Bioavailability of a Capsaicin Lipid Multi-particulate Formulation in Rats.

BACKGROUND AND OBJECTIVE: Because of the stomach-burning sensation it induces, capsaicin has been used at relatively low doses as a nutritional supplement, which has limited its bioavailability. The objective of this study was to investigate the serum bioavailability of capsaicin supplementation with or without a lipid multi-particulate (LMP) formulation. METHODS: Thirty-five rats were divided into five groups and administered capsaicin at either 0.2 or 1 mg/kg with or without the LMP formulation. Capsaicin bioavailability was assessed based on the area under the concentation-time curve (AUC), the time to peak concentration (Tmax), and the peak serum concentration (Cmax). RESULTS: For each formulation, the capsaicin Cmax was reached at 90 min and decreased thereafter. Serum capsaicin concentrations were greater in rats administered the higher dose of capsaicin (1 mg/kg) in the LMP formulation at all measurement times (P  ≤ 0.05). The AUC showed a significant increase, about 20%, when capsaicin was administered in the LMP formulation at the high dose (P = 0.002). The Tmax for oral capsaicin was similar whether or not administration was via the LMP formulation (P = 0.163). However, the Cmax of capsaicin increased in a dose-dependent manner (P < 0.05). Although the LMP formulation of the high dose of capsaicin resulted in a numerically higher Cmax, it was not statistically significantly higher (P = 0.068). CONCLUSIONS: The present work demonstrated that administration of capsaicin via the LMP formulation significantly impacted the pharmacokinetic parameters and the serum bioavailability of orally administered 1 mg/kg capsaicin in rats. The bioavailability of capsaicin in humans may also be increased by using the LMP formulation.

Capsaicin stability and bio-accessibility affected by complexation with high-amylose corn starch (HACS).

Delivery of pungent bioactives such as capsaicin from hot peppers is a scientific, technological and sensorial challenge. While capsaicin intake is positively related to various bowel diseases, its high pungency and instability upon digestion generate a problem in its delivery to the target organ. Helical V-amylose architectures have been shown to be a possible nano-sized delivery vehicle for such hydrophobic bioactives. This study sought to entrap capsaicin (CAP) within high amylose corn starch (HACS), quantitate and optimize the encapsulation efficiency and other techno-functional properties as well as evaluate the release of capsaicin in the duodenum. By adapting an acidification protocol, HACS was processed to form nanocapsules loaded with capsaicin. The capsaicin content and loading ratio were optimized to 44.0% (±0.4) and 1 : 1 (CAP : HACS, w/w), respectively. AFM and XRD measurements of the complexes confirmed the formed nanocapsules to be V-type crystals with a 1 : 10 (CAP : HACS, w/w) loading ratio showing the highest level of crystallinity. Laser scattering measurements demonstrated an increase in poly-dispersity as the loading ratio increased as well as a higher surface-area diameter. Scanning electron microscopy (SEM) revealed the formation of irregular circular starch inclusion complexes upon acidification treatment. Finally, an in vitro digestion model was utilized to ascertain capsaicin release under gastro-intestinal conditions that coincides with complex degradation under digestive conditions. Both adult and elderly in vitro digestion models were applied, showing the effect of age on the nanocapsule degradation and capsaicin bioaccessibility. Overall, this work provides practical information about the use of HACS for nano-encapsulation of capsaicin and its controlled release under digestive conditions, and provides insight regarding the correlation between nanocomplex characteristics and the consumer physiology. Such a nano-encapsulation platform could prove to be useful in the fortification and supplementation of starchy foods with challenging bioactives, such as the pungent capsaicin.

Nonpungent N-AVAM Capsaicin Analogues and Cancer Therapy.

Capsaicin displays robust growth-inhibitory activity in multiple human cancers. However, the feasibility of capsaicin as a clinically relevant anticancer drug is hampered by its adverse side effects. This concern has led to extensive research focused on the isolation and synthesis of second-generation nonpungent capsaicin analogues with potent antineoplastic activity. A major class of nonpungent capsaicin-like compounds belongs to the N-acyl-vanillylamide (N-AVAM) derivatives of capsaicin (hereafter referred as N-AVAM capsaicin analogues). This perspective discusses the isolation of N-AVAM capsaicin analogues from natural sources as well as their synthesis by chemical and enzymatic methods. The perspective describes the pharmacokinetic properties and anticancer activity of N-AVAM capsaicin analogues. The signaling pathways underlying the growth-inhibitory effects of N-AVAM capsaicin analogues have also been highlighted. It is hoped that the insights obtained in this perspective will facilitate the synthesis of a second generation of N-AVAM capsaicin analogues with improved stability and growth-suppressive activity in human cancer.

Capsaicin and TRPV1 Channels in the Cardiovascular System: The Role of Inflammation.

Capsaicin is a potent agonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel and is a common component found in the fruits of the genus Capsicum plants, which have been known to humanity and consumed in food for approximately 7000-9000 years. The fruits of Capsicum plants, such as chili pepper, have been long recognized for their high nutritional value. Additionally, capsaicin itself has been proposed to exhibit vasodilatory, antimicrobial, anti-cancer, and antinociceptive properties. However, a growing body of evidence reveals a vasoconstrictory potential of capsaicin acting via the vascular TRPV1 channel and suggests that unnecessary high consumption of capsaicin may cause severe consequences, including vasospasm and myocardial infarction in people with underlying inflammatory conditions. This review focuses on vascular TRPV1 channels that are endogenously expressed in both vascular smooth muscle and endothelial cells and emphasizes the role of inflammation in sensitizing the TRPV1 channel to capsaicin activation. Tilting the balance between the beneficial vasodilatory action of capsaicin and its unwanted vasoconstrictive effects may precipitate adverse outcomes such as vasospasm and myocardial infarction, especially in the presence of proinflammatory mediators.

Topical Capsaicin for the Treatment of Neuropathic Pain.

BACKGROUND: Neuropathic pain (NP) is an egregious problem worldwide. Due to the side-effects of oral drugs, drugs delivered directly to the affected area of pain are preferred. OBJECTIVE: Capsaicin, a chemical compound isolated from chili peppers, is used as an analgesic in topical ointments and dermal patches to alleviate pain. Objective of the study is to review the application and functionality of topical capsaicin in treatment of neuropathic pain. DATA SOURCES: To systematically review capsaicin's functions on NP, we retrieved articles from the PubMed database published in the last ten years. STUDY ELIGIBILITY CRITERIA: The inclusion criteria were capsaicin and the use of capsaicin for the treatment of NP; on the other hand, articles were excluded according to the mentioned criteria such as abstracts, articles written in any language other than English, incomplete articles, and conference papers. PARTICIPANTS AND INTERVENTIONS: Out of 265 articles, 108 articles were selected after filtering through the inclusion and exclusion criteria. The data and knowledge currently existing for capsaicin treatment in NP are summarized. RESULTS: This review indicates that capsaicin effectively improves NP treatment without affecting the motor and large nerve fibres involved in sensory function. Transient receptor potential channel vanilloid type 1 (TRPV1) is the capsaicin receptor expressed in central and peripheral terminals of a sensitive primary nerve cell. Conclusions and implications of key findings: Topical capsaicin has a sensible safety profile and is effective in reducing NP. Therefore, studies over the last decade suggest that capsaicin might be a potential drug for NP treatment.

Capsaicin-loaded solid lipid nanoparticles: design, biodistribution, in silico modeling and in vitro cytotoxicity evaluation.

Lower doses of capsaicin (8-methyl-N-vanillyl-6-nonenamide) have the potential to serve as an anticancer drug, however, due to its pungency, irritant effect, poor water solubility and high distribution volume often linked to various off-target effects, its therapeutic use is limited. This study aimed to determine the biodistribution and anticancer efficacy of capsaicin loaded solid lipid nanoparticles (SLNs) in human hepatocellular carcinoma in vitro. In this study, SLNs of stearic acid loaded with capsaicin was formulated by the solvent evaporation-emulsification technique and were instantly characterized for their encapsulation efficiency, morphology, loading capacity, stability, particle size, charge and in vitro drug release profile. Synthesized SLNs were predominantly spherical, 80 nm diameter particles that proved to be biocompatible with good stability in aqueous conditions. In vivo biodistribution studies of the formulated SLNs showed that 48 h after injection in the lateral tail vein, up to 15% of the cells in the liver, 1.04% of the cells in the spleen, 3.05% of the cells in the kidneys, 3.76% of the cells in the heart, 1.31% of the cells in the lungs and 0% of the cells in the brain of rats were determined. Molecular docking studies against the identified targets in HepG2 cells showed that the capsaicin is able to bind Abelson tyrosine-protein kinase, c-Src kinase, p38 MAP kinase and VEGF-receptor. Molecular dynamic simulation showed that capsaicin-VEGF receptor complex is highly stable at 50 nano seconds. The IC50 of capsaicin loaded SLNs in HepG2 cells in vitro was 21.36 µg × ml-1. These findings suggest that capsaicin loaded SLNs are stable in circulation for a period up to 3 d, providing a controlled release of loaded capsaicin and enhanced anticancer activity.

Inhibitory effect of Capsicum chinense and Piper nigrum fruits, capsaicin and piperine on aflatoxins production in Aspergillus parasiticus by downregulating the expression of aflD, aflM, aflR, and aflS genes of aflatoxins biosynthetic pathway.

Aflatoxins produced by Aspergillus parasiticus are toxic and carcinogenic metabolites. The biosynthesis of this mycotoxins is a complex process and involves at least 30 genes clustered within an approximately 82 kB gene cluster. In the present study, the effect of Capsicum chinense and Piper nigrum fruits on Aspergillus parasiticus growth and aflatoxin production were studied in relation to the expression of aflD, aflM, aflR, and aflS four; key genes of aflatoxins biosynthesis pathway. GC-EIMS analysis identified capsaicin (66,107 µg g-1) and piperine (1,138 µg g-1) as the most abundant compounds in C. chinense and P. nigrum fruits, respectively. The antifungal and anti-aflatoxigenic assays showed that C. chinense, P. nigrum, capsaicin, and piperine inhibited A. parasiticus growth and aflatoxins production in a dose-dependent manner. The piperine at 300 µg mL-1 produced higher radial growth inhibition (89%) and aflatoxin production inhibition (69%). The expression of aflatoxin biosynthetic genes was evaluated by quantitative real-time PCR (qRT-PCR) and revealed that aflatoxin inhibition occurring via downregulating the aflS and aflR, and subsequently aflD and aflM genes. These results will improve our understanding of the mechanism of aflatoxin regulation by C. chinense, P. nigrum, capsaicin, and piperine, and provides a reference for further study.

Differences of the tumour cell glycocalyx affect binding of capsaicin-loaded chitosan nanocapsules.

The glycocalyx regulates the interaction of mammalian cells with extracellular molecules, such as cytokines. However, it is unknown to which extend the glycocalyx of distinct cancer cells control the binding and uptake of nanoparticles. In the present study, exome sequencing data of cancer patients and analysis of distinct melanoma and bladder cancer cell lines suggested differences in cancer cell-exposed glycocalyx components such as heparan sulphate. Our data indicate that glycocalyx differences affected the binding of cationic chitosan nanocapsules (Chi-NCs). The pronounced glycocalyx of bladder cancer cells enhanced the internalisation of nanoencapsulated capsaicin. Consequently, capsaicin induced apoptosis in the cancer cells, but not in the less glycosylated benign urothelial cells. Moreover, we measured counterion condensation on highly negatively charged heparan sulphate chains. Counterion condensation triggered a cooperative binding of Chi-NCs, characterised by a weak binding rate at low Chi-NC doses and a strongly increased binding rate at high Chi-NC concentrations. Our results indicate that the glycocalyx of tumour cells controls the binding and biological activity of nanoparticles. This has to be considered for the design of tumour cell directed nanocarriers to improve the delivery of cytotoxic drugs. Differential nanoparticle binding may also be useful to discriminate tumour cells from healthy cells.

Capsaicin metabolites and GSH-associated detoxification and biotransformation pathways in human liver microsomes revealed by LC-HRMS/MS with data-mining tools.

Capsaicin (CAP) is a principal pungent ingredient in hot peppers, it is also employed as a common food additive, an efficient pharmaceutical component, or even a riot control agent. CAP exerts various pharmacological activities as well as associated adverse physiological responses and causes moderate toxicity if overused. A full screening and identification of CAP metabolites in combination with its main detoxification pathways are crucial for the clear demonstration on its pharmacological and toxicological significance. Here, we employed a post-acquisition data-mining metabolic screening approach to rapidly find and identify a broad range of CAP metabolites generated from in vitro human liver microsomes, based on an ultra-performance liquid chromatography-quadrupole orbitrap high resolution tandem mass spectrometric method. First, we collected full scan MS and MS/MS data sets by a data-dependent acquisition method in positive ion mode, and then we employed a modified mass defect filter and a diagnostic ion filter to screen and identify all the probable CAP metabolites, combining with information including retention time, accurate mass, characteristic fragments, and relevant drug biotransformation patterns. In comparison with the stable isotope-labeled CAP involved biotransformation products, we confirmed 19 functionalized metabolites and 13 glutathione (GSH) conjugates of CAP, in which 13 metabolites are reported for the first time. We then briefly depicted an overview metabolic pathway of CAP from the GSH detoxification viewpoint, revealed that various metabolites of CAP can be generated from single or multiple biotransformation and metabolic reactions. Both CAP and its reactive metabolites produced relevant GSH conjugates, which indicates a wide and important detoxification value of GSH conjugation way.

Rapid and sensitive LC-MS/MS method for simultaneous quantification of capsaicin and dihydrocapsaicin in microdialysis samples following dermal application.

A bioanalytical LC-MS/MS method was developed and validated for the simultaneous quantification of capsaicin (CAPS) and dihydrocapsaicin (D-CAPS) in dermal microdialysis samples from rats. Capsaicinoids were separated by using a C18 column, with a mobile phase of water and acetonitrile, both with 0.1% of formic acid, eluted as a gradient. Compounds were detected by using an electrospray ionization source operating in the positive mode (ESI+) to monitor the m/z transitions of 306.1 > 137.0 for CAPS and 308.1 > 137.0 for D-CAPS. The method showed linearity in the concentration range of 0.5-100 ng/ml for CAPS and 0.25-100 ng/ml for D-CAPS, with coefficients of determination of ≥ 0.99. The inter- and intra-day precision, accuracy, and compound stability in different conditions were in accordance with the limits established by the US Food and Drug Administration guidelines. The recovery of the drugs by microdialysis were dependent on the flow rate, but independent of drug concentration. For CAPS, calibration of the in vitro microdialysis probes by dialysis and retrodialysis resulted in statistically similar drug recovery of 68.5% ± 5.9% and 77.8% ± 6.6%, respectively, at a flow rate of 0.5 µl/min. For D-CAPS, the recovery by dialysis was lower than by retrodialysis, at 51.4% ± 6.6% and 92.6% ± 2.4%, respectively. This difference was attributed to the binding of D-CAPS to the plastic tubing, which was experimentally evaluated and mathematically modeled. In vivo recoveries were 75.7% ± 6.3% for CAPS and 81.9% ± 1.5% for D-CAPS at the same flow rate. The analytical method showed high specificity, accuracy, and sensitivity, and suitability for dermatopharmacokinetic studies. These results will allow the determination of the actual free concentration of these drugs in dermatopharmacokinetic experiments, as shown in a pilot experiment with a commercial cream containing capsaicinoids.

Intestinal absorption of black chokeberry cyanidin 3-glycosides is promoted by capsaicin and capsiate in a rat ligated small intestinal loop model.

Recent studies have shown that aronia (black chokeberry) and haskap fruits (contain anthocyanins) have beneficial health effects in animals and humans. However, some reports have shown that anthocyanin is poorly absorbed in the small intestine. In this study, we compared the intestinal absorption of aronia and haskap anthocyanins by using rats with a ligated small intestinal loop and cannulated portal vein. Our results clearly showed that the intestinal absorption of aronia anthocyanins was significantly lower than that of haskap anthocyanins, suggesting that the intestinal absorption of anthocyanins is influenced by the glycoside type (galactoside or glucoside). In addition, we also examined the effects of capsaicin and capsiate on intestinal anthocyanin absorption. The amount of aronia anthocyanins in portal blood was much higher when they were co-administered with capsaicin or capsiate. Our study is the first to show that the intestinal absorption of aronia anthocyanins is promoted by capsaicin and capsiate.

Formulation, characterization, and in vitro/in vivo studies of capsaicin-loaded albumin nanoparticles.

Capsaicin (CAP) is a secondary metabolite with high therapeutic potential. It displays several bioactive properties including hypolipidemic, antioxidant, anti-inflammatory and analgesic effects. However, CAP presents toxicity to healthy cells and poor pharmacokinetic profile, which is characterized by toxic metabolites and short half-life. In this study, CAP-loaded albumin nanoparticles were obtained by the desolvation-coacervation method. The preparation process was optimized by the application of a factorial design. Nanoparticles presented diameter of about 200 nm, quasi-spherical morphology, encapsulation efficiency of 98.3 ±â€¯7.4%, and negative zeta potential. The in vitro release assay demonstrated a biphasic profile, characterized by a fast release over 12 h followed by a prolonged release rate. Nanoencapsulated CAP showed significant antioxidant activity in an in vitro assay which was concentration - and time-dependent. In addition, the in vivo study demonstrated for the first time that both free and nanoencapsulated drug reduced TNF-alpha concentrations in the absence of inflammatory stimuli model. These novel findings indicate that albumin nanoparticles are potential CAP carriers and that this new drug formulation may be useful in several conditions, including cancer, inflammation, and neuropathic pain.

Capsaicin 8% Dermal Patch: A Review in Peripheral Neuropathic Pain.

The adhesive capsaicin dermal patch (Qutenza®) delivers a high concentration (8% w/w) of synthetic capsaicin, a highly selective agonist of transient receptor potential vanilloid-1 (TRPV-1), directly to the site of pain. The capsaicin 8% dermal patch is indicated in the EU for the treatment of peripheral neuropathic pain (PNP) in adults, either alone or in combination with other medicinal products for pain. In patients with painful diabetic peripheral neuropathy, a single 30-min application of the capsaicin 8% dermal patch provided 12 weeks of pain relief and improved sleep quality compared with placebo. Repeat treatment with the capsaicin 8% dermal patch plus standard of care over 52 weeks provided sustained pain relief, with no negative neurological effects compared with standard of care alone. The capsaicin 8% dermal patch was non-inferior to oral pregabalin in relieving pain in patients with non-diabetic PNP, with a faster onset of action and greater treatment satisfaction. A single 60-min application of the capsaicin 8% dermal patch provided rapid and sustained pain relief in patients with postherpetic neuralgia. Results in patients with HIV-associated neuropathy were equivocal, with a significant improvement in pain intensity observed in one trial, but not in the other. The capsaicin 8% dermal patch was generally well tolerated; transient application-site reactions were the most common adverse events. In conclusion, the capsaicin 8% dermal patch is a useful addition to the treatment options currently available for patients with PNP.

Fundamental pharmacological expressions on ocular exposure to capsaicin, the principal constituent in pepper sprays.

Eye irritation assessment is compulsory to anticipate health risks in military personnel exposed to riot control agents such as capsaicin, the principal constituent of oleoresin capsicum, or pepper sprays. The present work investigates certain fundamental yet unaddressed pharmacological manifestations on ocular exposure to capsaicin. Ocular pharmacology of capsaicin was studied using acute eye irritation (AEI), bovine corneal opacity and permeability (BCOP) assay, corneal fluorescein staining and indirect ophthalmoscopy studies, transcorneal permeation, Schirmer tear secretion test, nerve conduction velocity study and enzyme-linked immunosorbent assay (ELISA). Additionally, histopathology and scanning electron microscopy (SEM) of bovine corneas and rat optic nerves were done to further estimate capsaicin induced morphological variations. Our findings demonstrated that AEI, BCOP, corneal fluorescein staining and indirect ophthalmoscopy were useful in assessing capsaicin induced ocular irritation; AEI and BCOP also contributed towards indicating the eye irritation potential of capsaicin as per the United Nations Globally Harmonized System of Classification and Labelling of Chemicals categorization. Additional experimental observations include considerable transcorneal permeation of capsaicin, capsaicin induced reduction in tear secretions and nerve conduction velocity and increased expression of proinflammatory cytokines by ELISA. Histopathology and SEM were favourable techniques for the detection of capsaicin induced ocular physiological modifications.

Method to determine the impact of substantivity on ex vivo skin-permeation.

Topical formulations are the most common therapeutic agents in the treatment of skin diseases. They contain one or more active pharmaceutical ingredients (API) which need to penetrate or permeate the skin in order to exert their effect. However, after application a part of the formulation is removed from the skin due to contact with the environment. Therefore, a part of the active is then not available for penetration and thus, a loss in therapeutic effect will result. To achieve the desired therapeutic outcome a sufficient fraction of the formulation must remain on the skin. The extent to which the loss of preparation affects penetration and permeation is less investigated. This work presents a method to examine the influence of mechanical stress and formulation loss on skin permeation. A movable punch with a defined weight simulated contact between clothing or skin and the applied formulation. Weight of the tool, number of contacts and speed settings were variable and were investigated. Ex vivo permeation experiments were performed in Franz diffusion cells using porcine skin. Three preparations with nonivamide as active ingredient were chosen as model formulations: A semisolid cream, an oil-in-oil emulsion and a film-forming formulation. The last two show sustained permeation profiles. The method uses skin-to-formulation and clothing-to-formulation contact to simulate the removal of the formulations from the skin.

Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice.

Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P-gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, Kp, for the liver and kidney were higher in the piperine-pretreated group, while the Kp for kidney, brain and liver were higher in the capsaicin-pretreated group. [6]-Gingerol did not affect doxorubicin tissue distribution. The data demonstrated that the phytochemicals modulated doxorubicin tissue distribution, which suggested their potential to induce food-drug interactions and act as a strategy for the delivery of P-gp substrate drugs to target tissues and tumors.

Utility of in vitro and in vivo systems for studying the permeability of capsaicin and nonivamide through different intestinal regions.

1. The present study determined and compared the permeability of capsaicin and nonivamide along the length of the intestine in rats. Accordingly, the purpose was to evaluate this synthetic analog as a clinical substitute for capsaicin.. 2. Permeabilities of capsaicin and nonivamide were measured in experiments utilizing Ussing chambers and in vivo methods. Capsaicin concentrations were examined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). 3. Both capsaicin (0.80 × 10-6 cm/s) and nonivamide (0.22 × 10-6 cm/s, p > 0.05) had poor permeabilities across the jejunal membrane. The permeability of nonivamide (10.12 × 10-6 cm/s) was significantly greater than that of capsaicin (5.34 × 10-6 cm/s, p < 0.05) across the iliac membrane. In contrast, the permeability of nonivamide (8.42 × 10-6 cm/s) across the colonic membrane was markedly lower than that of capsaicin (14.48 × 10-6 cm/s, p < 0.05). In accordance with the in vitro study, the drug concentration-time curve of nonivamide was significantly higher in the ileum (F = 14.18, p < 0.05) but lower in the colon (F = 11.86, p < 0.05) compared with capsaicin. 4. The results demonstrate that capsaicin and nonivamide exhibit varying permeabilities across several different intestinal tissues. The relevance of such extended investigations to healthcare is underscored by the lower cost of nonivamide versus capsaicin, along with potential application in prevention and management of the disease.

Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment.

INTRODUCTION: Cannabinoid hyperemesis syndrome is a clinical disorder that has become more prevalent with increasing use of cannabis and synthetic cannabinoids, and which is difficult to treat. Standard antiemetics commonly fail to alleviate the severe nausea and vomiting characteristic of the syndrome. Curiously, cannabinoid hyperemesis syndrome patients often report dramatic relief of symptoms with hot showers and baths, and topical capsaicin. OBJECTIVES: In this review, we detail the pharmacokinetics and pharmacodynamics of capsaicin and explore possible mechanisms for its beneficial effect, including activation of transient receptor potential vanilloid 1 and neurohumoral regulation. Putative mechanisms responsible for the benefit of hot water hydrotherapy are also investigated. METHODS: An extensive search of PubMed, OpenGrey, and Google Scholar from inception to April 2017 was performed to identify known and theoretical thermoregulatory mechanisms associated with the endocannabinoid system. The searches resulted in 2417 articles. These articles were screened for relevant mechanisms behind capsaicin and heat activation having potential antiemetic effects. References from the selected articles were also hand-searched. A total of 137 articles were considered relevant and included. Capsaicin: Topical capsaicin is primarily used for treatment of neuropathic pain, but it has also been used successfully in some 20 cases of cannabinoid hyperemesis syndrome. The pharmacokinetics and pharmacodynamics of capsaicin as a transient receptor potential vanilloid 1 agonist may explain this effect. Topical capsaicin has a longer half-life than oral administration, thus its potential duration of benefit is longer. Capsaicin and transient receptor potential vanilloid 1: Topical capsaicin binds and activates the transient receptor potential vanilloid 1 receptor, triggering influx of calcium and sodium, as well as release of inflammatory neuropeptides leading to transient burning, stinging, and itching. This elicits a novel type of desensitization analgesia. Transient receptor potential vanilloid 1 receptors also respond to noxious stimuli, such as heat (>43 °C), acids (pH <6), pain, change in osmolarity, and endovanilloids. The action of topical capsaicin may mimic the effect of heat-activation of transient receptor potential vanilloid 1. Endocannabinoid system and transient receptor potential vanilloid 1: Cannabinoid hyperemesis syndrome may result from a derangement in the endocannabinoid system secondary to chronic exogenous stimulation. The relief of cannabinoid hyperemesis syndrome symptoms from heat and use of transient receptor potential vanilloid 1 agonists suggests a complex interrelation between the endocannabinoid system and transient receptor potential vanilloid 1. Temperature regulation: Hot water hydrotherapy is a mainstay of self-treatment for cannabinoid hyperemesis syndrome patients. This may be explained by heat-induced transient receptor potential vanilloid 1 activation. "Sensocrine" antiemetic effects: Transient receptor potential vanilloid 1 activation by heat or capsaicin results in modulation of tachykinins, somatostatin, pituitary adenylate-cyclase activating polypeptide, and calcitonin gene-related peptide as well as histaminergic, cholinergic, and serotonergic transmission. These downstream effects represent further possible explanations for transient receptor potential vanilloid 1-associated antiemesis. CONCLUSIONS: These complex interactions between the endocannabinoid systems and transient receptor potential vanilloid 1, in the setting of cannabinoid receptor desensitization, may yield important clues into the pathophysiology and treatment of cannabinoid hyperemesis syndrome. This knowledge can provide clinicians caring for these patients with additional treatment options that may reduce length of stay, avoid unnecessary imaging and laboratory testing, and decrease the use of potentially harmful medications such as opioids.

A Phase I study of the pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxymorphone transdermal patch system.

AIM: Characterize the pharmacokinetic profile and tolerability of two tocopheryl phosphate mixture/oxymorphone patch formulations in healthy subjects, and the active metabolite (6-OH-oxymorphone). MATERIALS & METHODS: Fifteen participants received a single application of oxymorphone patches +/- capsaicin for 72 h and were crossed-over for another 72 h. RESULTS: Plasma oxymorphone was detected approximately 7 h and 6-OH-oxymorphone after approximately 18-19 h postapplication of both formulations, respectively. For oxymorphone, median tmax was 24 h, and Cmax/Cmin ratio was approximately 2.4. The most frequently reported treatment-related adverse event was application site reaction, mainly with capsaicin formulation. CONCLUSION: Tocopheryl phosphate mixture/oxymorphone transdermal patches can successfully deliver therapeutic amounts of oxymorphone in a sustained manner over 72 h and are well tolerated. ANZCTR registration number: ACTRN12614000613606.

Ex vivo skin permeation and penetration of nonivamide from and in vivo skin tolerability of film-forming formulations containing porous silica.

AIM: The purpose of this study was to evaluate skin permeation and penetration of nonivamide which has been formulated in novel film-forming formulations (FFFs). These formulations aim to prolong the availability of capsaicinoids which are used in long-term treatment of chronic pruritus. METHODS: An oily solution of nonivamide was loaded into porous silica particles which then were suspended in an aqueous dispersion of a sustained release polymer. Permeation and penetration experiments were performed ex vivo with postauricular porcine skin using modified Franz diffusion cells. The penetrated drug amount was assessed ex vivo by skin surface biopsy followed by cryo-sectioning. Furthermore, in vivo skin irritation experiments were performed to compare the potential skin irritation caused by the FFFs to conventionally used semi-solid formulations. RESULTS: Permeation rates of nonivamide from FFF through the skin are comparable to that from clinically used immediate release formulations. This elucidates the therapeutic safety profile of the novel FFF. Penetration studies confirmed the prolonged drug availability at the site of action. FFFs were found not to irritate the skin of healthy volunteers. CONCLUSION: FFFs with sustained nonivamide penetration represent safe and easy-to-use formulations. They therefore may improve the treatment of chronic pruritus with capsaicinoids by enhancing patient compliance through a sustained release regime.