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1.
Artigo em Inglês | MEDLINE | ID: mdl-31704446

RESUMO

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.


Assuntos
Capsaicina , Cromatografia Líquida/métodos , Glutationa/metabolismo , Microssomos Hepáticos/metabolismo , Espectrometria de Massas em Tandem/métodos , Biotransformação , Capsaicina/metabolismo , Capsaicina/farmacocinética , Humanos
2.
J Pharm Biomed Anal ; 173: 126-133, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31129532

RESUMO

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.


Assuntos
Capsaicina/análogos & derivados , Capsaicina/análise , Fármacos do Sistema Sensorial/análise , Creme para a Pele/análise , Animais , Capsaicina/administração & dosagem , Capsaicina/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Derme/química , Masculino , Microdiálise/métodos , Modelos Animais , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fármacos do Sistema Sensorial/administração & dosagem , Fármacos do Sistema Sensorial/farmacocinética , Creme para a Pele/administração & dosagem , Creme para a Pele/farmacocinética , Espectrometria de Massas em Tandem/métodos , Distribuição Tecidual
3.
Food Chem ; 277: 323-326, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30502153

RESUMO

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.


Assuntos
Antocianinas/farmacocinética , Capsaicina/análogos & derivados , Capsaicina/farmacocinética , Glicosídeos/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Photinia/química , Animais , Frutas/química , Intestino Delgado/metabolismo , Masculino , Extratos Vegetais/farmacocinética , Ratos , Ratos Sprague-Dawley
4.
Mater Sci Eng C Mater Biol Appl ; 93: 70-79, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30274103

RESUMO

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.


Assuntos
Capsaicina , Nanocápsulas , Soroalbumina Bovina , Animais , Capsaicina/química , Capsaicina/farmacocinética , Capsaicina/farmacologia , Bovinos , Masculino , Nanocápsulas/química , Nanocápsulas/uso terapêutico , Ratos , Ratos Wistar , Soroalbumina Bovina/química , Soroalbumina Bovina/farmacocinética , Soroalbumina Bovina/farmacologia
5.
Drugs ; 78(14): 1489-1500, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30251173

RESUMO

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.


Assuntos
Capsaicina/uso terapêutico , Neuralgia/tratamento farmacológico , Adesivo Transdérmico , Administração Cutânea , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Capsaicina/administração & dosagem , Capsaicina/farmacocinética , Infecções por HIV/complicações , Infecções por HIV/fisiopatologia , Humanos , Neuralgia Pós-Herpética/tratamento farmacológico , Manejo da Dor/métodos , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Canais de Cátion TRPV/antagonistas & inibidores
6.
Sci Rep ; 8(1): 12153, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30108241

RESUMO

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.


Assuntos
Capsaicina/toxicidade , Córnea/efeitos dos fármacos , Opacidade da Córnea/induzido quimicamente , Substâncias para Controle de Distúrbios Civis/toxicidade , Animais , Bioensaio , Capsaicina/farmacocinética , Bovinos , Córnea/metabolismo , Córnea/ultraestrutura , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Aparelho Lacrimal/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Varredura , Militares , Condução Nervosa/efeitos dos fármacos , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/ultraestrutura , Permeabilidade , Coelhos , Ratos , Ratos Wistar , Substâncias para Controle de Distúrbios Civis/farmacocinética , Testes de Toxicidade Aguda
7.
Eur J Pharm Biopharm ; 131: 1-7, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30048744

RESUMO

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.


Assuntos
Fármacos Dermatológicos/farmacocinética , Absorção Cutânea , Administração Cutânea , Administração Tópica , Animais , Capsaicina/administração & dosagem , Capsaicina/análogos & derivados , Capsaicina/farmacocinética , Vestuário , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/química , Cultura em Câmaras de Difusão , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Emulsões , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Técnicas In Vitro , Pomadas , Pele/metabolismo , Suínos
8.
Rev. esp. enferm. dig ; 110(6): 372-379, jun. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-177691

RESUMO

Background and aim: the aim of the study was to use a validated questionnaire to identify factors associated with the development of gastric cancer (GC) in the Mexican population. Methods: the study included cases and controls that were paired by sex and ± 10 years of age at diagnosis. In relation to cases, 46 patients with a confirmed histopathological diagnosis of adenocarcinoma-type GC, as reported in the hospital records, were selected, and 46 blood bank donors from the same hospital were included as controls. The previously validated Questionnaire to Find Factors Associated with Gastric Cancer (QUFA-GC(c)) was used to collect data. Odds ratio (OR) and 95% confidence interval (IC) were estimated via univariate analysis (paired OR). Multivariate analysis was performed by logistic regression. A decision tree was constructed using the J48 algorithm. Results: an association was found by univariate analysis between GC risk and a lack of formal education, having smoked for ≥ 10 years, eating rapidly, consuming very hot food and drinks, a non-suitable breakfast within two hours of waking, pickled food and capsaicin. In contrast, a protective association against GC was found with taking recreational exercise and consuming fresh fruit and vegetables. No association was found between the development of GC and having an income that reflected poverty, using a refrigerator, perception of the omission of breakfast and time period of alcoholism. In the final multivariate analysis model, having no formal education (OR = 17.47, 95% CI = 5.17-76.69), consuming a non-suitable breakfast within two hours of waking (OR = 8.99, 95% CI = 2.85-35.50) and the consumption of capsaicin ˃ 29.9 mg capsaicin per day (OR = 3.77, 95% CI = 1.21-13.11) were factors associated with GC. Conclusions: an association was found by multivariate analysis between the presence of GC and education, type of breakfast and the consumption of capsaicin. These variables are susceptible to intervention and can be identified via the QUFA-GC(c)


No disponible


Assuntos
Humanos , Neoplasias Gástricas/epidemiologia , Infecções por Helicobacter/epidemiologia , Capsaicina/farmacocinética , Fatores de Risco , Neoplasias Gástricas/etiologia , México/epidemiologia , Escolaridade , Capsicum/efeitos adversos , Jejum/efeitos adversos , Tabagismo/epidemiologia
9.
Molecules ; 23(2)2018 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-29414892

RESUMO

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.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Compostos Fitoquímicos/farmacologia , Alcaloides/farmacocinética , Animais , Benzodioxóis/farmacocinética , Transporte Biológico/efeitos dos fármacos , Capsaicina/farmacocinética , Catecóis/farmacocinética , Álcoois Graxos/farmacocinética , Camundongos , Compostos Fitoquímicos/química , Piperidinas/farmacocinética , Alcamidas Poli-Insaturadas/farmacocinética , Distribuição Tecidual
10.
Xenobiotica ; 48(6): 541-545, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28627264

RESUMO

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.


Assuntos
Capsaicina/análogos & derivados , Absorção Intestinal , Mucosa Intestinal/metabolismo , Animais , Capsaicina/farmacocinética , Capsaicina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
11.
Clin Toxicol (Phila) ; 56(1): 15-24, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28730896

RESUMO

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.


Assuntos
Canabinoides/toxicidade , Capsaicina/uso terapêutico , Hidroterapia , Vômito/induzido quimicamente , Regulação da Temperatura Corporal , Capsaicina/farmacocinética , Capsaicina/farmacologia , Endocanabinoides/fisiologia , Humanos , Canais de Cátion TRPV/fisiologia , Vômito/terapia
12.
Pain Manag ; 7(6): 499-512, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28814158

RESUMO

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.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacocinética , Oximorfona/efeitos adversos , Oximorfona/farmacocinética , alfa-Tocoferol/análogos & derivados , Adulto , Analgésicos Opioides/sangue , Capsaicina/efeitos adversos , Capsaicina/farmacocinética , Estudos Cross-Over , Combinação de Medicamentos , Humanos , Masculino , Oximorfona/sangue , Manejo da Dor/métodos , Adesivo Transdérmico , Adulto Jovem , alfa-Tocoferol/efeitos adversos , alfa-Tocoferol/farmacocinética
13.
Eur J Pharm Sci ; 106: 34-40, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28546105

RESUMO

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.


Assuntos
Capsaicina/análogos & derivados , Dióxido de Silício/química , Absorção Cutânea/fisiologia , Administração Cutânea , Animais , Capsaicina/administração & dosagem , Capsaicina/química , Capsaicina/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Portadores de Fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Membranas Artificiais , Óleos/química , Permeabilidade , Polímeros/química , Porosidade , Suínos
14.
Protein Cell ; 8(3): 169-177, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28044278

RESUMO

Capsaicin in chili peppers bestows the sensation of spiciness. Since the discovery of its receptor, transient receptor potential vanilloid 1 (TRPV1) ion channel, how capsaicin activates this channel has been under extensive investigation using a variety of experimental techniques including mutagenesis, patch-clamp recording, crystallography, cryo-electron microscopy, computational docking and molecular dynamic simulation. A framework of how capsaicin binds and activates TRPV1 has started to merge: capsaicin binds to a pocket formed by the channel's transmembrane segments, where it takes a "tail-up, head-down" configuration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, capsaicin stabilizes the open state of TRPV1 by "pull-and-contact" with the S4-S5 linker. Understanding the ligand-host interaction will greatly facilitate pharmaceutical efforts to develop novel analgesics targeting TRPV1.


Assuntos
Capsaicina/química , Canais de Cátion TRPV/química , Sítios de Ligação , Capsaicina/farmacocinética , Humanos , Ligações de Hidrogênio , Ligação Proteica , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
15.
Drug Dev Ind Pharm ; 43(1): 98-107, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27487326

RESUMO

The aim of this study was to design and develop simultaneous optimal transinvasome formulations (OTV) to enhance the transdermal delivery of capsaicin. Using a central composite experimental design with duplicate centroids, 10 model formulations of transinvasomes (TVs) were demonstrated. The lipid compositions of the TV formulations were determined as formulation factors (Xn) and response variables (Yn), respectively. TV formulations containing a constant concentration of phosphatidylcholine, cholesterol, 0.15% capsaicin, and various percentages of d-limonene (X1) and cocamide diethanolamine (X2) were prepared. The physicochemical characteristics, e.g. the vesicle size, size distribution, zeta potential, entrapment efficiency, and skin permeability, of the TV formulations were experimentally investigated. The relationship among the formulation factor, the response variables, and the OTV was predicted using Design Expert® software. The accuracy and reliability of the OTV predicted using computer software were experimentally confirmed and investigated as an experimental transinvasome formulation (ETV). The results indicated that the skin permeability of the ETV was close to the OTV and was significantly higher than that of conventional liposomes and commercial products. The response surfaces estimated by the computer software were helpful in understanding the complicated relationship among the formulation factor, the response variables, and the stability of the TV formulation.


Assuntos
Capsaicina/química , Capsaicina/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Desenho de Drogas , Absorção Cutânea/efeitos dos fármacos , Administração Cutânea , Animais , Antipruriginosos/administração & dosagem , Antipruriginosos/química , Antipruriginosos/farmacocinética , Capsaicina/administração & dosagem , Química Farmacêutica , Elapidae , Lipossomos , Técnicas de Cultura de Órgãos , Absorção Cutânea/fisiologia
16.
Pharm Dev Technol ; 22(4): 487-491, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26754018

RESUMO

Skin diseases are usually treated using topical formulations. Frequently, multiple applications per day are necessary, as up to 90% of the formulation (and thus of the active) are withdrawn from the skin by contact with the environment. During the development of topical formulations ex vivo permeation and penetration experiments are deployed to characterize the formulations. Still, these tests do not take into account the removal of formulations during the application period. To date, only few methods exist to probe the substantivity of dermal formulations. The aim of this investigation was to develop methods that simulate skin-to-skin or clothing-to-skin contact and enable the determination of the amount of formulation that is removed from the skin due to the contact. Three different types of formulations were used to validate the systems: a conventional semisolid cream, an oil-in-oil-emulsion, and a film forming formulation. The results showed that the substantivity decreased in the order: film forming formulation > semisolid cream > oil-in-oil-emulsion. A similar trend could be determined with both methods although the total amounts of withdrawn formulation differed. The developed methods can add to the knowledge about the formulation and can be used to develop formulations that exhibit higher substantivity.


Assuntos
Capsaicina/análogos & derivados , Preparações de Ação Retardada/química , Emulsões/química , Óleos/química , Fármacos do Sistema Sensorial/administração & dosagem , Absorção Cutânea , Creme para a Pele/química , Administração Cutânea , Animais , Capsaicina/administração & dosagem , Capsaicina/farmacocinética , Composição de Medicamentos/métodos , Fármacos do Sistema Sensorial/farmacocinética , Pele/metabolismo , Suínos
17.
J Drug Target ; 25(5): 420-424, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27918217

RESUMO

Capsaicin-loaded dissolving microneedles (DMNs) were prepared to investigate the analgesic effect of capsaicin on the skin. The dimensions of each microneedle (MN) were as follows: diameter of the basement, 17 mm; length, 500 µm; and width, 300 µm. The average capsaicin content in the DMNs loaded with a low and high dose of capsaicin was 8.8 ± 0.5 mg and 12.5 ± 0.4 mg. Almost all the capsaicin, 99.3 ± 4.1% and 99.7 ± 2.2% for low-dose and high-dose DMNs were released within 20 min. High amounts of capsaicin were recovered with 102.8 ± 0.1% of capsaicin after storage at 23 °C for 90 days. The pharmacological activity of capsaicin DMNs was compared to that of capsaicin cream as a positive control, by measuring the idiospasm of depilated rat skin. The time required to achieve 50% idiospasm suppression was 26.3 ± 1.9 min and 53.0 ± 2.3 min for low-dose and high-dose DMNs. A pharmacokinetic study showed high tissue capsaicin levels of 660.2 ± 120.6 and 1805.3 ± 218.1 µg/g wet weight for low-dose and high-dose DMNs at 5 min after administration. The results suggest that DMNs could exert a rapid local analgesic action on the skin.


Assuntos
Capsaicina/administração & dosagem , Agulhas , Pele/metabolismo , Animais , Capsaicina/farmacocinética , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar
18.
Acta Pol Pharm ; 74(2): 321-329, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29624237

RESUMO

Capsicum annuum L. is a rich source of capsaicin, an alkaloid, which is a very pungent compound. Due to ever growing need of capsaicin, an extensive research on its efficient cultivation as well as chemical synthesis is underway. Owing to the pungent nature of capsaicin, its analogous molecules without pungent effect are being explored. The objective of this descriptive review is to comprehensively present the updates on the bioactivities of capsaicin. Additionally, the in silico target fishing approach has been used to identify the possible protein targets of capsaicin. This article will definitely provide future perspectives of research on capsaicin.


Assuntos
Capsaicina/uso terapêutico , Biologia Computacional/métodos , Simulação por Computador , Terapia de Alvo Molecular/métodos , Transdução de Sinais/efeitos dos fármacos , Animais , Capsaicina/efeitos adversos , Capsaicina/química , Capsaicina/farmacocinética , Humanos , Estrutura Molecular , Terapia de Alvo Molecular/efeitos adversos , Mapas de Interação de Proteínas , Relação Estrutura-Atividade
19.
J Agric Food Chem ; 64(23): 4735-41, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27170269

RESUMO

Capsaicin (CAP) is the major active component in chili peppers with health-promoting benefits. However, the low bioavailability and irritating quality of CAP greatly limit its applications in functional foods. The objective of this study was to develop a food-grade nanoemulsion to increase the dissolution and bioaccessibility of CAP and to alleviate its irritating effects. To achieve this goal, CAP was first dissolved in medium-chain triacylglycerol (MCT), followed by the addition of sucrose stearate S-370 as organogelator to develop CAP-loaded organogel. The oil-in-water (O/W) emulsion was formed using organogel as the oil phase and Tween 80 as the emulsifier. After ultrasonication treatment, droplet sizes of emulsion were decreased to 168 nm with enhanced dissolution rate and bioaccessibility. In vivo study further confirmed the reduced rat gastric mucosa irritation caused by CAP. The organogel-derived nanoemulsion was proved to be an effective delivery system for CAP-based functional food products.


Assuntos
Capsaicina/efeitos adversos , Capsaicina/farmacocinética , Emulsões/química , Mucosa Gástrica/efeitos dos fármacos , Nanoestruturas/química , Administração Oral , Animais , Disponibilidade Biológica , Capsaicina/administração & dosagem , Emulsificantes/química , Emulsões/administração & dosagem , Mucosa Gástrica/patologia , Géis/química , Masculino , Polissorbatos/química , Ratos Wistar
20.
J Neurophysiol ; 116(2): 619-28, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27226449

RESUMO

Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl(-) gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl(-) export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated Cl(-) equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl(-) import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl(-) import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl(-) gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions.


Assuntos
Cloretos/metabolismo , Endocanabinoides/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Sinapses/classificação , Sinapses/efeitos dos fármacos , Anilidas/farmacologia , Animais , Biofísica , Bumetanida/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Capsaicina/farmacocinética , Sistema Nervoso Central/citologia , Cinamatos/farmacologia , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Lactonas/farmacologia , Sanguessugas , Orlistate , Técnicas de Patch-Clamp , Fármacos do Sistema Sensorial/farmacologia , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Ácido gama-Aminobutírico/farmacologia
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