Effect of highly purified capsaicin on articular cartilage and rotator cuff tendon healing: An in vivo rabbit study

Highly purified capsaicin has emerged as a promising injectable compound capable of providing sustained pain relief following a single localized treatment during orthopedic surgical procedures. To further assess its reliability for clinical use, the potential effect of highly purified capsaicin on articular cartilage metabolism as well as tendon structure and function warrants clarification. In the current study, rabbits received unilateral supraspinatus transection and repair with a single 1 ml injection of capsaicin (R + C), PEG‐only placebo (R + P), or saline (R + S) into the glenohumeral joint (GHJ). An additional group received 1 ml capsaicin onto an intact rotator cuff (I + C). At 18 weeks post‐op, cartilage proteoglycan (PG) synthesis and content as well as cell viability were similar (p > 0.05) across treatment groups. Biomechanical testing revealed no differences (p > 0.05) among tendon repair treatment groups. Similarly, histologic features of both cartilage and repaired tendons showed minimal differences across groups. Hence, in this rabbit model, a single injection of highly purified capsaicin into the GHJ does not induce a deleterious response with regard to cartilage matrix metabolism and cell viability, or rotator cuff healing. These data provide further evidence supporting the use of injectable, highly purified capsaicin as a safe alternative for management of postoperative pain following GHJ surgery. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1854–1860, 2015.     

Therapeutic effect of capsaicin nasal treatment in patients with mixed rhinitis unresponsive to intranasal steroids

Literature is convincing regarding the efficacy of capsaicin nasal treatment in idiopathic rhinitis (IR). However, up to 50% of IR patients do not meet the strict inclusion criteria of the trials conducted so far. As a consequence, the efficacy of capsaicin is unknown in a significant number of IR patients that do not meet the strict inclusion/exclusion criteria (J Allergy Clin Immunol. 2014;133:1332, J Allergy Clin Immunol. 2017; [Epub ahead of print]). “Mixed rhinitis” (MR) patients have more than one major etiologic factor involved in the mucosal pathology. We have no idea about the efficacy of capsaicin nasal spray in these patients nor about the time interval to seek a second application. We report here that capsaicin nasal spray is effective in a broader group of IR than the purely selected ones described before, that subjective nasal hyper‐reactivity is a good predictor of positive outcome, and that the time interval for seeking a second treatment is likely to be shorter in MR patients than in the strictly selected IR patients.     

Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series

Background: Cannabinoid hyperemesis syndrome (CHS) is characterized by symptoms of cyclic abdominal pain, nausea, and vomiting in the setting of prolonged cannabis use. The transient receptor potential vanilloid 1 (TRPV1) receptor may be involved in this syndrome. Topical capsaicin is a proposed treatment for CHS; it binds TRPV1 with high specificity, impairing substance P signaling in the area postrema and nucleus tractus solitarius via overstimulation of TRPV1. This may explain its apparent antiemetic effect in this syndrome.

Purpose: We describe a series of thirteen cases of suspected cannabis hyperemesis syndrome treated with capsaicin in the emergency departments of two academic medical centers.

Methods: A query of the electronic health record at both centers identified thirteen patients with documented daily cannabis use and symptoms consistent with CHS who were administered topical capsaicin cream for symptom management.

Results: All 13 patients experienced symptom relief after administration of capsaicin cream.

Conclusion: Topical capsaicin was associated with improvement in symptoms of CHS after other treatments failed.     

Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist

Aims

Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy.

Methods

An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure−response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose−response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated.

Results

The results suggested that a 20 mg dose of MK-3207 (EC₅₀ of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose−response would be reached around 40–100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial.

Conclusions

The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose−response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.     

辣椒素对人大细胞肺癌NCI-H460细胞侵袭能力及E-钙黏蛋白、Snail蛋白表达的影响

目的观察辣椒素对人大细胞肺癌NCI-H460细胞侵袭能力及E-钙黏蛋白(E-cadherin)和Snail蛋白表达的影响,探讨其抗非小细胞肺癌的可能机制。方法体外培养NCI-H460细胞,以不同终浓度辣椒素进行处理,未加辣椒素为对照组。采用Hoechst33342核染色分析、Transwell小室细胞侵袭实验及Western blot检测,观察辣椒素对NCI-H460细胞凋亡、侵袭能力及E-cadherin、Snail蛋白表达变化的影响。结果与对照组比较,Hoechst33342核染色分析表明,辣椒素各浓度组可明显诱导NCI-H460细胞凋亡(P0.05);Transwell体外侵袭实验结果显示,辣椒素可显著抑制侵袭穿膜细胞数(P0.05);Western blot检测结果表明,辣椒素各浓度组E-cadherin表达水平明显升高、Snail表达水平明显降低(P0.05)。结论辣椒素能明显诱导NCI-H460细胞凋亡;降低Snail表达、刺激E-cadherin的表达从而抑制NCI-H460细胞侵袭能力,可能是其抗非小细胞肺癌的机制之一。     

Chemical analysis of freshly prepared and stored capsaicin solutions: implications for tussigenic challenges

The purpose of this study was to assess the stability of stored capsaicin solutions and the actual concentrations of prepared solutions. Capsaicin solutions ranging in concentration from 0.5 to 128 microM were mixed and analyzed using high performance liquid chromatography. Samples of varying concentrations were then stored under 4 environmental conditions: 4 degrees C and protected from light, room temperature (RT) exposed to light, RT protected from light, and -20 degrees C and protected from light. The concentrations were measured every other month for 1 year. Actual concentrations of freshly prepared solutions were on average 88.3% of predicted. For solutions stored at 4 degrees C, there was a decrease only in the lower concentrations (0.5, 1, and 2 microM) after 2 months (P=0.003). Solutions stored at RT exposed to light decreased in concentration after 6 months (P=0.020), and solutions stored at RT protected from light decreased in concentration after 4 months (P=0.026). The group stored at -20 degrees C decreased in concentration after 1 year (P=0.033). We conclude that the actual concentration of capsaicin solution is less than predicted, and solutions of 4 microM or higher concentration are stable for 1 year if stored at 4 degrees C protected from light.     

Pharmacokinetic effects of capsaicin on vinblastine in rats mediated by CYP3A and Mrp2

Capsaicin (trans‐8‐methyl‐N‐vanillyl‐6‐nonenamide, CAP) is an important ingredient in spicy foods consumed throughout the world. Vinblastine (VBL) is a naturally occurring alkaloid prescribed to cancer patients. Many cancer patients treated with VBL were taking CAP at the same time. This study attempted to investigate the effect of CAP on the pharmacokinetics of VBL, which is the substrate of CYP3A, P‐gp, and Mrp2. CAP, cyclosporine (CsA) or olive oil was given to rats for seven consecutive days, and on the seventh day, VBL (1.3 mg/kg) was administered intravenously. CsA was used as a CYP3A1/2 and transporter inhibitor, and olive oil was used as a vehicle. The results showed that pretreatment of rats with CAP (3.0 mg/kg) for seven consecutive days resulted in an increase in the AUC_0–t of VBL of about 29.8% (P < 0.05) compared with the control group. Moreover, CAP decreased the CL of VBL to 75.5% (P < 0.05). At this time, CYP3A1/2 and Mrp2/Abcc2 in the liver was decreased at the mRNA and protein levels. These results demonstrate that chronic ingestion of CAP will increase systemic exposure and reduce clearance of VBL in rats. The food–drug interaction between CAP and VBL appears to be due to modulation of CYP3A1/2 and Mpr2 expression by CAP.     

Thermography‐measured effect of capsaicin,methylprednisolone and mitomycin on the survival of random skin flaps in rats

Aims: This study was designed to determine if steroids, capsaicin and mytomicin improved skin flap survival in rats, and it has confirmed that thermography is an effective method to measured skin flap vitality. Methods: Forty female Wistar rats were randomised into four groups. A standardised full thickness inferiorly based dorsal random‐pattern skin flap was raised, and a gelatine sponge was placed before suturing between the flap and its recipient bed, soaked with 0.9 % saline in the control group and with capsaicin, methylprednisolone and mitomycini in the experimental groups. Vitality of the flap and of the survival area was measured by infrared thermography. Results: Methylprednisolone statistically significant decrease skin flap necrosis, approximately 56%, when compared with controls (P< 0.05). Conclusion: Corticosteroids applied subcutaneously in a single dose on a gelatine sponge produced a statistically significant improvement of the survival of random skin flaps in rats, whereas capsaicin and mitomycin showed no improvement.