doi: 10.1089/jmf.2004.7.267.
134. Lo Y.C., Yang Y.C., Wu I.C., Kuo F.C., Liu C.M., Wang H.W., Kuo C.H., Wu J.Y., Wu D.C. Capsaicin-induced cell death in a human gastric adenocarcinoma cell line. World J. Gastroenterol. 2005;11:6254–6257. doi: 10.3748/wjg.v11.i40.6254.
135. Mori A., Lehmann S., O’Kelly J., Kumagai T., Desmond J.C., Pervan M., McBride W.H., Kizaki M., Koeffler H.P. Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res. 2006;66:3222–3229. doi: 10.1158/0008-5472.CAN-05-0087.
136. Athanasiou A., Smith P.A., Vakilpour S., Kumaran N.M., Turner A.E., Bagiokou D., Layfield R., Ray D.E., Westwell A.D., Alexander S.P., et al. Vanilloid receptor agonists and antagonists are mitochondrial inhibitors: How vanilloids cause non-vanilloid receptor mediated cell death. Biochem. Biophys. Res. Commun. 2007;354:50–55. doi: 10.1016/j.bbrc.2006.12.179.
137. Pramanik K.C., Boreddy S.R., Srivastava S.K. Role of mitochondrial electron transport chain complexes in capsaicin mediated oxidative stress leading to apoptosis in pancreatic cancer cells. PLoS ONE. 2011;6:e20151. doi: 10.1371/journal.pone.0020151.
138. Yang R., Xiong Z., Liu C., Liu L. Inhibitory effects of capsaicin on voltage-gated potassium channels by TRPV1-independent pathway. Cell. Mol. Neurobiol. 2014;34:565–576. doi: 10.1007/s10571-014-0041-1.
139. Du X., Gamper N. Potassium channels in peripheral pain pathways: Expression, function and therapeutic potential. Curr. Neuropharmacol. 2013;11:621–640. doi: 10.2174/1570159X113119990042.
140. Oz M., Lorke D.E., Howarth F.C. Transient receptor potential vanilloid 1 (TRPV1)-independent actions of capsaicin on cellular excitability and ion transport. Med. Res. Rev. 2023;43:1038–1067. doi: 10.1002/med.21945.
141. Mohapatra D.P., Nau C. Regulation of Ca2+-dependent desensitization in the vanilloid receptor TRPV1 by calcineurin and cAMP-dependent protein kinase. J. Biol. Chem. 2005;280:13424–13432. doi: 10.1074/jbc.M410917200.
142. Shuba Y.M. Beyond Neuronal Heat Sensing: Diversity of TRPV1 Heat-Capsaicin Receptor-Channel Functions. Front. Cell. Neurosci. 2021;14:612480. doi: 10.3389/fncel.2020.612480.
143. Burks T.F., Buck S.H., Miller M.S. Mechanisms of depletion of substance P by capsaicin. Fed. Proc. 1985;44:2531–2534.
144. Dray A. Mechanism of action of capsaicin-like molecules on sensory neurons. Life Sci. 1992;51:1759–1765. doi: 10.1016/0024-3205(92)90045-Q.
145. Ding H., Kiguchi N., Dobbins M., Romero-Sandoval E.A., Kishioka S., Ko M.-C. Nociceptin Receptor-Related Agonists as Safe and Non-addictive Analgesics. Drugs. 2023;83:771–793. doi: 10.1007/s40265-023-01878-5.
146. Liu L., Oortgiesen M., Li L., Simon S.A. Capsaicin inhibits activation of voltage-gated sodium currents in capsaicin-sensitive trigeminal ganglion neurons. J. Neurophysiol. 2001;85:745–758. doi: 10.1152/jn.2001.85.2.745.
147. Pasierski M., Szulczyk B. Capsaicin inhibits sodium currents and epileptiform activity in prefrontal cortex pyramidal neurons. Neurochem. Int. 2020;135:104709. doi: 10.1016/j.neuint.2020.104709.
148. Nolano M., Simone D.A., Wendelschafer-Crabb G., Johnson T., Hazen E., Kennedy W.R. Topical capsaicin in humans: Parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81:135–145. doi: 10.1016/S0304-3959(99)00007-X.
149. Guo R., Qiu H., Li H., Ma D., Guan Y., Wang Y. The preemptive analgesic effect of capsaicin involves attenuations of epidermal keratinocytes proliferation and expression of pro-inflammatory mediators after plantar incision in rats. J. Pain. Res. 2023;16:141–149. doi: 10.2147/JPR.S395065.
150. Goodwin B., Chiplunkar M., Salerno R., Coombs K., Sannoh U., Shah V., Averell N., Al-Shebab U., Janora D. Topical capsaicin for the management of painful diabetic neuropathy: A narrative systematic review. Pain Manag. 2023;13:309–316. doi: 10.2217/pmt-2023-0006.
151. Vachiramon V., Tanratana P., Anuntrangsee T., Palakornkitti P., Yeesibsean N., Kungvalpivat P., Fabi S. The role of topical capsaicin gel in pain management during microfocused ultrasound treatment for neck laxity. Skin Res. Technol. 2023;29:e13240. doi: 10.1111/srt.13240.
152. Peel J., John K., Page J., Jeffries O., Heffernan S.M., Tallent J., Waldron M. Topical application of isolated menthol and combined menthol-capsaicin creams: Exercise tolerance, thermal perception, pain, attentional focus and thermoregulation in the heat. Eur. J. Sport. Sci. 2023;23:2038–2048. doi: 10.1080/17461391.2023.2211966.
153. Berger A., Henderson M., Nadoolman W., Duffy V., Cooper D., Saberski L., Bartoshuk L. Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. J. Pain. Symptom Manag. 1995;10:243–248. doi: 10.1016/0885-3924(94)00130-D.
154. Derry S., Wiffen P.J., Kalso E.A., Bell R.F., Aldington D., Phillips T., Gaskell H., Moore R.A. Topical analgesics for acute and chronic pain in adults—An overview of Cochrane Reviews. Cochrane Database Syst. Rev. 2017;5:Cd008609. doi: 10.1002/14651858.CD008609.pub2.
155. Wang X.R., Gao S.Q., Niu X.Q., Li L.J., Ying X.Y., Hu Z.J., Gao J.Q. Capsaicin-loaded nanolipoidal carriers for topical application: Design, characterization, and in vitro/in vivo evaluation. Int. J. Nanomed. 2017;12:3881–3898. doi: 10.2147/IJN.S131901.
156. Anantaworasakul P., Anuchapreeda S., Yotsawimonwat S., Naksuriya O., Lekawanvijit S., Tovanabutra N., Anantaworasakul P., Wattanasri W., Buranapreecha N., Ampasavate C. Nanomaterial Lipid-Based Carrier for Non-Invasive Capsaicin Delivery; Manufacturing Scale-Up and Human Irritation Assessment. Molecules. 2020;25:5575. doi: 10.3390/molecules25235575.
157. Contri R.V., Frank L.A., Kaiser M., Pohlmann A.R., Guterres S.S. The use of nanoencapsulation to decrease human skin irritation caused by capsaicinoids. Int. J. Nanomed. 2014;9:951–962. doi: 10.2147/ijn.S56579.
158. Raza K., Singh B., Mahajan A., Negi P., Bhatia A., Katare O.P. Design and evaluation of flexible membrane vesicles (FMVs) for enhanced topical delivery of capsaicin. J. Drug Target. 2011;19:293–302. doi: 10.3109/1061186X.2010.499464.
159. Hudita A., Galateanu B., Costache M., Negrei C., Ion R.M., Iancu L., Ginghina O. In Vitro Cytotoxic Protective Effect of Alginate-Encapsulated Capsaicin Might Improve Skin Side Effects Associated with the Topical Application of Capsaicin. Molecules. 2021;26:1455. doi: 10.3390/molecules26051455.
160. Raza K., Shareef M.A., Singal P., Sharma G., Negi P., Katare O.P. Lipid-based capsaicin-loaded nano-colloidal biocompatible topical carriers with enhanced analgesic potential and decreased dermal irritation. J. Liposome Res. 2014;24:290–296. doi: 10.3109/08982104.2014.911314.
161. Don P.C. Topical capsaicin for treatment of neuralgia associated with herpes zoster infection. J. Am. Acad. Dermatol. 1988;18:1135–1136. doi: 10.1016/S0190-9622(88)80017-3.
162. Lincoff N.S., Rath P.P., Hirano M. The treatment of periocular and facial pain with topical capsaicin. J. Neuroophthalmol. 1998;18:17–20. doi: 10.1097/00041327-199803000-00004.
163. Marks J.G., Jr. Treatment of apocrine chromhidrosis with topical capsaicin. J. Am. Acad. Dermatol. 1989;21:418–420. doi: 10.1016/S0190-9622(89)80050-7.
164. Cheshire W.P., Snyder C.R. Treatment of reflex sympathetic dystrophy with topical capsaicin. Case report. Pain. 1990;42:307–311. doi: 10.1016/0304-3959(90)91143-7.
165. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. The Capsaicin Study Group. Arch. Intern. Med. 1991;151:2225–2229. doi: 10.1001/archinte.1991.00400110079017.
166. Tandan R., Lewis G.A., Krusinski P.B., Badger G.B., Fries T.J. Topical capsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care. 1992;15:8–14. doi: 10.2337/diacare.15.1.8.
167. McCarthy G.M., McCarty D.J. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J. Rheumatol. 1992;19:604–607.
168. Leibsohn E. Treatment of notalgia paresthetica with capsaicin. Cutis. 1992;49:335–336.
169. Watson C.P., Tyler K.L., Bickers D.R., Millikan L.E., Smith S., Coleman E. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin. Ther. 1993;15:510–526. doi: 10.1097/00132586-199404000-00039.
170. Ellis C.N., Berberian B., Sulica V.I., Dodd W.A., Jarratt M.T., Katz H.I., Prawer S., Krueger G., Rex I.H., Jr., Wolf J.E. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J. Am. Acad. Dermatol. 1993;29:438–442. doi: 10.1016/0190-9622(93)70208-B.
171. Dini D., Bertelli G., Gozza A., Forno G.G. Treatment of the post-mastectomy pain syndrome with topical capsaicin. Pain. 1993;54:223–226. doi: 10.1016/0304-3959(93)90213-9.
172. Marks D.R., Rapoport A., Padla D., Weeks R., Rosum R., Sheftell F., Arrowsmith F. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia. 1993;13:114–116. doi: 10.1046/j.1468-2982.1993.1302114.x.
173. Lotti T., Teofoli P., Tsampau D. Treatment of aquagenic pruritus with topical capsaicin cream. J. Am. Acad. Dermatol. 1994;30:232–235. doi: 10.1016/S0190-9622(94)70022-2.
174. Muhiddin K.A., Gallen I.W., Harries S., Pearce V.R. The use of capsaicin cream in a case of erythromelalgia. Postgrad. Med. J. 1994;70:841–843. doi: 10.1136/pgmj.70.829.841.
175. Epstein J.B., Marcoe J.H. Topical application of capsaicin for treatment of oral neuropathic pain and trigeminal neuralgia. Oral Surg. Oral Med. Oral Pathol. 1994;77:135–140. doi: 10.1016/0030-4220(94)90275-5.
176. Mathias B.J., Dillingham T.R., Zeigler D.N., Chang A.S., Belandres P.V. Topical capsaicin for chronic neck pain. A pilot study. Am. J. Phys. Med. Rehabil. 1995;74:39–44. doi: 10.1097/00002060-199501000-00007.
177. Puig L., Alegre M., de Moragas J.M. Treatment of meralgia paraesthetica with topical capsaicin. Dermatology. 1995;191:73–74. doi: 10.1159/000246496.
178. Iinuma T., Sawada Y. Topical application of capsaicin and flap survival. Br. J. Plast. Surg. 1996;49:319–320. doi: 10.1016/S0007-1226(96)90163-0.
179. Frucht-Pery J., Feldman S.T., Brown S.I. The use of capsaicin in herpes zoster ophthalmicus neuralgia. Acta Ophthalmol. Scand. 1997;75:311–313. doi: 10.1111/j.1600-0420.1997.tb00782.x.
180. Robbins W.R., Staats P.S., Levine J., Fields H.L., Allen R.W., Campbell J.N., Pappagallo M. Treatment of intractable pain with topical large-dose capsaicin: Preliminary report. Anesth. Analg. 1998;86:579–583. doi: 10.1213/00000539-199803000-00027.
181. Weisshaar E., Heyer G., Forster C., Handwerker H.O. Effect of topical capsaicin on the cutaneous reactions and itching to histamine in atopic eczema compared to healthy skin. Arch. Dermatol. Res. 1998;290:306–311. doi: 10.1007/s004030050309.
182. Baudoin T., Kalogjera L., Hat J. Capsaicin significantly reduces sinonasal polyps. Acta Otolaryngol. 2000;120:307–311. doi: 10.1080/000164800750001143.
183. Sandford P.R., Benes P.S. Use of capsaicin in the treatment of radicular pain in spinal cord injury. J. Spinal Cord. Med. 2000;23:238–243. doi: 10.1080/10790268.2000.11753532.
184. Ständer S., Luger T., Metze D. Treatment of prurigo nodularis with topical capsaicin. J. Am. Acad. Dermatol. 2001;44:471–478. doi: 10.1067/mjd.2001.110059.
185. Ribbers G.M., Stam H.J. Complex regional pain syndrome type I treated with topical capsaicin: A case report. Arch. Phys. Med. Rehabil. 2001;82:851–852. doi: 10.1053/apmr.2001.21911.
186. Marsella R., Nicklin C.F., Melloy C. The effects of capsaicin topical therapy in dogs with atopic dermatitis: A randomized, double-blinded, placebo-controlled, cross-over clinical trial. Vet. Dermatol. 2002;13:131–139. doi: 10.1046/j.1365-3164.2002.00292.x.
187. McPartland J.M. Use of capsaicin cream for abdominal wall scar pain. Am. Fam. Physician. 2002;65:2211; author reply 2212.
188. Weisshaar E., Dunker N., Gollnick H. Topical capsaicin therapy in humans with hemodialysis-related pruritus. Neurosci. Lett. 2003;345:192–194. doi: 10.1016/S0304-3940(03)00511-1.
189. Dux M., Sántha P., Jancsó G. Capsaicin-sensitive neurogenic sensory vasodilatation in the dura mater of the rat. J. Physiol. 2003;552:859–867. doi: 10.1113/jphysiol.2003.050633.
190. Perkins P., Morgan S., Closs S.P. Topical capsaicin for saphenous neuralgia. J. Pain. Symptom Manag. 2003;26:785–786. doi: 10.1016/S0885-3924(03)00280-X.
191. Lazzeri M., Spinelli M., Zanollo A., Turini D. Intravesical vanilloids and neurogenic incontinence: Ten years experience. Urol. Int. 2004;72:145–149. doi: 10.1159/000075969.
192. Petruzzi M., Lauritano D., De Benedittis M., Baldoni M., Serpico R. Systemic capsaicin for burning mouth syndrome: Short-term results of a pilot study. J. Oral. Pathol. Med. 2004;33:111–114. doi: 10.1111/j.1600-0714.2004.0194n.x.
193. Yosipovitch G., Mengesha Y., Facliaru D., David M. Topical capsaicin for the treatment of acute lipodermatosclerosis and lobular panniculitis. J. Dermatol. Treat. 2005;16:178–180. doi: 10.1080/09546630510041079.
194. Kim K.S., Nam Y.M. The analgesic effects of capsicum plaster at the Zusanli point after abdominal hysterectomy. Anesth. Analg. 2006;103:709–713. doi: 10.1213/01.ane.0000228864.74691.9f.
195. Harada N., Okajima K. Effect of topical application of capsaicin and its related compounds on dermal insulin-like growth factor-I levels in mice and on facial skin elasticity in humans. Growth Horm. IGF Res. 2007;17:171–176. doi: 10.1016/j.ghir.2006.12.005.
196. Simpson D.M., Estanislao L., Brown S.J., Sampson J. An open-label pilot study of high-concentration capsaicin patch in painful HIV neuropathy. J. Pain. Symptom Manag. 2008;35:299–306. doi: 10.1016/j.jpainsymman.2007.04.015.
197. Kim K.S., Kim K.N., Hwang K.G., Park C.J. Capsicum plaster at the Hegu point reduces postoperative analgesic requirement after orthognathic surgery. Anesth. Analg. 2009;108:992–996. doi: 10.1213/ane.0b013e318195b78f.
198. Cianchetti C. Capsaicin jelly against migraine pain. Int. J. Clin. Pract. 2010;64:457–459. doi: 10.1111/j.1742-1241.2009.02294.x.
199. Chrubasik S., Weiser T., Beime B. Effectiveness and safety of topical capsaicin cream in the treatment of chronic soft tissue pain. Phytother. Res. 2010;24:1877–1885. doi: 10.1002/ptr.3335.
200. Redington K.L., Disenhouse T., Strantzas S.C., Gladstone R., Wei C., Tropak M.B., Dai X., Manlhiot C., Li J., Redington A.N. Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. Basic. Res. Cardiol. 2012;107:241. doi: 10.1007/s00395-011-0241-5.
201. Sayanlar J., Guleyupoglu N., Portenoy R., Ashina S. Trigeminal postherpetic neuralgia responsive to treatment with capsaicin 8% topical patch: A case report. J. Headache Pain. 2012;13:587–589. doi: 10.1007/s10194-012-0467-0.
202. Lee G.R., Shin M.K., Yoon D.J., Kim A.R., Yu R., Park N.H., Han I.S. Topical application of capsaicin reduces visceral adipose fat by affecting adipokine levels in high-fat diet-induced obese mice. Obesity. 2013;21:115–122. doi: 10.1002/oby.20246.
203. Casanueva B., Rodero B., Quintial C., Llorca J., González-Gay M.A. Short-term efficacy of topical capsaicin therapy in severely affected fibromyalgia patients. Rheumatol. Int. 2013;33:2665–2670. doi: 10.1007/s00296-012-2490-5.
204. Maihöfner C.G., Heskamp M.L. Treatment of peripheral neuropathic pain by topical capsaicin: Impact of pre-existing pain in the QUEPP-study. Eur. J. Pain. 2014;18:671–679. doi: 10.1002/j.1532-2149.2013.00415.x.
205. Zis P., Apsokardos A., Isaia C., Sykioti P., Vadalouca A. Posttraumatic and postsurgical neuropathic pain responsive to treatment with capsaicin 8% topical patch. Pain. Physician. 2014;17:E213–E218.
206. Kumar Sarwa K., Rudrapal M., Mazumder B. Topical ethosomal capsaicin attenuates edema and nociception in arthritic rats. Drug Deliv. 2015;22:1043–1052. doi: 10.3109/10717544.2013.861041.
207. Teixeira M.J., Menezes L.M., Silva V., Galhardoni R., Sasson J., Okada M., Duarte K.P., Yeng L.T., Andrade D.C. Liposomal topical capsaicin in post-herpetic neuralgia: A safety pilot study. Arq. Neuropsiquiatr. 2015;73:237–240. doi: 10.1590/0004-282X20140232.
208. Lu S., Baad-Hansen L., Zhang Z., Svensson P. Spatial and Temporal Effects of Capsaicin and Menthol on Intraoral Somatosensory Sensitivity. J. Oral. Facial Pain. Headache. 2015;29:257–264. doi: 10.11607/ofph.1106.
209. Zeidler C., Metze D., Ständer S. Successful treatment of lichen amyloidosis using capsaicin 8% patch. J. Eur. Acad. Dermatol. Venereol. 2016;30:1236–1238. doi: 10.1111/jdv.13165.
210. Dezieck L., Hafez Z., Conicella A., Blohm E., O’Connor M.J., Schwarz E.S., Mullins M.E. Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: A case series. Clin. Toxicol. 2017;55:908–913. doi: 10.1080/15563650.2017.1324166.
211. Jørgensen M.R., Pedersen A.M. Analgesic effect of topical oral capsaicin gel in burning mouth syndrome. Acta Odontol. Scand. 2017;75:130–136. doi: 10.1080/00016357.2016.1269191.
212. Baron R., Treede R.D., Birklein F., Cegla T., Freynhagen R., Heskamp M.L., Kern K.U., Maier C., Rolke R., Seddigh S., et al. Treatment of painful radiculopathies with capsaicin 8% cutaneous patch. Curr. Med. Res. Opin. 2017;33:1401–1411. doi: 10.1080/03007995.2017.1322569.
213. Bae S., Yu J., Jeong H., Oh T. Anti-pruritic effect of topical capsaicin against histamine-induced pruritus on canine skin. Pol. J. Vet. Sci. 2018;21:789–796. doi: 10.24425/pjvs.2018.125599.
214. Járomi P., Garab D., Hartmann P., Bodnár D., Nyíri S., Sántha P., Boros M., Jancsó G., Szabó A. Capsaicin-induced rapid neutrophil leukocyte activation in the rat urinary bladder microcirculatory bed. Neurourol. Urodyn. 2018;37:690–698. doi: 10.1002/nau.23376.
215. Romero V., Lara J.R., Otero-Espinar F., Salgado M.H., Modolo N.S.P., Barros G.A.M. [Capsaicin topical cream (8%) for the treatment of myofascial pain syndrome] Braz. J. Anesthesiol. 2019;69:432–438. doi: 10.1016/j.bjan.2019.06.008.
216. Kocak A.O., Dogruyol S., Akbas I., Menekse T.S., Gur S.T.A., Kocak M.B., Cekmen B., Orun S., Cakir Z. Comparison of topical capsaicin and topical piroxicam in the treatment of acute trauma-induced pain: A randomized double-blind trial. Am. J. Emerg. Med. 2020;38:1767–1771. doi: 10.1016/j.ajem.2020.05.104.
217. de Lourdes Medina-Contreras J.M., Mailloux-Salinas P., Colado-Velazquez J.I., Gómez-Viquez N., Velázquez-Espejel R., Del Carmen Susunaga-Notario A., Arias-Chávez D.J., Bravo G. Topical capsaicin cream with moderate exercise protects against hepatic steatosis, dyslipidemia and increased blood pressure in hypoestrogenic obese rats. J. Sci. Food Agric. 2020;100:3212–3219. doi: 10.1002/jsfa.10357.
218. Agoons B.B., Dehayem Yefou M., Katte J.C., Etoa Etoga M.C., Agoons D.D., Yepnjio F., Boli A., Wasnyo Y., Sobngwi E., Mbanya J.C. Effect of Topical Capsaicin on Painful Sensory Peripheral Neuropathy in Patients with Type 2 Diabetes: A Double-Blind Placebo-Controlled Randomised Clinical Trial. Cureus. 2020;12:e11147. doi: 10.7759/cureus.11147.
219. Wang S., Bian C., Yang J., Arora V., Gao Y., Wei F., Chung M.K. Ablation of TRPV1+ Afferent Terminals by Capsaicin Mediates Long-Lasting Analgesia for Trigeminal Neuropathic Pain. eNeuro. 2020;7:ENEURO.0118-20.2020. doi: 10.1523/ENEURO.0118-20.2020.
220. Chan T.C., Lee M.S., Huang W.C., Chang W.Y., Krueger J.G., Tsai T.F. Capsaicin attenuates imiquimod-induced epidermal hyperplasia and cutaneous inflammation in a murine model of psoriasis. Biomed. Pharmacother. 2021;141:111950. doi: 10.1016/j.biopha.2021.111950.
221. Hoesli R.C., Wingo M.L., Wajsberg B., Bastian R.W. Topical Capsaicin for the Treatment of Sensory Neuropathic Cough. OTO Open. 2021;5:2473974x211065668. doi: 10.1177/2473974X211065668.
222. Kum V., Bell A., Fang W., VanWert E. Efficacy of topical capsaicin for cannabinoid hyperemesis syndrome in a pediatric and adult emergency department. Am. J. Emerg. Med. 2021;49:343–351. doi: 10.1016/j.ajem.2021.06.049.
223. Lo Vecchio S., Andersen H.H., Elberling J., Arendt-Nielsen L. Sensory defunctionalization induced by 8% topical capsaicin treatment in a model of ultraviolet-B-induced cutaneous hyperalgesia. Exp. Brain Res. 2021;239:2873–2886. doi: 10.1007/s00221-021-06170-0.
224. Van Gerven L., Steelant B., Cools L., Callebaut I., Backaert W., de Hoon J., Ampe E., Talavera K., Hellings P.W. Low-dose capsaicin (0.01 mM) nasal spray is equally effective as the current standard treatment for idiopathic rhinitis: A randomized, double-blind, placebo-controlled trial. J. Allergy Clin. Immunol. 2021;147:397–400.e4. doi: 10.1016/j.jaci.2020.04.054.
225. Silva-Clavería F., Bernabeu-Wittel J., Monserrat M.T. Topical capsaicin patch for pain management in PTEN hamartoma tumor syndromes. J. Dtsch. Dermatol. Ges. 2022;20:1221–1223. doi: 10.1111/ddg.14826.
226. Cleary D., Burton S., Cardon B. Time to consider topical capsaicin for acute trauma pain? J. Fam. Pract. 2022;71:176–177. doi: 10.12788/jfp.0403.
227. Schäfer R.C., Sohn A., Kersten A., Amr A., Held M., Wenger A. Quantification of Dermal Microcirculatory Changes after Topical Administration of Capsaicin: A Randomized Placebo-Controlled Study in 46 Subjects. J. Investig. Surg. 2022;35:1673–1678. doi: 10.1080/08941939.2022.2091694.
228. Laude-Pagniez E., Leclerc J., Lok C., Chaby G., Arnault J.P. Capsaicin 8% patch as therapy for neuropathic chronic postsurgical pain after melanoma excision surgery: A single center case series. JAAD Case Rep. 2022;30:70–75. doi: 10.1016/j.jdcr.2022.09.032.
229. Sendel M., Dunst A., Forstenpointner J., Hüllemann P., Baron R. Capsaicin treatment in neuropathic pain: Axon reflex vasodilatation after 4 weeks correlates with pain reduction. Pain. 2023;164:534–542. doi: 10.1097/j.pain.0000000000002735.
230. Ercan N., Uludag M.O., Agis E.R., Demirel-Yilmaz E. The anti-inflammatory effect of diclofenac is considerably augmented by topical capsaicinoids-containing patch in carrageenan-induced paw oedema of rat. Inflammopharmacology. 2013;21:413–419. doi: 10.1007/s10787-013-0175-7.
231. Payan D.G. Neuropeptides and inflammation: The role of substance P. Annu. Rev. Med. 1989;40:341–352. doi: 10.1146/annurev.me.40.020189.002013.
232. O’Connor T.M., O’Connell J., O’Brien D.I., Goode T., Bredin C.P., Shanahan F. The role of substance P in inflammatory disease. J. Cell. Physiol. 2004;201:167–180. doi: 10.1002/jcp.20061.
233. Bartold P., Kylstra A., Lawson R. Substance P: An immunohistochemical and biochemical study in human gingival tissues. A role for neurogenic inflammation? J. Periodontol. 1994;65:1113–1121. doi: 10.1902/jop.1994.65.12.1113.
234. DeVane C.L. Substance P: A new era, a new role. Pharmacother. J. Hum. Pharmacol. Drug Ther. 2001;21:1061–1069. doi: 10.1592/phco.21.13.1061.34612.
235. Hägermark O., Hökfelt T., Pernow B. Flare and itch induced by substance P in human skin. Nation. 1978;12:13. doi: 10.1111/1523-1747.ep12515092.
236. Simone D.A., Nolano M., Johnson T., Wendelschafer-Crabb G., Kennedy W.R. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: Correlation with sensory function. J. Neurosci. 1998;18:8947–8959. doi: 10.1523/JNEUROSCI.18-21-08947.1998.
237. Caruntu C., Boda D., Musat S., Caruntu A., Mandache E. Stress-induced mast cell activation in glabrous and hairy skin. Mediat. Inflamm. 2014;2014:105950. doi: 10.1155/2014/105950.
238. Brodin E., Nilsson G. Concentration of substance P-like immunoreactivity (SPLI) in tissues of dog, rat and mouse. Acta Physiol. Scand. 1981;112:305–312. doi: 10.1111/j.1748-1716.1981.tb06821.x.
239. Mistrova E., Kruzliak P., Dvorakova M.C. Role of substance P in the cardiovascular system. Neuropeptides. 2016;58:41–51. doi: 10.1016/j.npep.2015.12.005.
240. Geppetti P., Bertrand C., Baker J., Yamawaki I., Piedimonte G., Nadel J.A. Ruthenium red, but not capsazepine reduces plasma extravasation by cigarette smoke in rat airways. Br. J. Pharmacol. 1993;108:646–650. doi: 10.1111/j.1476-5381.1993.tb12855.x.
241. Figini M., Emanueli C., Bertrand C., Javdan P., Geppetti P. Evidence that tachykinins relax the guinea-pig trachea via nitric oxide release and by stimulation of a septide-insensitive NK1 receptor. Br. J. Pharmacol. 1996;117:1270–1276. doi: 10.1111/j.1476-5381.1996.tb16725.x.
242. Hauser-Kronberger C., Hacker G.W., Franz P., Albegger K., Dietze O. CGRP and substance P in intraepithelial neuronal structures of the human upper respiratory system. Regul. Pept. 1997;72:79–85. doi: 10.1016/S0167-0115(97)01040-9.
243. Barthó L., Holzer P. Search for a physiological role of substance P in gastrointestinal motility. Neuroscience. 1985;16:1–32. doi: 10.1016/0306-4522(85)90043-0.
244. Costa M., Furness J.B., Gibbins I.L. Chapter 15 Chemical coding of enteric neurons. In: Hökfelt T., Fuxe K., Pernow B., editors. Progress in Brain Research. Volume 68. Elsevier; Amsterdam, The Netherlands: 1986. pp. 217–239.
245. Hökfelt T., Pernow B., Wahren J. Substance P: A pioneer amongst neuropeptides. J. Intern. Med. 2001;249:27–40. doi: 10.1046/j.0954-6820.2000.00773.x.
246. Watts S.W., Cohen M.L. Effect of bombesin, bradykinin, substance P and CGRP in prostate, bladder body and neck. Peptides. 1991;12:1057–1062. doi: 10.1016/0196-9781(91)90060-3.
247. Maggi C.A. Tachykinins and calcitonin gene-related peptide (CGRP) as co-transmitters released from peripheral endings of sensory nerves. Prog. Neurobiol. 1995;45:1–98. doi: 10.1016/0301-0082(94)e0017-b.
248. Edvinsson L., Rosendal-Helgesen S., Uddman R. Substance P: Localization, concentration and release in cerebral arteries, choroid plexus and dura mater. Cell Tissue Res. 1983;234:1–7. doi: 10.1007/BF00217397.
249. Petersson J., Zygmunt P.M., Brandt L., Högestätt E.D. Substance P-induced relaxation and hyperpolarization in human cerebral arteries. Br. J. Pharmacol. 1995;115:889. doi: 10.1111/j.1476-5381.1995.tb15893.x.
250. Harrison S., Geppetti P. Substance P. Int. J. Biochem. Cell Biol. 2001;33:555–576. doi: 10.1016/S1357-2725(01)00031-0.
251. Mehboob R., Oehme P., Pfaff G. The role of Substance P in the defense line of the respiratory tract and neurological manifestations post COVID-19 infection. Front. Neurol. 2023;14:1052811. doi: 10.3389/fneur.2023.1052811.
252. Chen F.X., Wan Q., Fang J., Peng L., Li Q.L., Hu J. The Src1-PGC1α-AP1 complex-dependent secretion of substance P induces inflammation and apoptosis in encephalomyocarditis virus-infected mice. Cytokine. 2023;165:156186. doi: 10.1016/j.cyto.2023.156186.
253. Arruda-Vasconcelos R., Chiarelli-Neto V.M., Louzada L.M., Aveiro E., Alves-Silva E.G., de-Jesus-Soares A., Ferraz C.C.R., Almeida J.F.A., Marciano M.A., Pecorari V.G.A., et al. Quantitative analysis of culturable bacteria, levels of endotoxins, inflammatory mediators and substance P in teeth with symptomatic irreversible pulpitis and in teeth with vital normal pulp tissues. Int. Endod. J. 2023;56:827–836. doi: 10.1111/iej.13922.
254. Johnson M.B., Suptela S.R., Sipprell S.E., Marriott I. Substance P Exacerbates the Inflammatory and Pro-osteoclastogenic Responses of Murine Osteoclasts and Osteoblasts to Staphylococcus aureus. Inflammation. 2023;46:256–269. doi: 10.1007/s10753-022-01731-z.
255. Scheau C., Ilie Ghita M., Grigore O., Mihailescu A., Caruntu A., Mihai L., Bădărău I., Boda D., Caruntu C. Modulation of capsaicin-induced neurogenic vasodilation by acute psychological stress. Farmacia. 2021;69:778–784. doi: 10.31925/farmacia.2021.4.20.
256. Xiang Y., Xu X., Zhang T., Wu X., Fan D., Hu Y., Ding J., Yang X., Lou J., Du Q., et al. Beneficial effects of dietary capsaicin in gastrointestinal health and disease. Exp. Cell Res. 2022;417:113227. doi: 10.1016/j.yexcr.2022.113227.
257. Patowary P., Pathak M.P., Zaman K., Raju P.S., Chattopadhyay P. Research progress of capsaicin responses to various pharmacological challenges. Biomed. Pharmacother. 2017;96:1501–1512. doi: 10.1016/j.biopha.2017.11.124.
258. Kunjiappan S., Sankaranarayanan M., Karan Kumar B., Pavadai P., Babkiewicz E., Maszczyk P., Glodkowska-Mrowka E., Arunachalam S., Ram Kumar Pandian S., Ravishankar V., et al. Capsaicin-loaded solid lipid nanoparticles: Design, biodistribution, in silico modeling and in vitro cytotoxicity evaluation. Nanotechnology. 2021;32:095101. doi: 10.1088/1361-6528/abc57e.
259. Ahmady A.R., Solouk A., Saber-Samandari S., Akbari S., Ghanbari H., Brycki B.E. Capsaicin-loaded alginate nanoparticles embedded polycaprolactone-chitosan nanofibers as a controlled drug delivery nanoplatform for anticancer activity. J. Colloid. Interface Sci. 2023;638:616–628. doi: 10.1016/j.jcis.2023.01.139.
260. Thán M., Németh J., Szilvássy Z., Pintér E., Helyes Z., Szolcsányi J. Systemic anti-inflammatory effect of somatostatin released from capsaicin-sensitive vagal and sciatic sensory fibres of the rat and guinea-pig. Eur. J. Pharmacol. 2000;399:251–258. doi: 10.1016/S0014-2999(00)00341-1.
261. Lauritano D., Petruzzi M., Baldoni M. [Preliminary protocol for systemic administration of capsaicin for the treatment of the burning mouth syndrome] Minerva Stomatol. 2003;52:273–278.
262. Luqman S., Rizvi S.I. Protection of lipid peroxidation and carbonyl formation in proteins by capsaicin in human erythrocytes subjected to oxidative stress. Phytother. Res. 2006;20:303–306. doi: 10.1002/ptr.1861.
263. Lee I.O., Lee K.H., Pyo J.H., Kim J.H., Choi Y.J., Lee Y.C. Anti-inflammatory Effect of Capsaicin in Helicobacter pylori-Infected Gastric Epithelial Cells. Helicobacter. 2007;12:510–517. doi: 10.1111/j.1523-5378.2007.00521.x.
264. Wu Y., Starzinski-Powitz A., Guo S.W. Capsaicin inhibits proliferation of endometriotic cells in vitro. Gynecol. Obstet. Investig. 2008;66:59–62. doi: 10.1159/000124275.
265. Bortolotti M., Porta S. Effect of red pepper on symptoms of irritable bowel syndrome: Preliminary study. Dig. Dis. Sci. 2011;56:3288–3295. doi: 10.1007/s10620-011-1740-9.
266. Yu Q., Wang Y., Yu Y., Li Y., Zhao S., Chen Y., Waqar A.B., Fan J., Liu E. Expression of TRPV1 in rabbits and consuming hot pepper affects its body weight. Mol. Biol. Rep. 2012;39:7583–7589. doi: 10.1007/s11033-012-1592-1.
267. Ternesten-Hasséus E., Johansson E.L., Millqvist E. Cough reduction using capsaicin. Respir. Med. 2015;109:27–37. doi: 10.1016/j.rmed.2014.11.001.
268. Chen K.S., Chen P.N., Hsieh Y.S., Lin C.Y., Lee Y.H., Chu S.C. Capsaicin protects endothelial cells and macrophage against oxidized low-density lipoprotein-induced injury by direct antioxidant action. Chem. Biol. Interact. 2015;228:35–45. doi: 10.1016/j.cbi.2015.01.007.
269. He H., Zhou Y., Huang J., Wu Z., Liao Z., Liu D., Yin D., He M. Capsaicin Protects Cardiomyocytes against Anoxia/Reoxygenation Injury via Preventing Mitochondrial Dysfunction Mediated by SIRT1. Oxid. Med. Cell. Longev. 2017;2017:1035702. doi: 10.1155/2017/1035702.
270. Ren X., Roessler A.E., Lynch T.L., 4th, Haar L., Mallick F., Lui Y., Tranter M., Ren M.H., Xie W.R., Fan G.-C., et al. Cardioprotection via the skin: Nociceptor-induced conditioning against cardiac MI in the NIC of time. Am. J. Physiol.-Heart Circ. Physiol. 2019;316:H543–H553. doi: 10.1152/ajpheart.00094.2018.
271. Yang S., Liu L., Meng L., Hu X. Capsaicin is beneficial to hyperlipidemia, oxidative stress, endothelial dysfunction, and atherosclerosis in Guinea pigs fed on a high-fat diet. Chem. Biol. Interact. 2019;297:1–7. doi: 10.1016/j.cbi.2018.10.006.
272. Shin M.K., Yang S.-M., Han I.-S. Capsaicin suppresses liver fat accumulation in high-fat diet-induced NAFLD mice. Anim. Cells Syst. 2020;24:214–219. doi: 10.1080/19768354.2020.1810771.
273. Segawa Y., Hashimoto H., Maruyama S., Shintani M., Ohno H., Nakai Y., Osera T., Kurihara N. Dietary capsaicin-mediated attenuation of hypertension in a rat model of renovascular hypertension. Clin. Exp. Hypertens. 2020;42:352–359. doi: 10.1080/10641963.2019.1665676.
274. Grüter T., Blusch A., Motte J., Sgodzai M., Bachir H., Klimas R., Ambrosius B., Gold R., Ellrichmann G., Pitarokoili K. Immunomodulatory and anti-oxidative effect of the direct TRPV1 receptor agonist capsaicin on Schwann cells. J. Neuroinflammation. 2020;17:145. doi: 10.1186/s12974-020-01821-5.
275. Abdel-Salam O.M.E., Sleem A.A., Sayed M., Youness E.R., Shaffie N. Capsaicin Exerts Anti-convulsant and Neuroprotective Effects in Pentylenetetrazole-Induced Seizures. Neurochem. Res. 2020;45:1045–1061. doi: 10.1007/s11064-020-02979-3.
276. Nawaka N., Wanmasae S., Makarasen A., Dechtrirat D., Techasakul S., Jeenduang N. Allicin and Capsaicin Ameliorated Hypercholesterolemia by Upregulating LDLR and Downregulating PCSK9 Expression in HepG2 Cells. Int. J. Mol. Sci. 2022;23:14299. doi: 10.3390/ijms232214299.
277. Zhang Q., Luo P., Xia F., Tang H., Chen J., Zhang J., Liu D., Zhu Y., Liu Y., Gu L., et al. Capsaicin ameliorates inflammation in a TRPV1-independent mechanism by inhibiting PKM2-LDHA-mediated Warburg effect in sepsis. Cell Chem. Biol. 2022;29:1248–1259.e6. doi: 10.1016/j.chembiol.2022.06.011.
278. Warburg O. The metabolism of carcinoma cells. J. Cancer Res. 1925;9:148–163. doi: 10.1158/jcr.1925.148.
279. Warburg O., Wind F., Negelein E. Ueber den stoffwechsel von tumoren im körper. Klin. Wochenschr. 1926;5:829–832. doi: 10.1007/BF01726240.
280. Liberti M.V., Locasale J.W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem. Sci. 2016;41:211–218. doi: 10.1016/j.tibs.2015.12.001.
281. Palsson-McDermott E.M., O’neill L.A. The Warburg effect then and now: From cancer to inflammatory diseases. Bioessays. 2013;35:965–973. doi: 10.1002/bies.201300084.
282. Kozal K., Jóźwiak P., Krześlak A. Contemporary perspectives on the Warburg effect inhibition in cancer therapy. Cancer Control. 2021;28:10732748211041243. doi: 10.1177/10732748211041243.
283. Hawkey C. COX-2 inhibitors. Lancet. 1999;353:307–314. doi: 10.1016/S0140-6736(98)12154-2.
284. Stichtenoth D.O., Frölich J.C. The second generation of COX-2 inhibitors: What advantages do the newest offer? Drugs. 2003;63:33–45. doi: 10.2165/00003495-200363010-00003.
285. Zarghi A., Arfaei S. Selective COX-2 inhibitors: A review of their structure-activity relationships. Iran. J. Pharm. Res. IJPR. 2011;10:655.
286. Movahed P., Jönsson B.A., Birnir B., Wingstrand J.A., Jørgensen T.D., Ermund A., Sterner O., Zygmunt P.M., Högestätt E.D. Endogenous unsaturated C18 N-acylethanolamines are vanilloid receptor (TRPV1) agonists. J. Biol. Chem. 2005;280:38496–38504. doi: 10.1074/jbc.M507429200.
287. Wong G.Y., Gavva N.R. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks. Brain Res. Rev. 2009;60:267–277. doi: 10.1016/j.brainresrev.2008.12.006.
288. Gharat L.A., Szallasi A. Advances in the design and therapeutic use of capsaicin receptor TRPV1 agonists and antagonists. Expert. Opin. Ther. Pat. 2008;18:159–209. doi: 10.1517/13543776.18.2.159.
289. Khairatkar-Joshi N., Szallasi A. TRPV1 antagonists: The challenges for therapeutic targeting. Trends Mol. Med. 2009;15:14–22. doi: 10.1016/j.molmed.2008.11.004.
290. Kym P.R., Kort M.E., Hutchins C.W. Analgesic potential of TRPV1 antagonists. Biochem. Pharmacol. 2009;78:211–216. doi: 10.1016/j.bcp.2009.02.014.
291. Kort M.E., Kym P.R. TRPV1 antagonists: Clinical setbacks and prospects for future development. Prog. Med. Chem. 2012;51:57–70. doi: 10.1016/B978-0-12-396493-9.00002-9.
292. Brandt M.R., Beyer C.E., Stahl S.M. TRPV1 antagonists and chronic pain: Beyond thermal perception. Pharmaceuticals. 2012;5:114–132. doi: 10.3390/ph5020114.
293. Chow J., Norng M., Zhang J., Chai J. TRPV6 mediates capsaicin-induced apoptosis in gastric cancer cells--Mechanisms behind a possible new “hot” cancer treatment. Biochim. Biophys. Acta. 2007;1773:565–576. doi: 10.1016/j.bbamcr.2007.01.001.
294. Jun H.S., Park T., Lee C.K., Kang M.K., Park M.S., Kang H.I., Surh Y.J., Kim O.H. Capsaicin induced apoptosis of B16-F10 melanoma cells through down-regulation of Bcl-2. Food Chem. Toxicol. 2007;45:708–715. doi: 10.1016/j.fct.2006.10.011.
295. Anandakumar P., Kamaraj S., Jagan S., Ramakrishnan G., Vinodhkumar R., Devaki T. Stabilization of pulmonary mitochondrial enzyme system by capsaicin during benzo(a)pyrene induced experimental lung cancer. Biomed. Pharmacother. 2008;62:390–394. doi: 10.1016/j.biopha.2007.09.005.
296. Zhang R., Humphreys I., Sahu R.P., Shi Y., Srivastava S.K. In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. Apoptosis. 2008;13:1465–1478. doi: 10.1007/s10495-008-0278-6.
297. Brown K.C., Witte T.R., Hardman W.E., Luo H., Chen Y.C., Carpenter A.B., Lau J.K., Dasgupta P. Capsaicin displays anti-proliferative activity against human small cell lung cancer in cell culture and nude mice models via the E2F pathway. PLoS ONE. 2010;5:e10243. doi: 10.1371/journal.pone.0010243.
298. Bai H., Li H., Zhang W., Matkowskyj K.A., Liao J., Srivastava S.K., Yang G.Y. Inhibition of chronic pancreatitis and pancreatic intraepithelial neoplasia (PanIN) by capsaicin in LSL-KrasG12D/Pdx1-Cre mice. Carcinogenesis. 2011;32:1689–1696. doi: 10.1093/carcin/bgr191.
299. Chang H.C., Chen S.T., Chien S.Y., Kuo S.J., Tsai H.T., Chen D.R. Capsaicin may induce breast cancer cell death through apoptosis-inducing factor involving mitochondrial dysfunction. Hum. Exp. Toxicol. 2011;30:1657–1665. doi: 10.1177/0960327110396530.
300. Ip S.W., Lan S.H., Huang A.C., Yang J.S., Chen Y.Y., Huang H.Y., Lin Z.P., Hsu Y.M., Yang M.D., Chiu C.F. Capsaicin induces apoptosis in SCC-4 human tongue cancer cells through mitochondria-dependent and-independent pathways. Environ. Toxicol. 2012;27:332–341. doi: 10.1002/tox.20646.
301. Lee S.H., Richardson R.L., Dashwood R.H., Baek S.J. Capsaicin represses transcriptional activity of β-catenin in human colorectal cancer cells. J. Nutr. Biochem. 2012;23:646–655. doi: 10.1016/j.jnutbio.2011.03.009.
302. Chen D., Yang Z., Wang Y., Zhu G., Wang X. Capsaicin induces cycle arrest by inhibiting cyclin-dependent-kinase in bladder carcinoma cells. Int. J. Urol. 2012;19:662–668. doi: 10.1111/j.1442-2042.2012.02981.x.
303. Lin C.H., Lu W.C., Wang C.W., Chan Y.C., Chen M.K. Capsaicin induces cell cycle arrest and apoptosis in human KB cancer cells. BMC Complement. Altern. Med. 2013;13:46. doi: 10.1186/1472-6882-13-46.
304. Park S.Y., Kim J.Y., Lee S.M., Jun C.H., Cho S.B., Park C.H., Joo Y.E., Kim H.S., Choi S.K., Rew J.S. Capsaicin induces apoptosis and modulates MAPK signaling in human gastric cancer cells. Mol. Med. Rep. 2014;9:499–502. doi: 10.3892/mmr.2013.1849.
305. Wutka A., Palagani V., Barat S., Chen X., El Khatib M., Götze J., Belahmer H., Zender S., Bozko P., Malek N.P., et al. Capsaicin treatment attenuates cholangiocarcinoma carcinogenesis. PLoS ONE. 2014;9:e95605. doi: 10.1371/journal.pone.0095605.
306. Skrzypski M., Sassek M., Abdelmessih S., Mergler S., Grötzinger C., Metzke D., Wojciechowicz T., Nowak K.W., Strowski M.Z. Capsaicin induces cytotoxicity in pancreatic neuroendocrine tumor cells via mitochondrial action. Cell Signal. 2014;26:41–48. doi: 10.1016/j.cellsig.2013.09.014.
307. Gilardini Montani M.S., D’Eliseo D., Cirone M., Di Renzo L., Faggioni A., Santoni A., Velotti F. Capsaicin-mediated apoptosis of human bladder cancer cells activates dendritic cells via CD91. Nutrition. 2015;31:578–581. doi: 10.1016/j.nut.2014.05.005.
308. Zheng L., Chen J., Ma Z., Liu W., Yang F., Yang Z., Wang K., Wang X., He D., Li L. Capsaicin causes inactivation and degradation of the androgen receptor by inducing the restoration of miR-449a in prostate cancer. Oncol. Rep. 2015;34:1027–1034. doi: 10.3892/or.2015.4055.
309. Lin M.H., Lee Y.H., Cheng H.L., Chen H.Y., Jhuang F.H., Chueh P.J. Capsaicin Inhibits Multiple Bladder Cancer Cell Phenotypes by Inhibiting Tumor-Associated NADH Oxidase (tNOX) and Sirtuin1 (SIRT1) Molecules. 2016;21:849. doi: 10.3390/molecules21070849.
310. Wang F., Zhao J., Liu D., Zhao T., Lu Z., Zhu L., Cao L., Yang J., Jin J., Cai Y. Capsaicin reactivates hMOF in gastric cancer cells and induces cell growth inhibition. Cancer Biol. Ther. 2016;17:1117–1125. doi: 10.1080/15384047.2016.1235654.
311. Ramos-Torres Á., Bort A., Morell C., Rodríguez-Henche N., Díaz-Laviada I. The pepper’s natural ingredient capsaicin induces autophagy blockage in prostate cancer cells. Oncotarget. 2016;7:1569–1583. doi: 10.18632/oncotarget.6415.
312. Liu T., Wang G., Tao H., Yang Z., Wang Y., Meng Z., Cao R., Xiao Y., Wang X., Zhou J. Capsaicin mediates caspases activation and induces apoptosis through P38 and JNK MAPK pathways in human renal carcinoma. BMC Cancer. 2016;16:790. doi: 10.1186/s12885-016-2831-y.
313. Lv L., Zhuang Y.X., Zhang H.W., Tian N.N., Dang W.Z., Wu S.Y. Capsaicin-loaded folic acid-conjugated lipid nanoparticles for enhanced therapeutic efficacy in ovarian cancers. Biomed. Pharmacother. 2017;91:999–1005. doi: 10.1016/j.biopha.2017.04.097.
314. Lin Y.T., Wang H.C., Hsu Y.C., Cho C.L., Yang M.Y., Chien C.Y. Capsaicin Induces Autophagy and Apoptosis in Human Nasopharyngeal Carcinoma Cells by Downregulating the PI3K/AKT/mTOR Pathway. Int. J. Mol. Sci. 2017;18:1343. doi: 10.3390/ijms18071343.
315. Mao X., Zhu H., Luo D., Ye L., Yin H., Zhang J., Zhang Y., Zhang Y. Capsaicin inhibits glycolysis in esophageal squamous cell carcinoma by regulating hexokinase-2 expression. Mol. Med. Rep. 2018;17:6116–6121. doi: 10.3892/mmr.2018.8574.
316. Kamaruddin M.F., Hossain M.Z., Mohamed Alabsi A., Mohd Bakri M. The Antiproliferative and Apoptotic Effects of Capsaicin on an Oral Squamous Cancer Cell Line of Asian Origin, ORL-48. Medicina. 2019;55:322. doi: 10.3390/medicina55070322.
317. Bao Z., Dai X., Wang P., Tao Y., Chai D. Capsaicin induces cytotoxicity in human osteosarcoma MG63 cells through TRPV1-dependent and-independent pathways. Cell Cycle. 2019;18:1379–1392. doi: 10.1080/15384101.2019.1618119.
318. Wu D., Jia H., Zhang Z., Li S. Capsaicin suppresses breast cancer cell viability by regulating the CDK8/PI3K/Akt/Wnt/β-catenin signaling pathway. Mol. Med. Rep. 2020;22:4868–4876. doi: 10.3892/mmr.2020.11585.
319. Zhu M., Yu X., Zheng Z., Huang J., Yang X., Shi H. Capsaicin suppressed activity of prostate cancer stem cells by inhibition of Wnt/β-catenin pathway. Phytother. Res. 2020;34:817–824. doi: 10.1002/ptr.6563.
320. Jia G., Cang S., Ma P., Song Z. Capsaicin: A “hot” KDM1A/LSD1 inhibitor from peppers. Bioorg Chem. 2020;103:104161. doi: 10.1016/j.bioorg.2020.104161.
321. Szoka L., Palka J. Capsaicin up-regulates pro-apoptotic activity of thiazolidinediones in glioblastoma cell line. Biomed. Pharmacother. 2020;132:110741. doi: 10.1016/j.biopha.2020.110741.
322. Chen M., Xiao C., Jiang W., Yang W., Qin Q., Tan Q., Lian B., Liang Z., Wei C. Capsaicin Inhibits Proliferation and Induces Apoptosis in Breast Cancer by Down-Regulating FBI-1-Mediated NF-κB Pathway. Drug Des. Dev. Ther. 2021;15:125–140. doi: 10.2147/DDDT.S269901.
323. Han T.H., Park M.K., Nakamura H., Ban H.S. Capsaicin inhibits HIF-1α accumulation through suppression of mitochondrial respiration in lung cancer cells. Biomed. Pharmacother. 2022;146:112500. doi: 10.1016/j.biopha.2021.112500.
324. Que T., Ren B., Fan Y., Liu T., Hou T., Dan W., Liu B., Wei Y., Lei Y., Zeng J., et al. Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy. Chem. Biol. Interact. 2022;366:110043. doi: 10.1016/j.cbi.2022.110043.
325. Liu X.-Y., Wei D.-G., Li R.-S. Capsaicin induces ferroptosis of NSCLC by regulating SLC7A11/GPX4 signaling in vitro. Sci. Rep. 2022;12:11996. doi: 10.1038/s41598-022-16372-3.
326. Xie Z.Q., Li H.X., Hou X.J., Huang M.Y., Zhu Z.M., Wei L.X., Tang C.X. Capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of hepatic progenitor cells via SIRT1/SOX2 signaling pathway. Cancer Med. 2022;11:4283–4296. doi: 10.1002/cam4.4777.
327. Wu L., Xu S., Cheng X., Zhang L., Wang Y., Wu J., Bao J., Yu H., Lu R. Capsaicin inhibits the stemness of anaplastic thyroid carcinoma cells by triggering autophagy-lysosome mediated OCT4A degradation. Phytother. Res. 2022;36:938–950. doi: 10.1002/ptr.7361.
328. Adetunji T.L., Olawale F., Olisah C., Adetunji A.E., Aremu A.O. Capsaicin: A Two-Decade Systematic Review of Global Research Output and Recent Advances Against Human Cancer. Front. Oncol. 2022;12:908487. doi: 10.3389/fonc.2022.908487.
329. Lau J.K., Brown K.C., Dom A.M., Witte T.R., Thornhill B.A., Crabtree C.M., Perry H.E., Brown J.M., Ball J.G., Creel R.G., et al. Capsaicin induces apoptosis in human small cell lung cancer via the TRPV6 receptor and the calpain pathway. Apoptosis. 2014;19:1190–1201. doi: 10.1007/s10495-014-1007-y.
330. Caruntu C., Boda D., Constantin C., Caruntu A., Neagu M. Catecholamines increase in vitro proliferation of murine B16F10 melanoma cells. Acta Endocrinol. 2014;10:545–558. doi: 10.4183/aeb.2014.545.
331. Scheau C., Draghici C., Ilie M.A., Lupu M., Solomon I., Tampa M., Georgescu S.R., Caruntu A., Constantin C., Neagu M., et al. Neuroendocrine Factors in Melanoma Pathogenesis. Cancers. 2021;13:2277. doi: 10.3390/cancers13092277.
332. Venier N.A., Colquhoun A.J., Sasaki H., Kiss A., Sugar L., Adomat H., Fleshner N.E., Klotz L.H., Venkateswaran V. Capsaicin: A novel radio-sensitizing agent for prostate cancer. Prostate. 2015;75:113–125. doi: 10.1002/pros.22896.
333. Min J.K., Han K.Y., Kim E.C., Kim Y.M., Lee S.W., Kim O.H., Kim K.W., Gho Y.S., Kwon Y.G. Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res. 2004;64:644–651. doi: 10.1158/0008-5472.CAN-03-3250.
334. Vendrely V., Peuchant E., Buscail E., Moranvillier I., Rousseau B., Bedel A., Brillac A., de Verneuil H., Moreau-Gaudry F., Dabernat S. Resveratrol and capsaicin used together as food complements reduce tumor growth and rescue full efficiency of low dose gemcitabine in a pancreatic cancer model. Cancer Lett. 2017;390:91–102. doi: 10.1016/j.canlet.2017.01.002.
335. Friedman J.R., Perry H.E., Brown K.C., Gao Y., Lin J., Stevenson C.D., Hurley J.D., Nolan N.A., Akers A.T., Chen Y.C., et al. Capsaicin synergizes with camptothecin to induce increased apoptosis in human small cell lung cancers via the calpain pathway. Biochem. Pharmacol. 2017;129:54–66. doi: 10.1016/j.bcp.2017.01.004.
336. Dai N., Ye R., He Q., Guo P., Chen H., Zhang Q. Capsaicin and sorafenib combination treatment exerts synergistic anti-hepatocellular carcinoma activity by suppressing EGFR and PI3K/Akt/mTOR signaling. Oncol. Rep. 2018;40:3235–3248. doi: 10.3892/or.2018.6754.
337. Friedman J.R., Richbart S.D., Merritt J.C., Perry H.E., Brown K.C., Akers A.T., Nolan N.A., Stevenson C.D., Hurley J.D., Miles S.L., et al. Capsaicinoids enhance chemosensitivity to chemotherapeutic drugs. Adv. Cancer Res. 2019;144:263–298. doi: 10.1016/bs.acr.2019.05.002.
338. Tampa M., Georgescu S.R., Mitran C.I., Mitran M.I., Matei C., Scheau C., Constantin C., Neagu M. Recent Advances in Signaling Pathways Comprehension as Carcinogenesis Triggers in Basal Cell Carcinoma. J. Clin. Med. 2020;9:3010. doi: 10.3390/jcm9093010.
339. Szolcsányi J., Barthó L. Capsaicin-sensitive afferents and their role in gastroprotection: An update. J. Physiol. Paris. 2001;95:181–188. doi: 10.1016/S0928-4257(01)00023-7.
340. Szolcsányi J., Helyes Z., Oroszi G., Németh J., Pintér E. Release of somatostatin and its role in the mediation of the anti-inflammatory effect induced by antidromic stimulation of sensory fibres of rat sciatic nerve. Br. J. Pharmacol. 1998;123:936–942. doi: 10.1038/sj.bjp.0701685.
341. Helyes Z., Thán M., Oroszi G., Pintér E., Németh J., Kéri G., Szolcsányi J. Anti-nociceptive effect induced by somatostatin released from sensory nerve terminals and by synthetic somatostatin analogues in the rat. Neurosci. Lett. 2000;278:185–188. doi: 10.1016/S0304-3940(99)00936-2.
342. Pintér E., Helyes Z., Szolcsányi J. Inhibitory effect of somatostatin on inflammation and nociception. Pharmacol. Ther. 2006;112:440–456. doi: 10.1016/j.pharmthera.2006.04.010.
343. Szolcsányi J. Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides. 2004;38:377–384. doi: 10.1016/j.npep.2004.07.005.
344. Evers B.M., Parekh D., Townsend C.M., Jr., Thompson J.C. Somatostatin and analogues in the treatment of cancer. A review. Ann. Surg. 1991;213:190–198. doi: 10.1097/00000658-199103000-00002.
345. Weckbecker G., Raulf F., Stolz B., Bruns C. Somatostatin analogs for diagnosis and treatment of cancer. Pharmacol. Ther. 1993;60:245–264. doi: 10.1016/0163-7258(93)90009-3.
346. Scarpignato C., Pelosini I. Somatostatin Analogs for Cancer Treatment and Diagnosis: An Overview. Chemotherapy. 2001;47((Suppl. 2)):1–29. doi: 10.1159/000049157.
347. Lamberts S.W.J., de Herder W.W., Hofland L.J. Somatostatin analogs in the diagnosis and treatment of cancer. Trends Endocrinol. Metab. 2002;13:451–457. doi: 10.1016/S1043-2760(02)00667-7.
348. Froidevaux S., Eberle A.N. Somatostatin analogs and radiopeptides in cancer therapy. Pept. Sci. 2002;66:161–183. doi: 10.1002/bip.10256.
349. Klironomos S., Notas G., Sfakianaki O., Kiagiadaki F., Xidakis C., Kouroumalis E. Octreotide modulates the effects on fibrosis of TNF-α, TGF-β and PDGF in activated rat hepatic stellate cells. Regul. Pept. 2014;188:5–12. doi: 10.1016/j.regpep.2013.11.002.
350. Ayiomamitis G.D., Notas G., Zaravinos A., Drygiannakis I., Georgiadou M., Sfakianaki O., Mastrodimou N., Thermos K., Kouroumalis E. Effects of octreotide and insulin on colon cancer cellular proliferation and correlation with hTERT activity. Oncoscience. 2014;1:457. doi: 10.18632/oncoscience.58.
351. Kouroumalis E., Samonakis D., Notas G. Somatostatin in hepatocellular carcinoma: Experimental and therapeutic implications. Hepatoma Res. 2018;4:34. doi: 10.20517/2394-5079.2018.33.
352. Periferakis A., Tsigas G., Periferakis A.-T., Badarau I.A., Scheau A.-E., Tampa M., Georgescu S.R., Didilescu A.C., Scheau C., Caruntu C. Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma. Anal. Cell. Pathol. 2021;2021:1840069. doi: 10.1155/2021/1840069.
353. Kouroumalis E., Tsomidis I., Voumvouraki A. Is There a Place for Somatostatin Analogues for the Systemic Treatment of Hepatocellular Carcinoma in the Immunotherapy Era? Livers. 2022;2:315–335. doi: 10.3390/livers2040024.
354. Qin J.C., Yu W.T., Li H.X., Liang Y.Q., Nong F.F., Wen B. Cold exposure and capsaicin promote 1,2-dimethylhyrazine-induced colon carcinogenesis in rats correlates with extracellular matrix remodeling. World J. Gastroenterol. 2021;27:6615–6630. doi: 10.3748/wjg.v27.i39.6615.
355. Kim H.S., Kwon H.J., Kim G.E., Cho M.H., Yoon S.Y., Davies A.J., Oh S.B., Lee H., Cho Y.K., Joo C.H., et al. Attenuation of natural killer cell functions by capsaicin through a direct and TRPV1-independent mechanism. Carcinogenesis. 2014;35:1652–1660. doi: 10.1093/carcin/bgu091.
356. Liu Z., Zhu P., Tao Y., Shen C., Wang S., Zhao L., Wu H., Fan F., Lin C., Chen C., et al. Cancer-promoting effect of capsaicin on DMBA/TPA-induced skin tumorigenesis by modulating inflammation, Erk and p38 in mice. Food Chem. Toxicol. 2015;81:1–8. doi: 10.1016/j.fct.2015.04.002.
357. Cheng P., Wu J., Zong G., Wang F., Deng R., Tao R., Qian C., Shan Y., Wang A., Zhao Y., et al. Capsaicin shapes gut microbiota and pre-metastatic niche to facilitate cancer metastasis to liver. Pharmacol. Res. 2023;188:106643. doi: 10.1016/j.phrs.2022.106643.
358. Andrews J. Peppers: The Domesticated Capsicums. University of Texas Press; Austin, TX, USA: 1995.
359. Nabhan G.P. Why Some Like It Hot: Food, Genes, and Cultural Diversity. Island Press; Washington, DC, USA: 2004.
360. Kim S., Park M., Yeom S.I., Kim Y.M., Lee J.M., Lee H.A., Seo E., Choi J., Cheong K., Kim K.T., et al. Genome sequence of the hot pepper provides insights into the evolution of pungency in Capsicum species. Nat. Genet. 2014;46:270–278. doi: 10.1038/ng.2877.
361. Basu S.K., De A.K. Capsicum. CRC Press; Boca Raton, FL, USA: 2003. Capsicum: Historical and botanical perspectives; pp. 21–35.
362. Eshbaugh W.H. Genetic and biochemical systematic studies of chili peppers (Capsicum-Solanaceae) Bull. Torrey Bot. Club. 1975;102:396–403. doi: 10.2307/2484766.
363. Eshbaugh W.H. Peppers: Botany, Production and Uses. CAB International; Wallingford UK: 2012. The taxonomy of the genus Capsicum; pp. 14–28.
364. Heiser C.B., Jr., Pickersgill B. Names for the Cultivated Capsicum Species (Solanaceae) Taxon. 1969;18:277–283. doi: 10.2307/1218828.
365. Votava E.J., Baral J.B., Bosland P.W. Genetic diversity of chile (Capsicum annuum var. annuum L.) landraces from northern New Mexico, Colorado, and Mexico. Econ. Bot. 2005;59:8–17. doi: 10.1663/0013-0001(2005)059[0008:GDOCCA]2.0.CO;2.
366. Dewitt D., Bosland P.W. The Complete Chile Pepper Book—A Gardener’s Guide to Choosing, Growing, Preserving and Cooking. Timber Press; London, UK: 2009.
367. Carmack R.M., Gasco J.L., Gossen G.H. The Legacy of Mesoamerica: History and Culture of a Native American Civilization. Routledge; Oxfordshire, UK: 2016.
368. Pilcher J.M. Tamales or timbales: Cuisine and the formation of Mexican national identity, 1821–1911. Americas. 1996;53:193–216. doi: 10.2307/1007616.
369. Haverluk T.W. Chile peppers and identity construction in Pueblo, Colorado. J. Study Food Soc. 2002;6:45–59. doi: 10.2752/152897902786732653.
370. Meotti F.C., Lemos de Andrade E., Calixto J.B. TRP modulation by natural compounds. Handb. Exp. Pharmacol. 2014;223:1177–1238. doi: 10.1007/978-3-319-05161-1_19.
371. Padilha H., Barbieri R. Plant breeding of chili peppers (Capsicum, Solanaceae)-A review. Aust. J. Basic. Appl. Sci. 2016;10:148–154.
372. Romero Cóndor C., Acurio L., Paucar-Ayala S., Herrera-Robalino J., Cabrera H., Albán-Villacreces A., Sangucho-Montenegro C., Veliz-Zambrano M. Brief Historical review of the geological cartography in Ecuador. Cienc. Lat. Rev. Científica Multidiscip. 2023;7:2584–2621. doi: 10.37811/cl_rcm.v7i4.7128.
373. Grieder T., Bueno Mendoza A., Smith C.E., Malina R.M. La Galgada, Peru: A Preceramic Culture in Transition. University of Texas Press; Austin, TX, USA: 1988. La Galgada in the World of Its Time; pp. 192–203.
374. Pearsall D.M. The Handbook of South American Archaeology. Springer; Berlin/Heidelberg, Germany: 2008. Plant domestication and the shift to agriculture in the Andes; pp. 105–120.
375. Lanning E.P. Peru before the Incas. Prentice-Hall; Saddle River, NJ, USA: 1967.
376. Sarmiento de Gamboa P. The History of the Incas. University of Texas Press; Austin, TX, USA: 2007.
377. Thompson J.E.S. Maya History and Religion. Volume 99 University of Oklahoma Press; Norman, OK, USA: 1990.
378. Smith M.E. The Aztecs. John Wiley & Sons; Hoboken, NJ, USA: 2013.
379. Periferakis A. Geology and the Aztecs: How the Ore Deposits of Mesoamerica Influenced the Socioeconomic Development of an Empire, from its Emergence to its Downfall; Proceedings of the 15th International Congress of the Geological Society of Greece; Athens, Greece. 22–24 May 2019; pp. 700–701.
380. Periferakis A. The Influence of Ore Deposits to the Development and Collapse of the Inca Civilisation between the 15th and the 16th Century; Proceedings of the 15th International Congress of the Geological Society of Greece; Athens, Greece. 22–24 May 2019; pp. 702–703.
381. De Feo V. The ritual use of Brugmansia species in traditional Andean medicine in Northern Peru. Econ. Bot. 2004;58:S221–S229. doi: 10.1663/0013-0001(2004)58[S221:TRUOBS]2.0.CO;2.
382. Dafni A., Petanidou T., Vallianatou I., Kozhuharova E., Blanché C., Pacini E., Peyman M., Dajić Stevanovic Z., Franchi G.G., Benítez G. Myrtle, Basil, Rosemary, and Three-Lobed Sage as Ritual Plants in the Monotheistic Religions: An Historical–Ethnobotanical Comparison. Econ. Bot. 2020;74:330–355. doi: 10.1007/s12231-019-09477-w.
383. Kohek M., Sánchez Avilés C., Romaní O., Bouso J.C. Ancient psychoactive plants in a global village: The ritual use of cannabis in a self-managed community in Catalonia. Int. J. Drug Policy. 2021;98:103390. doi: 10.1016/j.drugpo.2021.103390.
384. Yaldiz G., Ozguven M., Sekeroglu N. Variation in capsaicin contents of different Capsicum species and lines by varying drying parameters. Ind. Crops Prod. 2010;32:434–438. doi: 10.1016/j.indcrop.2010.06.013.
385. Cho H., Kwon Y. Development of a database of capsaicinoid contents in foods commonly consumed in Korea. Food Sci. Nutr. 2020;8:4611–4624. doi: 10.1002/fsn3.1785.
386. Ganguly S., Praveen P.K., Para P.A., Sharma V. Medicinal Properties of chilli pepper in human diet: An editorial. ARC J. Public. Health Community Med. 2017;2:6–7.
387. Aguilar-Meléndez A., Vásquez-Dávila M.A., Manzanero-Medina G.I., Katz E. Chile (Capsicum spp.) as Food-Medicine Continuum in Multiethnic Mexico. Foods. 2021;10:2502. doi: 10.3390/foods10102502.
388. Martínez-Aceviz Y., Sobrevilla-Navarro A.A., Ramos-Lopez O. Dietary Intake of Capsaicin and Its Association with Markers of Body Adiposity and Fatty Liver in a Mexican Adult Population of Tijuana. Healthcare. 2023;11:3001. doi: 10.3390/healthcare11223001.
389. Meghvansi M.K., Siddiqui S., Khan M.H., Gupta V.K., Vairale M.G., Gogoi H.K., Singh L. Naga chilli: A potential source of capsaicinoids with broad-spectrum ethnopharmacological applications. J. Ethnopharmacol. 2010;132:1–14. doi: 10.1016/j.jep.2010.08.034.
390. Saleh B.K., Omer A., Teweldemedhin B. Medicinal uses and health benefits of chili pepper (Capsicum spp.): A review. MOJ Food Process Technol. 2018;6:325–328. doi: 10.15406/mojfpt.2018.06.00183.
391. Montiel-Oseguera A. La Persistencia de la Costumbre Pima. Interpretaciones Desde La Antropología Cognitiva. UAM, INAH y ENAH del Norte de México; Mexico City, Mexico: 2013.
392. Long-Solís J. Capsicum y Cultura: La Historia Del Chilli. Fondo De Cultura Economica; Mexico City, Mexico: 2013.
393. Rakhshandehroo E., Asadpour M., Jafari A., Malekpour S.H. The effectiveness of Cinnamomum zeylanicum, Punica granatum flower and Capsicum annuum extracts against Parascaris equorum infective larvae. İstanbul Üniversitesi Vet. Fakültesi Derg. 2016;42:132–137. doi: 10.16988/iuvfd.2016.91882.
394. Frei B., Baltisberger M., Sticher O., Heinrich M. Medical ethnobotany of the Zapotecs of the Isthmus-Sierra (Oaxaca, Mexico): Documentation and assessment of indigenous uses. J. Ethnopharmacol. 1998;62:149–165. doi: 10.1016/S0378-8741(98)00051-8.
395. Irigoyen-Rascón F., Paredes A. Tarahumara Medicine: Ethnobotany and Healing among the Rarámuri of Mexico. University of Oklahoma Press; Norman, OK, USA: 2015.
396. Alcorn J.B. Huastec Mayan Ethnobotany. University of Texas Press; Austin, TX, USA: 1984.
397. Martínez T.H.L. Master’s Thesis. Colegio de postgraduados, campus Montecillo Botánica; Montecillo, Mexico: 2007. Etnobotánica del Chile Quipín (Capsicum annuum var. glabriusculum) en la Sierra Gorda y Semidesierto de Querétaro.
398. Fiedor J., Burda K. Potential role of carotenoids as antioxidants in human health and disease. Nutrients. 2014;6:466–488. doi: 10.3390/nu6020466.
399. da Silva L.R., Silva B. Natural Bioactive Compounds from Fruits and Vegetables as Health Promoters Part I. Bentham Science Publishers; Sharjah, United Arab Emirates: 2016.
400. Roys R.L. The Ethno-Botany of the Maya. Tulane University; New Orleans, LA, USA: 1931.
401. López Austin A. Textos acerca de las partes del cuerpo humano y de las enfermedades y medicinas en los primeros memoriales de Sahagún. Estud. Cult. Nahuatl. 1972;10:129–153.
402. Madero R.A. Recetario Totonaco de la Costa de Veracruz. Dirección General de Culturas Populares de Conaculta; Mexico City, Mexico: 2000.
403. Bañuelos N., Salido P.L., Gardea A. Etnobotánica del chiltepín: Pequeño gran señor en la cultura de los sonorenses. Estud. Soc. 2008;16:177–205.
404. Magaña Alejandro M.A., Gama Campillo L.M., Mariaca Méndez R. El uso de las plantas medicinales en las comunidades Maya-Chontales de Nacajuca, Tabasco, México. Polibotánica. 2010;29:213–262.
405. Cook S. The Forest of the Lacandon Maya: An Ethnobotanical Guide. Springer; Berlin/Heidelberg, Germany: 2016.
406. Aguilar-Meléndez A., Vásquez M.A., Katz E., Colorado M.R.H. Los Chiles Que le Dan Sabor al Mundo: Contribuciones MULTIDISCIPLINARIAS. IRD Éditions; Paris, France: 2018.
407. Breedlove D.E., Laughlin R.M. Flowering of Man: A Tzotzil Botany of Zinacantán. Volume 2 Smithsonian Institution Press; Washington, DC, USA: 1993.
408. Chemin Bassler H. Recetario Pame de San Luis Potosí y Querétaro. Dirección General de Culturas Populares, Consejo Nacional para la Cultura y las Artes; Coyoacán, México: 2000.
409. Laughlin R.M. Handbook of Middle American Indians. Volume 7. University of Texas Press; Austin, TX, USA: 1969. The Huastec; pp. 298–311.
410. Fernández D.L. Medicina indígena y males infantiles entre los nahuas de Texcoco: Pérdida de la guía, caída de mollera, tiricia y mal de ojo. Proc. An. De Antropol. 2015;49:101–148. doi: 10.1016/S0185-1225(15)30005-9.
411. Geck M.S., Cabras S., Casu L., Reyes García A.J., Leonti M. The taste of heat: How humoral qualities act as a cultural filter for chemosensory properties guiding herbal medicine. J. Ethnopharmacol. 2017;198:499–515. doi: 10.1016/j.jep.2017.01.027.
412. Alayza Escardó F. Historia de la Cirugia en el Peru. Editorial Monterrico, S.A.; Lima, Peru: 1992. Historia de la Cirugía en el Perú.
413. Froeschner E.H. Two examples of ancient skull surgery. J. Neurosurg. 1992;76:550–552. doi: 10.3171/jns.1992.76.3.0550.
414. Periferakis A. A review of obsidian source exploitation in pre-columbian south America. Bull. Geol. Soc. Greece. 2019;55:65–108. doi: 10.12681/bgsg.20997.
415. Schmiedel U., Araya Y., Bortolotto M.I., Boeckenhoff L., Hallwachs W., Janzen D., Kolipaka S.S., Novotny V., Palm M., Parfondry M., et al. Contributions of paraecologists and parataxonomists to research, conservation, and social development. Conserv. Biol. 2016;30:506–519. doi: 10.1111/cobi.12661.
416. Nabhan G.P. Ethnobiology for the Future: Linking Cultural and Ecological Diversity. University of Arizona Press; Tucson, AZ, USA: 2016.
417. Fan Y., Kim D.H., Gwak Y.S., Ahn D., Ryu Y., Chang S., Lee B.H., Bills K.B., Steffensen S.C., Yang C.H., et al. The role of substance P in acupuncture signal transduction and effects. Brain Behav. Immun. 2021;91:683–694. doi: 10.1016/j.bbi.2020.08.016.
418. Du G.-h., Yuan T.-y., Du L.-d., Zhang Y.-x. Chapter Twelve—The Potential of Traditional Chinese Medicine in the Treatment and Modulation of Pain. In: Barrett J.E., editor. Advances in Pharmacology. Volume 75. Academic Press; Cambridge, MA, USA: 2016. pp. 325–361.
419. Li S.-H., Li L., Yang R.-N., Liang S.-D. Compounds of traditional Chinese medicine and neuropathic pain. Chin. J. Nat. Med. 2020;18:28–35. doi: 10.1016/S1875-5364(20)30002-9.
420. Ghiţă M.A., Căruntu C., Rosca A.E., Căruntu A., Moraru L., Constantin C., Neagu M., Boda D. Real-Time Investigation of Skin Blood Flow Changes Induced by Topical Capsaicin. Acta Dermatovenerol. Croat. 2017;25:223–227.
421. Final report on the safety assessment of capsicum annuum extract, capsicum annuum fruit extract, capsicum annuum resin, capsicum annuum fruit powder, capsicum frutescens fruit, capsicum frutescens fruit extract, capsicum frutescens resin, and capsaicin. Int. J. Toxicol. 2007;26((Suppl. 1)):3–106. doi: 10.1080/10915810601163939.
422. Surh Y.-J., Sup Lee S. Capsaicin, a double-edged sword: Toxicity, metabolism, and chemopreventive potential. Life Sci. 1995;56:1845–1855. doi: 10.1016/0024-3205(95)00159-4.
423. Weinberg R.B. Hunan hand. N. Engl. J. Med. 1981;305:1020.
424. Williams S.R., Clark R.F., Dunford J.V. Contact Dermatitis Associated with Capsaicin: Hunan Hand Syndrome. Ann. Emerg. Med. 1995;25:713–715. doi: 10.1016/S0196-0644(95)70188-5.
425. Jancsó G., Király E., Such G., Joó F., Nagy A. Neurotoxic effect of capsaicin in mammals. Acta Physiol. Hung. 1987;69:295–313.
426. Ritter S., Dinh T.T. Capsaicin-induced neuronal degeneration in the brain and retina of preweanling rats. J. Comp. Neurol. 1990;296:447–461. doi: 10.1002/cne.902960310.
427. Lechner A., Alderson T., Gautam S., Flaker G. Ventricular fibrillation due to coronary spasm after pepper spray. Pacing Clin. Electrophysiol. 2021;44:548–551. doi: 10.1111/pace.14146.
428. Xu Y., Gu Q., Qu C. Capsaicin pretreatment reversed pulmonary arterial hypertension by alleviating inflammation via p38MAPK pathway. Exp. Lung Res. 2017;43:8–18. doi: 10.1080/01902148.2016.1271481.
429. Baz R.A., Scheau C., Niscoveanu C., Bordei P. Morphometry of the Entire Internal Carotid Artery on CT Angiography. Medicina. 2021;57:832. doi: 10.3390/medicina57080832.
430. Augustin H.G., Koh G.Y. Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology. Science. 2017;357:eaal2379. doi: 10.1126/science.aal2379.
431. MacAlpin R.N. Contribution of dynamic vascular wall thickening to luminal narrowing during coronary arterial constriction. Circulation. 1980;61:296–301. doi: 10.1161/01.CIR.61.2.296.
432. Liu B., Yang H., Song Y.S., Sorenson C.M., Sheibani N. Thrombospondin-1 in vascular development, vascular function, and vascular disease. Semin. Cell Dev. Biol. 2024;155:32–44. doi: 10.1016/j.semcdb.2023.07.011.
433. Bergren D.R. Capsaicin challenge, reflex bronchoconstriction, and local action of substance P. Am. J. Physiol. 1988;254:R845–R852. doi: 10.1152/ajpregu.1988.254.5.R845.
434. Thomas K.C., Ethirajan M., Shahrokh K., Sun H., Lee J., Cheatham T.E., 3rd, Yost G.S., Reilly C.A. Structure-activity relationship of capsaicin analogs and transient receptor potential vanilloid 1-mediated human lung epithelial cell toxicity. J. Pharmacol. Exp. Ther. 2011;337:400–410. doi: 10.1124/jpet.110.178491.
435. Trevisan G., Rossato M.F., Hoffmeister C., Oliveira S.M., Silva C.R., Matheus F.C., Mello G.C., Antunes E., Prediger R.D., Ferreira J. Mechanisms involved in abdominal nociception induced by either TRPV1 or TRPA1 stimulation of rat peritoneum. Eur. J. Pharmacol. 2013;714:332–344. doi: 10.1016/j.ejphar.2013.07.029.
436. Lee K.J., Vos R., Tack J. Effects of capsaicin on the sensorimotor function of the proximal stomach in humans. Aliment. Pharmacol. Ther. 2004;19:415–425. doi: 10.1046/j.1365-2036.2004.01823.x.
437. Kwon Y. Estimation of Dietary Capsaicinoid Exposure in Korea and Assessment of Its Health Effects. Nutrients. 2021;13:2461. doi: 10.3390/nu13072461.
438. Lassen C.L., Meyer K., Bredthauer A., Klier T.W. Facial and Oral Cross-Contamination of a 3-Year-Old Child with High Concentration Capsaicin: A Case Report. A A Pract. 2020;14:e01258. doi: 10.1213/XAA.0000000000001258.
439. Forrester M.B., Holloway C. Characteristics of pepper spray-related injuries reported to the National Electronic Injury Surveillance System during 2000–2020. Clin. Toxicol. 2022;60:348–355. doi: 10.1080/15563650.2021.1966028.
440. Dragosloveanu C.D.M., Celea C.G., Dragosloveanu S. Comparison of 360 degrees circumferential trabeculotomy and conventional trabeculotomy in primary pediatric glaucoma surgery: Complications, reinterventions and preoperative predictive risk factors. Int. Ophthalmol. 2020;40:3547–3554. doi: 10.1007/s10792-020-01544-9.
441. Yenigun O.M., Thanassi M. Capsaicin: An Uncommon Exposure and Unusual Treatment. Clin. Pract. Cases Emerg. Med. 2019;3:219–221. doi: 10.5811/cpcem.2019.3.41231.
442. Kim-Katz S.Y., Anderson I.B., Kearney T.E., MacDougall C., Hudmon K.S., Blanc P.D. Topical antacid therapy for capsaicin-induced dermal pain: A poison center telephone-directed study. Am. J. Emerg. Med. 2010;28:596–602. doi: 10.1016/j.ajem.2009.02.007.
443. Yeung M.F., Tang W.Y. Clinicopathological effects of pepper (oleoresin capsicum) spray. Hong Kong Med. J. 2015;21:542–552. doi: 10.12809/hkmj154691.
444. Çirakli S., Doganay S., Kaya Ozcora G.D., Canpolat M., Kumandas S. Biber gazı maruziyeti sonucu gelişen Guillain-Barre sendromunu taklit eden polinöropati. Türk. Pediatri. Arşivi. 2019;54:53–56. doi: 10.14744/TurkPediatriArs.2019.52533.
445. Snyman T., Stewart M.J., Steenkamp V. A fatal case of pepper poisoning. Forensic Sci. Int. 2001;124:43–46. doi: 10.1016/S0379-0738(01)00571-0.
446. Akçay A.B., Ozcan T., Seyis S., Acele A. Coronary vasospasm and acute myocardial infarction induced by a topical capsaicin patch. Turk. Kardiyol. Dern. Ars. 2009;37:497–500.
447. Xie M., Wu H., Bian J., Huang S., Xia Y., Qin Y., Yan Z. Synthesis and biological evaluation of capsaicin analogues as antioxidant and neuroprotective agents. RSC Adv. 2023;13:32150–32159. doi: 10.1039/D3RA05107B.
448. Dou F., Wu B., Chen J., Liu T., Yu Z., Chen C. Capsaicin inhibits A7r5 cell senescence via the mitochondrial carrier protein Slc25a12. Exp. Cell Res. 2023;433:113856. doi: 10.1016/j.yexcr.2023.113856.
449. Xu S., Hao K., Xiong Y., Xu R., Huang H., Wang H. Capsaicin alleviates neuronal apoptosis and schizophrenia-like behavioral abnormalities induced by early life stress. Schizophrenia. 2023;9:77. doi: 10.1038/s41537-023-00406-4.
450. Wang L., Liu Y., Li S., Zha Z., Chen Y., Wang Q., Zhou S., Huang X., Xu M. Capsaicin alleviates doxorubicin-induced acute myocardial injury by regulating iron homeostasis and PI3K-Akt signaling pathway. Aging. 2023;15:11845–11859. doi: 10.18632/aging.205138.
451. Dragoș D., Petran M., Gradinaru T.C., Gilca M. Phytochemicals and Inflammation: Is Bitter Better? Plants. 2022;11:2991. doi: 10.3390/plants11212991.
452. D’Urso O., Drago F. Pharmacological significance of extra-oral taste receptors. Eur. J. Pharmacol. 2021;910:174480. doi: 10.1016/j.ejphar.2021.174480.
453. Töle J.C., Behrens M., Meyerhof W. Taste receptor function. Handb. Clin. Neurol. 2019;164:173–185. doi: 10.1016/b978-0-444-63855-7.00011-3.
454. Behrens M., Lang T. Extra-Oral Taste Receptors-Function, Disease, and Perspectives. Front. Nutr. 2022;9:881177. doi: 10.3389/fnut.2022.881177.
455. Nevo S., Kadouri N., Abramson J. Tuft cells: From the mucosa to the thymus. Immunol. Lett. 2019;210:1–9. doi: 10.1016/j.imlet.2019.02.003.
456. O’Leary C.E., Schneider C., Locksley R.M. Tuft Cells-Systemically Dispersed Sensory Epithelia Integrating Immune and Neural Circuitry. Annu. Rev. Immunol. 2019;37:47–72. doi: 10.1146/annurev-immunol-042718-041505.
457. Howitt M.R., Cao Y.G., Gologorsky M.B., Li J.A., Haber A.L., Biton M., Lang J., Michaud M., Regev A., Garrett W.S. The Taste Receptor TAS1R3 Regulates Small Intestinal Tuft Cell Homeostasis. Immunohorizons. 2020;4:23–32. doi: 10.4049/immunohorizons.1900099.
458. Ki S.Y., Jeong Y.T. Taste Receptors beyond Taste Buds. Int. J. Mol. Sci. 2022;23:9677. doi: 10.3390/ijms23179677.
459. Hendel S.K., Kellermann L., Hausmann A., Bindslev N., Jensen K.B., Nielsen O.H. Tuft Cells and Their Role in Intestinal Diseases. Front. Immunol. 2022;13:822867. doi: 10.3389/fimmu.2022.822867.
460. Sell E.A., Ortiz-Carpena J.F., Herbert D.R., Cohen N.A. Tuft cells in the pathogenesis of chronic rhinosinusitis with nasal polyps and asthma. Ann. Allergy Asthma Immunol. 2021;126:143–151. doi: 10.1016/j.anai.2020.10.011.
461. Xiong Z., Zhu X., Geng J., Xu Y., Wu R., Li C., Fan D., Qin X., Du Y., Tian Y., et al. Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine. Immunity. 2022;55:686–700.e7. doi: 10.1016/j.immuni.2022.03.001.
462. O’Leary C.E., Sbierski-Kind J., Kotas M.E., Wagner J.C., Liang H.E., Schroeder A.W., de Tenorio J.C., von Moltke J., Ricardo-Gonzalez R.R., Eckalbar W.L., et al. Bile acid-sensitive tuft cells regulate biliary neutrophil influx. Sci. Immunol. 2022;7:eabj1080. doi: 10.1126/sciimmunol.abj1080.
463. Merritt J.C., Richbart S.D., Moles E.G., Cox A.J., Brown K.C., Miles S.L., Finch P.T., Hess J.A., Tirona M.T., Valentovic M.A., et al. Anti-cancer activity of sustained release capsaicin formulations. Pharmacol. Ther. 2022;238:108177. doi: 10.1016/j.pharmthera.2022.108177.
464. Chapa-Oliver A.M., Mejía-Teniente L. Capsaicin: From Plants to a Cancer-Suppressing Agent. Molecules. 2016;21:931. doi: 10.3390/molecules21080931.
465. Cassano R., Serini S., Curcio F., Trombino S., Calviello G. Preparation and Study of Solid Lipid Nanoparticles Based on Curcumin, Resveratrol and Capsaicin Containing Linolenic Acid. Pharmaceutics. 2022;14:1593. doi: 10.3390/pharmaceutics14081593.
466. Matei A.-M., Caruntu C., Tampa M., Georgescu S.R., Matei C., Constantin M.M., Constantin T.V., Calina D., Ciubotaru D.A., Badarau I.A., et al. Applications of Nanosized-Lipid-Based Drug Delivery Systems in Wound Care. Appl. Sci. 2021;11:4915. doi: 10.3390/app11114915.
467. Anantaworasakul P., Chaiyana W., Michniak-Kohn B.B., Rungseevijitprapa W., Ampasavate C. Enhanced Transdermal Delivery of Concentrated Capsaicin from Chili Extract-Loaded Lipid Nanoparticles with Reduced Skin Irritation. Pharmaceutics. 2020;12:463. doi: 10.3390/pharmaceutics12050463.
468. Zhen X., Xie C., Jiang Y., Ai X., Xing B., Pu K. Semiconducting Photothermal Nanoagonist for Remote-Controlled Specific Cancer Therapy. Nano Lett. 2018;18:1498–1505. doi: 10.1021/acs.nanolett.7b05292.
469. Bhagwat D.A., Swami P.A., Nadaf S.J., Choudhari P.B., Kumbar V.M., More H.N., Killedar S.G., Kawtikwar P.S. Capsaicin Loaded Solid SNEDDS for Enhanced Bioavailability and Anticancer Activity: In-Vitro, In-Silico, and In-Vivo Characterization. J. Pharm. Sci. 2021;110:280–291. doi: 10.1016/j.xphs.2020.10.020.
470. Xu M., Zhang J., Mu Y., Foda M.F., Han H. Activation of TRPV1 by capsaicin-loaded CaCO3 nanoparticle for tumor-specific therapy. Biomaterials. 2022;284:121520. doi: 10.1016/j.biomaterials.2022.121520.
471. Periferakis A., Periferakis A.-T., Troumpata L., Dragosloveanu S., Timofticiuc I.-A., Georgatos-Garcia S., Scheau A.-E., Periferakis K., Caruntu A., Badarau I.A., et al. Use of Biomaterials in 3D Printing as a Solution to Microbial Infections in Arthroplasty and Osseous Reconstruction. Biomimetics. 2024;9:154. doi: 10.3390/biomimetics9030154.
472. Timofticiuc I.-A., Călinescu O., Iftime A., Dragosloveanu S., Caruntu A., Scheau A.-E., Badarau I.A., Didilescu A.C., Caruntu C., Scheau C. Biomaterials Adapted to Vat Photopolymerization in 3D Printing: Characteristics and Medical Applications. J. Funct. Biomater. 2024;15:7. doi: 10.3390/jfb15010007.
473. Yu T., Tong L., Ao Y., Zhang G., Liu Y., Zhang H. Novel design of NIR-triggered plasmonic nanodots capped mesoporous silica nanoparticles loaded with natural capsaicin to inhibition of metastasis of human papillary thyroid carcinoma B-CPAP cells in thyroid cancer chemo-photothermal therapy. J. Photochem. Photobiol. B. 2019;197:111534. doi: 10.1016/j.jphotobiol.2019.111534.
474. Lee J.Y., Lee S.Y., Kim G.G., Hur M.G., Yang S.D., Park J.H., Kim S.W. Development of (68)Ga-SCN-DOTA-Capsaicin as an Imaging Agent Targeting Apoptosis and Cell Cycle Arrest in Breast Cancer. Cancer Biother. Radiopharm. 2017;32:169–175. doi: 10.1089/cbr.2017.2186.
475. Dong Y., Yin Y., Vu S., Yang F., Yarov-Yarovoy V., Tian Y., Zheng J. A distinct structural mechanism underlies TRPV1 activation by piperine. Biochem. Biophys. Res. Commun. 2019;516:365–372. doi: 10.1016/j.bbrc.2019.06.039.
476. McNamara F.N., Randall A., Gunthorpe M.J. Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1) Br. J. Pharmacol. 2005;144:781–790. doi: 10.1038/sj.bjp.0706040.
477. Arunprasert K., Pornpitchanarong C., Piemvuthi C., Siraprapapornsakul S., Sripeangchan S., Lertsrimongkol O., Opanasopit P., Patrojanasophon P. Nanostructured lipid carrier-embedded polyacrylic acid transdermal patches for improved transdermal delivery of capsaicin. Eur. J. Pharm. Sci. 2022;173:106169. doi: 10.1016/j.ejps.2022.106169.
478. Kolonko A.K., Efing J., González-Espinosa Y., Bangel-Ruland N., van Driessche W., Goycoolea F.M., Weber W.M. Capsaicin-Loaded Chitosan Nanocapsules for wtCFTR-mRNA Delivery to a Cystic Fibrosis Cell Line. Biomedicines. 2020;8:364. doi: 10.3390/biomedicines8090364.
479. Manzo E., Schiano Moriello A., Tinto F., Verde R., Allarà M., De Petrocellis L., Pagano E., Izzo A.A., Di Marzo V., Petrosino S. A Glucuronic Acid-Palmitoylethanolamide Conjugate (GLUPEA) Is an Innovative Drug Delivery System and a Potential Bioregulator. Cells. 2021;10:450. doi: 10.3390/cells10020450.
480. Scheau C., Mihai L., Badarau I.A., Caruntu C. Emerging applications of some important natural compounds in the field of oncology. Farmacia. 2020;68:984–991. doi: 10.31925/farmacia.2020.6.4.
481. Rajput H., Nangare S., Khan Z., Patil A., Bari S., Patil P. Design of lactoferrin functionalized carboxymethyl dextran coated egg albumin nanoconjugate for targeted delivery of capsaicin: Spectroscopic and cytotoxicity studies. Int. J. Biol. Macromol. 2023;256:128392. doi: 10.1016/j.ijbiomac.2023.128392.
482. Leibing E., Leonhardt U., Köster G., Goerlitz A., Rosenfeldt J.-A., Hilgers R., Ramadori G. Acupuncture treatment of chronic low-back pain—A randomized, blinded, placebo-controlled trial with 9-month follow-up. Pain. 2002;96:189–196. doi: 10.1016/S0304-3959(01)00444-4.
483. Mavrommatis C.I., Argyra E., Vadalouka A., Vasilakos D.G. Acupuncture as an adjunctive therapy to pharmacological treatment in patients with chronic pain due to osteoarthritis of the knee: A 3-armed, randomized, placebo-controlled trial. Pain. 2012;153:1720–1726. doi: 10.1016/j.pain.2012.05.005.
484. Müller M., Schmucker C., Naumann J., Schlueter N., Huber R., Lederer A.K. Acupuncture in management of acute dental pain—A systematic review and meta-analysis. Jpn. Dent. Sci. Rev. 2023;59:114–128. doi: 10.1016/j.jdsr.2023.02.005.
485. Zhou M., Zhang Q., Huo M., Song H., Chang H., Cao J., Fang Y., Zhang D. The mechanistic basis for the effects of electroacupuncture on neuropathic pain within the central nervous system. Biomed. Pharmacother. 2023;161:114516. doi: 10.1016/j.biopha.2023.114516.
486. Lu W.W., Zhang J.M., Lv Z.T., Chen A.M. Update on the Clinical Effect of Acupuncture Therapy in Patients with Gouty Arthritis: Systematic Review and Meta-Analysis. Evid. Based Complement. Altern. Med. 2016;2016:9451670. doi: 10.1155/2016/9451670.
487. Chen Y., Chen X., Qian H., Li B., Su X. Acupuncture alleviates acute peritonitis: A case report. Heliyon. 2023;9:e15290. doi: 10.1016/j.heliyon.2023.e15290.
488. Periferakis K., Periferakis A. Treating gout caused by renal insufficiency with acupuncture and moxibustion: A case report. Rom. J. Clin. Res. 2023;6:21–28.
489. Chen B., Liu D., Li T., Zheng L., Lan L., Yang N., Huang Y. Research Hotspots and Trends on Acupuncture for Anti-Inflammation: A Bibliometric Analysis from 2011 to 2021. J. Pain Res. 2023;16:1197–1217. doi: 10.2147/JPR.S398393.
490. Marini E., Magi G., Mingoia M., Pugnaloni A., Facinelli B. Antimicrobial and Anti-Virulence Activity of Capsaicin Against Erythromycin-Resistant, Cell-Invasive Group A Streptococci. Front. Microbiol. 2015;6:1281. doi: 10.3389/fmicb.2015.01281.
491. Das J., Deka M., Gogoi K. Antimicrobial activity of chilli extracts (Capsicum chinense) against food borne pathogens Escherichia coli and Staphylococcus aureus. Int. J. Res. Anal. Rev. (IJRAR) 2018;5:717–720.
492. Periferakis A.-T., Periferakis A., Periferakis K., Caruntu A., Badarau I.A., Savulescu-Fiedler I., Scheau C., Caruntu C. Antimicrobial Properties of Capsaicin: Available Data and Future Research Perspectives. Nutrients. 2023;15:4097. doi: 10.3390/nu15194097.
493. Buitimea-Cantúa G.V., Buitimea-Cantúa N.E., Rocha-Pizaña M.d.R., Hernández-Morales A., Magaña-Barajas E., Molina-Torres J. Inhibitory effect of Capsicum chinense and Piper nigrum fruits, capsaicin and piperine on aflatoxins production in Aspergillus parasiticus by downregulating the expression of afl D, afl M, afl R, and afl S genes of aflatoxins biosynthetic pathway. J. Environ. Sci. Health Part B. 2020;55:835–843. doi: 10.1080/03601234.2020.1787758.
494. Behbehani J.M., Irshad M., Shreaz S., Karched M. Anticandidal Activity of Capsaicin and Its Effect on Ergosterol Biosynthesis and Membrane Integrity of Candida albicans. Int. J. Mol. Sci. 2023;24:1046. doi: 10.3390/ijms24021046.
495. Chang A.Y., Mann T.S., McFawn P.K., Han L., Dong X., Henry P.J. Investigating the role of MRGPRC11 and capsaicin-sensitive afferent nerves in the anti-influenza effects exerted by SLIGRL-amide in murine airways. Respir. Res. 2016;17:1–14. doi: 10.1186/s12931-016-0378-8.
496. Menezes R.P., Bessa M.A.S., Siqueira C.P., Teixeira S.C., Ferro E.A.V., Martins M.M., Cunha L.C.S., Martins C.H.G. Antimicrobial, Antivirulence, and Antiparasitic Potential of Capsicum chinense Jacq. Extracts and Their Isolated Compound Capsaicin. Antibiotics. 2022;11:1154. doi: 10.3390/antibiotics11091154.
497. Tatsimo S.J.N., Tamokou J.d.D., Havyarimana L., Csupor D., Forgo P., Hohmann J., Kuiate J.-R., Tane P. Antimicrobial and antioxidant activity of kaempferol rhamnoside derivatives from Bryophyllum pinnatum. BMC Res. Notes. 2012;5:158. doi: 10.1186/1756-0500-5-158.
498. Periferakis A., Periferakis K., Badarau I.A., Petran E.M., Popa D.C., Caruntu A., Costache R.S., Scheau C., Caruntu C., Costache D.O. Kaempferol: Antimicrobial Properties, Sources, Clinical, and Traditional Applications. Int. J. Mol. Sci. 2022;23:15054. doi: 10.3390/ijms232315054.
499. Bangar S.P., Chaudhary V., Sharma N., Bansal V., Ozogul F., Lorenzo J.M. Kaempferol: A flavonoid with wider biological activities and its applications. Crit. Rev. Food Sci. Nutr. 2022;63:9580–9604. doi: 10.1080/10408398.2022.2067121.
500. Periferakis A., Periferakis A.-T., Troumpata L., Periferakis K., Scheau A.-E., Savulescu-Fiedler I., Caruntu A., Badarau I.A., Caruntu C., Scheau C. Kaempferol: A Review of Current Evidence of Its Antiviral Potential. Int. J. Mol. Sci. 2023;24:16299. doi: 10.3390/ijms242216299.
501. Hirai I., Okuno M., Katsuma R., Arita N., Tachibana M., Yamamoto Y. Characterisation of anti-Staphylococcus aureus activity of quercetin. Int. J. Food Sci. Technol. 2010;45:1250–1254. doi: 10.1111/j.1365-2621.2010.02267.x.
502. Shu Y., Liu Y., Li L., Feng J., Lou B., Zhou X., Wu H. Antibacterial activity of quercetin on oral infectious pathogens. Afr. J. Microbiol. Res. 2011;5:5358–5361.
503. Jaisinghani R.N. Antibacterial properties of quercetin. Microbiol. Res. 2017;8:6877. doi: 10.4081/mr.2017.6877.
504. Teow S.-Y., Ali S.A. Synergistic antibacterial activity of Curcumin with antibiotics against Staphylococcus aureus. Pak. J. Pharm. Sci. 2015;28:2109–2114.
505. Yun D.G., Lee D.G. Antibacterial activity of curcumin via apoptosis-like response in Escherichia coli. Appl. Microbiol. Biotechnol. 2016;100:5505–5514. doi: 10.1007/s00253-016-7415-x.
506. Gunes H., Gulen D., Mutlu R., Gumus A., Tas T., Topkaya A.E. Antibacterial effects of curcumin: An in vitro minimum inhibitory concentration study. Toxicol. Ind. Health. 2016;32:246–250. doi: 10.1177/0748233713498458.
507. Liao Y., Yao Y., Yu Y., Zeng Y. Enhanced antibacterial activity of curcumin by combination with metal ions. Colloid. Interface Sci. Commun. 2018;25:1–6. doi: 10.1016/j.colcom.2018.04.009.
508. Ojala T., Remes S., Haansuu P., Vuorela H., Hiltunen R., Haahtela K., Vuorela P. Antimicrobial activity of some coumarin containing herbal plants growing in Finland. J. Ethnopharmacol. 2000;73:299–305. doi: 10.1016/S0378-8741(00)00279-8.
509. Smyth T., Ramachandran V.N., Smyth W.F. A study of the antimicrobial activity of selected naturally occurring and synthetic coumarins. Int. J. Antimicrob. Agents. 2009;33:421–426. doi: 10.1016/j.ijantimicag.2008.10.022.
510. Al-Rifai A.a.A., Ayoub M.T., Shakya A.K., Abu Safieh K.A., Mubarak M.S. Synthesis, characterization, and antimicrobial activity of some new coumarin derivatives. Med. Chem. Res. 2012;21:468–476. doi: 10.1007/s00044-011-9553-0.
511. Wallock-Richards D., Doherty C.J., Doherty L., Clarke D.J., Place M., Govan J.R.W., Campopiano D.J. Garlic Revisited: Antimicrobial Activity of Allicin-Containing Garlic Extracts against Burkholderia cepacia Complex. PLoS ONE. 2014;9:e112726. doi: 10.1371/journal.pone.0112726.
512. Choo S., Chin V.K., Wong E.H., Madhavan P., Tay S.T., Yong P.V.C., Chong P.P. Review: Antimicrobial properties of allicin used alone or in combination with other medications. Folia Microbiol. 2020;65:451–465. doi: 10.1007/s12223-020-00786-5.
513. Nakamoto M., Kunimura K., Suzuki J.I., Kodera Y. Antimicrobial properties of hydrophobic compounds in garlic: Allicin, vinyldithiin, ajoene and diallyl polysulfides (Review) Exp. Ther. Med. 2020;19:1550–1553. doi: 10.3892/etm.2019.8388.
514. Neu H.C. The Crisis in Antibiotic Resistance. Science. 1992;257:1064–1073. doi: 10.1126/science.257.5073.1064.
515. Miyakis S., Pefanis A., Tsakris A. The Challenges of Antimicrobial Drug Resistance in Greece. Clin. Infect. Dis. 2011;53:177–184. doi: 10.1093/cid/cir323.
516. Rafila A., Talapan D., Dorobăţ O.M., Popescu G.A., Piţigoi D., Florea D., Buicu F.C. Emergence of Carbapenemase-producing Enterobacteriaceae, a Public Health Threat: A Romanian Infectious Disease Hospital Based Study/Emergenţa Enterobacteriaceaelor producătoare de carbapenemaze, o ameninţare pentru sănătatea publică: Un studiu realizat într-un spital romanesc de boli infectioase. Rev. Romana De Med. De Lab. 2015;23:295–301. doi: 10.1515/rrlm-2015-0024.
517. Frieri M., Kumar K., Boutin A. Antibiotic resistance. J. Infect. Public. Health. 2017;10:369–378. doi: 10.1016/j.jiph.2016.08.007.
518. MacGowan A., Macnaughton E. Antibiotic resistance. Medicine. 2017;45:622–628. doi: 10.1016/j.mpmed.2017.07.006.
519. Popa L.I., Gheorghe I., Barbu I.C., Surleac M., Paraschiv S., Măruţescu L., Popa M., Pîrcălăbioru G.G., Talapan D., Niţă M., et al. Multidrug Resistant Klebsiella pneumoniae ST101 Clone Survival Chain from Inpatients to Hospital Effluent after Chlorine Treatment. Front. Microbiol. 2021;11:610296. doi: 10.3389/fmicb.2020.610296.
520. Tălăpan D., Rafila A. Five-Year Survey of Asymptomatic Colonization with Multidrug-Resistant Organisms in a Romanian Tertiary Care Hospital. Infect. Drug Resist. 2022;15:2959–2967. doi: 10.2147/IDR.S360048.
521. Jumaah O., Abu-Abaa M., Huang K., Hasan S. The Rare Adverse Effect of Cefepime-Induced Neutropenia. Cureus. 2023;15:e38274. doi: 10.7759/cureus.38274.
522. Massoth C., Saadat-Gilani K., Wenk M. [allergy to penicillin—No beta-lactam antibiotics?] Anasthesiol. Intensivmed. Notfallmed Schmerzther. 2023;58:264–266. doi: 10.1055/a-1933-2408.
523. Periferakis A., Caruntu A., Periferakis A.-T., Scheau A.-E., Badarau I.A., Caruntu C., Scheau C. Availability, Toxicology and Medical Significance of Antimony. Int. J. Environ. Res. Public Health. 2022;19:4669. doi: 10.3390/ijerph19084669.
524. Kang C., Wang B., Kaliannan K., Wang X., Lang H., Hui S., Huang L., Zhang Y., Zhou M., Chen M., et al. Gut Microbiota Mediates the Protective Effects of Dietary Capsaicin against Chronic Low-Grade Inflammation and Associated Obesity Induced by High-Fat Diet. mBio. 2017;8:e00470-17. doi: 10.1128/mBio.00470-17.
525. Rosca A.E., Iesanu M.I., Zahiu C.D.M., Voiculescu S.E., Paslaru A.C., Zagrean A.M. Capsaicin and Gut Microbiota in Health and Disease. Molecules. 2020;25:5681. doi: 10.3390/molecules25235681.
526. Weng G., Duan Y., Zhong Y., Song B., Zheng J., Zhang S., Yin Y., Deng J. Plant Extracts in Obesity: A Role of Gut Microbiota. Front. Nutr. 2021;8:727951. doi: 10.3389/fnut.2021.727951.
527. Dumitrache M.D., Jieanu A.S., Scheau C., Badarau I.A., Popescu G.D.A., Caruntu A., Costache D.O., Costache R.S., Constantin C., Neagu M., et al. Comparative effects of capsaicin in chronic obstructive pulmonary disease and asthma (Review) Exp. Ther. Med. 2021;22:917. doi: 10.3892/etm.2021.10349.
528. Popescu G.D.A., Scheau C., Badarau I.A., Dumitrache M.D., Caruntu A., Scheau A.E., Costache D.O., Costache R.S., Constantin C., Neagu M., et al. The Effects of Capsaicin on Gastrointestinal Cancers. Molecules. 2020;26:94. doi: 10.3390/molecules26010094.
529. Yao W., Li Y., Ding G. Interstitial fluid flow: The mechanical environment of cells and foundation of meridians. Evid. Based Complement. Altern. Med. 2012;2012:853516. doi: 10.1155/2012/853516.
530. Li H.Y., Yang J.F., Chen M., Xu L., Wang W.C., Wang F., Tong J.B., Wang C.Y. Visualized regional hypodermic migration channels of interstitial fluid in human beings: Are these ancient meridians? J. Altern. Complement. Med. 2008;14:621–628. doi: 10.1089/acm.2007.0606.
531. Ma W., Tong H., Xu W., Hu J., Liu N., Li H., Cao L. Perivascular space: Possible anatomical substrate for the meridian. J. Altern. Complement. Med. 2003;9:851–859. doi: 10.1089/107555303771952208.
532. Zhang W.B., Zhao Y., Kjell F. Understanding propagated sensation along meridians by volume transmission in peripheral tissue. Chin. J. Integr. Med. 2013;19:330–339. doi: 10.1007/s11655-013-1456-0.