In vitro decontamination efficacy of the RSDL® (Reactive Skin Decontamination Lotion Kit) lotion component against riot control agents: Capsaicin, Mace™ (CN) and CS.

The study examined the degradation of riot control agents (RCAs): 2-chloroacetophenone (CN), 2-chlorobenzalmalononitrile (CS), and capsaicin, using the Reactive Skin Decontamination Lotion Kit (RSDL®) lotion and evaluated the the direct liquid phase reactivity of the RSDL lotion component with each RCA. RSDL lotion was mixed with the selected RCAs at different molar ratios. Reactivity of the active ingredient potassium 2,3-butanedione monoximate (KBDO) with the RCA was observed for one hour. Samples of 10 µL were taken and quenched, analyzed for residual RCA using LC-MS. CN, was degraded at molar ratios of two and above in less than 2 min. At a molar ratio of 1:1 KBDO:CN, ∼90 % of CN was degraded within 2 min, the remaining 10 % residual CN was observed for one hour without any change. CS, degradation of more than 68 % of CS was achieved at 20:1 M ratio of KBDO:CS within 1 h of reaction time. For capsaicin, no degradation was observed regardless of the higher molar ratios of up to 20:1 and longer reaction times of up to one hour. This study provides evaluation of neutralizing action of the RSDL lotion without assessment of the physical removal component by the RSDL Kit.

Gaining Insights into Specific Drug Formulation Additives for Solubilizing a Potential Anti-Alzheimer Disease Drug B4A1.

The pharmacological profiles of small molecule drugs are often challenged by their poor water solubility. Sequence-defined peptides attached to poly(ethylene glycol) (PEG) offer opportunities to overcome these difficulties by acting as drug-specific formulation additives. The peptide-PEG conjugates enable specific, noncovalent drug binding via tailored peptide/drug interactions as well as provide water solubility and drug shielding by well-solvated PEG-blocks. A systematic set of specific solubilizers for B4A1 as a potential anti-Alzheimer disease drug is synthesized and variations involve the length of the PEG-blocks as well as the sequences of the peptidic drug-binding domain. The solubilizer/B4A1 complexes are studied in order to understand contributions of both PEG and peptide segments on drug payload capacities, drug/carrier aggregate sizes, and influences on inhibition of the Tau-protein aggregation in an in vitro assay.

Harnessing the Therapeutic Potential of Capsaicin and Its Analogues in Pain and Other Diseases.

Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti-inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neuro-protective functions. Moreover, emerging data indicate its clinical significance in treating vascular-related diseases, metabolic syndrome, and gastro-protective effects. The dearth of potent drugs for management of such disorders necessitates the urge for further research into the pharmacological aspects of capsaicin. This review summarizes the historical background, source, structure and analogues of capsaicin, and capsaicin-triggered TRPV1 signaling and desensitization processes. In particular, we will focus on the therapeutic roles of capsaicin and its analogues in both normal and pathophysiological conditions.

A novel 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime compound is a potent Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and V1) receptor antagonist.

Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1, TRPV1) ion channels expressed on nociceptive primary sensory neurons are important regulators of pain and inflammation. TRPA1 is activated by several inflammatory mediators including formaldehyde and methylglyoxal that are products of the semicarbazide-sensitive amine-oxidase enzyme (SSAO). SZV-1287 is a new 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime SSAO inhibitor, its chemical structure is similar to other oxime derivatives described as TRPA1 antagonists. Therefore, we investigated its effects on TRPA1 and TRPV1 receptor activation on the cell bodies and peripheral terminals of primary sensory neurons and TRPA1 or TRPV1 receptor-expressing cell lines. Calcium influx in response to the TRPA1 agonist allyl-isothiocyanate (AITC) (200 µM) and the TRPV1 stimulator capsaicin (330 nM) in rat trigeminal neurons or TRPA1 and TRPV1 receptor-expressing cell lines was measured by microfluorimetry or radioactive (45)Ca(2+) uptake experiments. Calcitonin gene-related peptide (CGRP) release as the indicator of 100 µM AITC - or 100 nM capsaicin-induced peripheral sensory nerve terminal activation was measured by radioimmunoassay. SZV-1287 (100, 500 and 1000 nM) exerted a concentration-dependent significant inhibition on both AITC- and capsaicin-evoked calcium influx in trigeminal neurons and TRPA1 or TRPV1 receptor-expressing cell lines. It also significantly inhibited the TRPA1, but not the TRPV1 activation-induced CGRP release from the peripheral sensory nerve endings in a concentration-dependent manner. In contrast, the reference SSAO inhibitor LJP 1207 with a different structure had no effect on TRPA1 or TRPV1 activation in either model system. This is the first evidence that our novel oxime compound SZV-1287 originally developed as a SSAO inhibitor has a potent dual antagonistic action on TRPA1 and TRPV1 ion channels on primary sensory neurons.

Comparison of in vitro metabolism and cytotoxicity of capsaicin and dihydrocapsaicin.

Capsaicin and dihydrocapsaicin are the major active components in pepper spray products, which are widely used for law enforcement and self-protection. The use of pepper sprays, due to their irreversible and other health effects has been under a strong debate. In this study, we compared metabolism and cytotoxicity of capsaicin and dihydrocapsaicin using human and pig liver cell fractions and human lung carcinoma cell line (A549) in vitro. Metabolites were screened and identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Using liver cell fractions, a novel aliphatic hydroxylated metabolite (m/z 322) was detected to dihydrocapsaicin but no structure was found corresponding to capsaicin. Instead, a novel phase I metabolite of capsaicin, corresponding to the structure of aliphatic demethylation and dehydrogenation (m/z 294) was identified. In addition, two novel conjugates, glycine conjugates (m/z 363 and m/z 365) and bi-glutathione (GSH) conjugates (m/z 902 and m/z 904), were identified for both capsaicin and dihydrocapsaicin. The medium of the exposed A549 cells contained ω-hydroxylated (m/z 322) and alkyl dehydrogenated (m/z 304) forms, as well as a glycine conjugate of capsaicin. As to dihydrocapsaicin, an alkyl dehydrogenated (m/z 306) form, a novel alkyl hydroxylated form, and a novel glycine conjugate were found. In A549 cells, dihydrocapsaicin evoked vacuolization and decreased cell viability more efficiently than capsaicin. Furthermore, both compounds induced p53 protein and G1 phase cell cycle arrest. Usefulness of the found metabolites as biomarkers for capsaicinoid exposures will need further investigations with additional toxicity endpoints.

Discovery of non-electrophilic capsaicinoid-type TRPA1 ligands.

Replacement of the benzylamide motif of synthetic capsaicin (nonivamide, 1c) with a tetrazole moiety was detrimental for TRPV1 binding, but unexpectedly generated a potent and non-electrophilic TRPA1 agonist (4a). Spurred by this observation and by the relatively small number of non-covalent TRPA1 ligands reported so far, the benzylamide-to-tetrazole swap was investigated in the more lipophilic and powerful vanilloids olvanil (1d), rinvanil (1e), and phenylacetylrinvanil (1f). In all cases, the replacement was detrimental for TRPV1 binding, but a clear modulation of TRPA1 activity was observed. These observations show that the capsaicinoid pharmacophore displays orthogonal structure-activity relationships for TRPV1 and TRPA1 binding, and suggest the possibility of obtaining compounds with dual TRPV1/TRPA1 modulatory properties by exploration of the chemical space around the capsaicin motif.

Combined effect of polymeric nanocapsules and chitosan hydrogel on the increase of capsaicinoids adhesion to the skin surface.

This work explored the effect of the encapsulation in polymeric nanocapsules, as well as of the incorporation of such nanoparticles in a chitosan hydrogel, on the skin adhesion and skin penetration/permeation of capsaicinoids (capsaicin and dihydrocapsaicin), which are used as topical analgesic to treat chronic pain. The skin experiments were performed using a modified (drug adhesion and drug diffusion) and a normal Franz diffusion cell (drug diffusion) with porcine skin as membrane. The AUC0-h of the washability profile (% washed away vs. time) determined for the formulation combining both factors studied (chitosan hydrogel containing drug-loaded nanocapsules) was 198.88 +/- 10.05/153.53 +/- 5.99, for capsaicin and dihydrocapsaicin respectively, significantly lower than the values observed for the chitosan hydrogel containing free drug (291.57 +/- 3.83/278.18 +/- 5.28) and for the hydroxyethyl cellulose containing drug-loaded nanocapsules (245.47 +/- 13.18/197.69 +/- 15.78). By adequate fitting to the monoexponential first order equation, the washing rate values indicated that the nanocapsules were more efficient in increasing the drugs skin adhesion than the chitosan gel. Regarding the skin penetration/permeation study, after washing the skin, the formulation which presented the lowest washing rate (chitosan gel containing nanocapsules) was the one which led to a higher amount of capsaicinoids in the skin layers (epidermis and dermis). Without washing the skin, the nanoencapsules caused retention of the drugs in the outer skin layer (epidermis). In conclusion, the skin adhesion of the nanocapsules and their capability of controlling the drug diffusion were shown. Combining chitosan gel to nanocapsules led to a formulation of great skin bioadhesion.

The anti-inflammatory effect of diclofenac is considerably augmented by topical capsaicinoids-containing patch in carrageenan-induced paw oedema of rat.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most used drugs in musculoskeletal disorders, but their systemic adverse effects limit their therapeutic benefit in local inflammation. On the other hand, topical preparations of capsaicinoids are widely used for musculoskeletal disorders as a complementary therapy. In this study, the effects of both topical capsaicinoids-containing patch and local subcutaneous capsaicin application on the anti-inflammatory action of NSAID were examined. Carrageenan-induced paw oedema of rats was used as the inflammation model. The volume and weight of the paw oedema and plasma extravasation in the paw were determined after carrageenan injection. The systemic application of diclofenac (3 mg/kg), which is an NSAID, significantly decreased the volume and weight of the paw oedema. Topical capsaicinoids-containing patch application or local capsaicin injection (2, 10, 20 µg/paw) alone did not cause any effect on oedema volume and weight. However, the combination of diclofenac with topical capsaicinoids-containing patch significantly increased the effectiveness of diclofenac on inflammation. Evans blue content of the paws that represents plasma extravasation was decreased by capsaicinoids-containing patch with and without diclofenac and diclofenac combination with the lowest dose of capsaicin injection. The results of this study indicate that topical application of capsaicinoids-containing patch enhances the anti-inflammatory effect of diclofenac and its beneficial effect may not purely relate to its capsaicin content. In the treatment of local inflammatory disorders, the combination of NSAID with topical capsaicinoids-containing patch could increase the anti-inflammatory efficiency of drug without systemic side effects.

Nanoparticle formulation for controlled release of capsaicin.

Capsaicin might be an effective pharmacological agent for the treatment of discogenic back pain due to its effect on pain control neuronal degeneration. Therefore, capsaicin-loaded nano- and micro-particles for sustained release were formulated by nano-precipitation or oil-in-water single emulsion solvent evaporation/extraction method. First, the capsaicin-loaded PLGA nanoparticles were prepared by nano-precipitation method. By increasing the volume of oil-water ratio from 1:2 to 1:5, slight changes in size from 162 +/- 3 nm to 153 +/- 3 nm and in drug loading efficiency from 25% to 20% were observed, whereas the drug release period was significantly changed from 11 days for 1:2 to 5 days for 1:5 ratio. To get a more sustained release, a modified single emulsion method was applied with three kinds of biocompatible polymers (PLLA, PLGA, and PCL). Among them, PLLA particles showed a much sustained release profile than PLGA or PCL ones with the similar size. For PLLA particles, particles size and drug encapsulation efficiency increased as the oil/water ratio decreased, and the bigger particles showed the slower release profiles as well as the higher drug-loading efficiency, thus about 1 month release was obtained with 800 nm particles. In conclusion, formulation for the controlled release of capsaicin from 1 week to 1 month was prepared by using biocompatible nanoparticles.

Molecular dynamics at ambient and elevated pressure of the amorphous pharmaceutical: nonivamide (pelargonic acid vanillylamide).

Broadband dielectric spectroscopy was employed to investigate the relaxation dynamics of supercooled and glassy nonivamide-the synthetic form of capsaicin being the most spicy-hot substance known to man. The material is of great importance in the pharmaceutical industry because it has wide usage in the medical field for relief of pain, and more recently it has been shown to be effective in fighting cancers. Dielectric measurements carried out at various isobaric and isothermal conditions (pressure up to 400 MPa) revealed very narrow α-loss peak and unresolved secondary relaxations appearing in the form of an excess wing on the high frequency flank. Moreover, our studies have shown the shape of dielectric loss spectrum at any fixed loss peak frequency is invariant to different combinations of temperature and pressure, i.e., validity of the time-temperature-pressure superpositioning. We also found the fragility index is nearly constant on varying pressure. This property is likely due to the unusual structure of nonivamide, which has a part characteristic of van der Waals glass-former and another part characteristic of hydrogen-bonded glass-former.

Nanosized TiO2 caused minor airflow limitation in the murine airways.

The use of nanotechnology is increasing exponentially, whereas the possible adverse health effects of engineered nanoparticles (NPs) are so far less known. Standardized mouse bioassay was used to study sensory and pulmonary irritation, airflow limitation, and inflammation potency of nanosized TiO(2). Single exposure (0.5 h) to in situ generated TiO(2) (primary particle size 20 nm; geometric mean diameters of 91, 113, and 130 nm at mass concentrations of 8, 20, and 30 mg/m(3), respectively; crystal phase anatase + brookite (3:1)) caused airflow limitation in the conducting airways at each studied exposure concentration, which was shown as a reduction in expiratory flow, being at the lowest 73% of baseline. The response was not dose dependent. Repeated exposures (altogether 16 h, 1 h/day, 4 days/week for 4 weeks) to TiO(2) at mass concentration of 30 mg/m(3) caused as intense airflow limitation effect as the single exposures, and the extent of the responses stayed about the same along the exposure days. Sensory irritation was fairly minor. Pulmonary irritation was more pronounced during the latter part of the repeated exposures compared to the single exposures and the beginning of the repeated exposures. Sensory and pulmonary irritation were observed also in the control group, and, therefore, reaction by-products (NO(2) and C(3)H(6)) may have contributed to the irritation effects. TiO(2) NPs accumulated mainly in the pulmonary macrophages, and they did not cause nasal or pulmonary inflammation. In conclusion, the irritation and inflammation potencies of studied TiO(2) seemed to be low.

Qutenza®: a capsaicin 8% patch for the management of postherpetic neuralgia.

Despite currently available treatments, postherpetic neuralgia continues to be a challenging pain condition to treat. Many patients remain in pain or suffer side effects from the (combination) therapies. A patch containing 8% capsaicin (research code NGX-4010 and marketed under the trade name Qutenza(®)), approved both in the EU and USA, provides a localized therapy with effects lasting up to 12 weeks after a single 60-min application. This review will summarize clinical trial evidence on the safety, efficacy and unique attributes of this capsaicin 8% patch in the treatment of postherpetic neuralgia. The action of capsaicin on the transient receptor potential cation channel, subfamily V, member 1 receptors will be discussed.

Design and evaluation of flexible membrane vesicles (FMVs) for enhanced topical delivery of capsaicin.

Capsaicin, extracted from the fruits of Capsicum, is a powerful local stimulant with strong rubifacient action, devoid of vesication. Topical use of capsaicin is quite common in the treatment of various pain-associated musculo-skeletal disorders, itching and neuropathy. Despite its high pharmacodynamic potential, the patient compliance to the drug is reported to be poor owing to multiple skin problems like irritation, burning sensation, and erythma. The present study targets the encasement of drug in the interiors of flexible membrane vesicles (FMVs), as these are reported to have better penetration in the deeper layers of skin, thus leading to enhanced localization of drug and consequently, decreased skin irritation. Multilamellar drug-loaded FMVs, prepared by thin-film hydration were evaluated for their efficacy in vitro and in vivo. When compared with conventional liposomes, the formulated FMVs showed higher skin retention during ex vivo permeation studies employing LACA mice skin, higher analgesic potential using radiant tail-flick method in mice, and better flexibility in regaining their size. Being less of an irritant, these vesicular carriers were also found to be more comfortable on human skin. Thus, the capsaicin-loaded FMVs offer high potential as topical drug delivery technologies with improved patient acceptance and effectiveness.

[The TRPV1 channel as a target for the treatment of pain]. / El canal TRPV1 como diana para tratar el dolor.

INTRODUCTION: Pain results from the processing of a large number of signals produced at different levels of the central and peripheral nervous system, which are generated in response to stimuli from the environment or from the organism itself. One of the strategies for generating new analgesics consists in studying the molecular bases that underlie the detection of painful stimuli, that is to say, the receptors. One receptor that plays a very important role in sensory and pain physiology is TRPV1, which is responsible for detecting mechanical, chemical and thermal stimuli. AIMS. The aim of this study is to discuss the structural and functional aspects of the TRPV1 channel, as well as its participation in certain pathological processes and the possible perspectives for clinical research. DEVELOPMENT: TRPV1 activation in sensory neurons generates signals that reach the central nervous system, where they are interpreted as pain, as well as triggering the peripheral release of pro-inflammatory substances that make other neurons sensitive to subsequent stimuli. TRPV1 is a receptor that is structurally similar to other voltage-dependent ion channels, with the capacity to detect and integrate several different stimuli from the environment, such as dangerously high temperatures or irritants. Furthermore, the activity of this channel is linked to several signalling chains related with inflammatory processes. CONCLUSIONS: The central role of TRPV1 in the physiology of pain will surely encourage the development of drugs aimed at this receptor which can be used in the treatment of several types of pain.

Capsaicin: tailored chemical defence against unwanted "frugivores".

Why are chilli peppers hot? The vanillyl amide, capsaicin, has long been known as the pungent principle of peppers, but only in their recent work have Tewksbury et al. addressed its ecological roles: to distract unsuitable seed dispensers and to protect the seeds against fungal infection by Fusarium.

Roles of transient receptor potential vanilloid subtype 1 and cannabinoid type 1 receptors in the brain: neuroprotection versus neurotoxicity.

Transient receptor potential vanilloid subtype 1 (TRPV1), also known as vanilloid receptor 1 (VR1), is a nonselective cation channel that is activated by a variety of ligands, such as exogenous capsaicin (CAP) or endogenous anandamide (AEA), as well as products of lipoxygenases. Cannabinoid type 1 (CB1) receptor belongs to the G protein-coupled receptor superfamily and is activated by cannabinoids such as AEA and exogenous Delta-9-tetrahydrocannabinol (THC). TRPV1 and CB1 receptors are widely expressed in the brain and play many significant roles in various brain regions; however, the issue of whether TRPV1 or CB1 receptors mediate neuroprotection or neurotoxicity remains controversial. Furthermore, functional crosstalk between these two receptors has been recently reported. It is therefore timely to review current knowledge regarding the functions of these two receptors and to consider new directions of investigation on their roles in the brain.