Topical treatment with mastic (resin from Pistacia lentiscus) elicits anti-inflammatory and anti-pruritic responses by modulating keratinocyte activation in a mouse model of allergic dermatitis

BackgroundAs the number of patients with skin allergies, including atopic dermatitis, has increased rapidly, therapeutic options such as anti-IL-31 antibody and Janus kinase inhibitor have been developed recently. However, many concerns remain regarding the adverse effects and cost of these drugs; therefore, development of supplements that could support the effect of therapeutic agents is always required.PurposeThe aim of this study was to develop preventive and supportive options for skin allergies by focusing on a natural product called “Mastic”. Methods: Initially, the anti-inflammatory and anti-pruritic responses of 3% and 30% Mastic topical treatment were investigated in a mouse model of allergic contact dermatitis, generated by topical application of toluene-2,4-diisocyanate (TDI), a hapten that induces type 2 helper T cells. After itch behaviour and ear-swelling response were monitored, serum, auricular lymph nodes, and skin tissues were collected to analyse immunocyte differentiation, cytokine determination, and histological changes.ResultsOur findings indicated that topical treatment with mastic significantly ameliorated ear swelling, itch behaviour, immunocyte infiltration, and cytokine production. Histological evaluation confirmed the occurrence of anti-inflammatory responses. The anti-inflammatory and anti-pruritic effects of topical treatment with mastic (3% and 5%) were further confirmed in a mouse model of atopic dermatitis which was generated by topical application of TDI in NC/Nga mice. Thickness of the back skin, AD score, transepidermal water loss (TEWL), and itch behaviour were measured weekly, and immunocyte differentiation, cytokine determination, and histological changes were also analysed. Mastic treatment significantly attenuated the skin thickness, AD score, TEWL, and itch behaviour. Corroborated reduction was observed in the numbers of T cells and IgE-B cells, as well as in pro-inflammatory cytokine production. The reproducibility of the effects of mastic was confirmed with 1% mastic ointment in a setting similar to the AD mouse model. In vitro evaluation of keratinocytes indicated that mastic pre-exposure induced a significant dose-dependent decrease in cytokine production.ConclusionOur findings thus demonstrate that topical treatment with mastic significantly ameliorate inflammatory and pruritic responses in a mouse model of allergic dermatitis.     

A novel acoustic evaluation system of scratching in mouse dermatitis: rapid and specific detection of invisibly rapid scratch in an atopic dermatitis model mouse

Scratching is an essential and a skin specific behavior induced by itching, which is a common symptom of atopic dermatitis (AD) and other types of dermatitis. Itching sensation and scratching are closely associated and thus scratching times are currently used for evaluating itching in animal models. However, objective measuring systems of scratching to assess the grade of dermatitis and the effectiveness of anti-pruritic drugs in animal dermatitis models are lacking. To investigate a quantitative evaluation system for itching, we have developed a novel acoustic scratching counting system and compared its accuracy with time-consuming slow-motion video recording system. We have also objectively evaluated the efficacy of an antihistamine using this novel system. Scratching behavior of an AD model mouse (K14 driven IL-18 transgenic mouse) was recorded visually and acoustically. Specific scratching sound produced by mice was recorded and counted using a software we have developed, and the results obtained using our acoustic system were not statistically different from data obtained using slow motion video system. Surprisingly, mice scratched more than 10 times/second, which was invisibly rapid motion and revealed inaccuracy of conventional hand counting system. Results were identical to that of measured by 10 times time costing slow-motion video analysis. The antihistamine is clearly effective for suppression of scratching as demonstrated using this objective and accurate method. This novel motion analysis system will open a window for physiological and pathological analysis for animal models and development of anti-pruritic drugs.     

Observations on the Antipruritic Effect of Guanethidine in Atopic Dermatitis

Guanethidine, 0.75 to 1.25 mg. per kg. per day, was found to alleviate the pruritus of acute atopic dermatitis in 19 out of 20 patients. It was not effective in patients with other dermatoses. An apparent partial tolerance to this treatment developed in six out of 10 patients re-treated. It had little or no therapeutic effect in 10 patients with a variety of other pruritic dermatoses, suggesting that this drug has a specific antipruritic action in patients with atopic dermatitis. In a double-blind study, 11 of 12 patients with atopic dermatitis treated with guanethidine experienced relief of pruritus. Four out of 12 patients using a placebo had complete or partial relief. Guanethidine, 1% to 10%, used topically was therapeutically no more effective than placebo. In view of the reported side effects and the anesthetic hazard encountered with guanethidine, further long-term studies are indicated before this drug is adopted for clinical use in the treatment of atopic dermatitis. The findings support the hypothesis that atopic dermatitis may be a manifestation of a hereditary defect in cutaneous noradrenaline binding.     

Atopic Dermatitis (Eczema): An Appraisal

Atopic (spontaneous) allergies and nonatopic (induced) allergies are often confused. The meaning of these terms is definite, but the occurrence of either (in a given individual) may depend upon his autonomic nervous system control. The evidence that allergens produce the cutaneous changes in atopic dermatitis is flimsy, and neurodermatitis would be a more appropriate term since the entity falls into that pattern of skin changes. Treatment carried out, from infancy sometimes to old age, consists of careful management of the patient in the physical and emotional spheres, avoidance of external irritation and the use of a multiplicity of anti-pruritic, anti-inflammatory and sedative agents.     

A randomized,placebo controlled,trial of preoperative sustained release Betamethasone plus non-controlled intraoperative Ketorolac or Fentanyl on pain after diagnostic laparoscopy or laparoscopic tubal ligation [ISRCTN52633712

BACKGROUND: Gynecological laparoscopic surgery procedures are often complicated by postoperative pain resulting in an unpleasant experience for the patient, delayed discharge, and increased cost. Glucocorticosteroids have been suggested to reduce the severity and incidence of postoperative pain. METHODS: This study examines the efficacy of a sustained release betamethasone preparation to reduce postoperative pain and the requirement for pain relief drugs after either diagnostic laparoscopy or tubal ligation. Patients were recruited, as presenting, after obtaining informed consent. Prior to surgery, patients were randomly selected by a computer generated table to receive either pharmacy-coded betamethasone (12 mg IM Celestone trade mark ) or an optically identical placebo injection of Intralipid trade mark and isotonic saline mixture. The effect of non-controlled prophylactic intraoperative treatment with either fentanyl or ketorolac per surgeon's orders was also noted in this study. Blood samples taken at recovery and at discharge times were extracted and analyzed for circulating betamethasone. Visual analog scale data on pain was gathered at six post-recovery time points in a triple blind fashion and statistically compared. The postoperative requirement for pain relief drugs was also examined. RESULTS: Although the injection achieved a sustained therapeutic concentration, no beneficial effect of IM betamethasone on postoperative pain or reduction in pain relief drugs was observed during the postoperative period. Indeed, the mean combined pain scores during the 2 hour postoperative period, adjusted for postoperative opioids as the major confounding factor, were higher approaching statistical significance (P = 0.056) in the treatment group. Higher pain scores were also observed for the tubal ligation patients relative to diagnostic laparoscopy. Intraoperative fentanyl treatment did not significantly lower the average pain score during the 2 hour postoperative period. Intraoperative ketorolac treatment significantly lowered (P = 0.027) pain scores and reduced the postoperative requirement for additional pain relief drugs. CONCLUSIONS: There was a lack of efficacy of preoperative sustained release betamethasone in reducing postoperative pain despite maintaining a therapeutic concentration during the postoperative period. Intraoperative Ketorolac did afford some short-term pain relief in the postoperative period and reduced the need for additional pain relief drugs.     

Nicotinic Acid as Adjuvant Therapy in Newly Admitted Schizophrenic Patients

A placebo-controlled, comparative clinical study was conducted to test the hypothesis that nicotinic acid as an adjuvant medication has a beneficial therapeutic effect over and above the effect which can be achieved by the administration of phenothiazine drugs alone, over a six-month period, in newly (recently) admitted schizophrenic patients.The most important single finding was that no statistically significant therapeutic difference was seen between the active treatment and the placebo groups; i.e., the addition of nicotinic acid or nicotinamide to the regular phenothiazine treatment regimen did not have any measurable therapeutic effect in this sample of patients. It was shown that patients in the placebo group received a lower total daily amount of phenothiazine drugs than those on either of the active substances. Furthermore, it was noted that the addition of the active substances did not reduce the number of days of hospitalization.     

A New Lotion for the Treatment of Acne Vulgaris

A therapeutic assessment of a new lotion containing methylprednisolone, neomycin, colloidal sulfur and aluminum chlorhydroxide complex (Neo-Medrol Acne Lotion) was carried out on 187 patients suffering from acne vulgaris.Of the 187 patients, 165 showed excellent or good response. Following enthusiastic acceptance of the lotion by the patients in the initial study, a second random study with an additional 134 subjects was undertaken to compare the active lotion with the lotion base alone.The active lotion was superior to the placebo lotion in this study, at a statistically significant level. The overall findings suggest that this lotion is an efficient preparation for the control of acne vulgaris (early and late types) and it also showed promise in the treatment of a few cases of acne rosacea and seborrheic dermatitis facialis.     

Scratching of their skin by NC/Nga mice leads to development of dermatitis

Effects of scratching behavior on dermatitis, transepidermal water loss (TEWL) and serum IgE concentrations were examined in NC/Nga (NC) mice with toenails (WIT) and without toenails (WOT). The first study was a preventive treatment done to cut off hind toenails before dermatitis induction and the second study was a therapeutic treatment by cutting off hind toenails of NC mice with severe dermatitis. In the preventive study, scratching behavior significantly increased in both WIT and WOT after dermatitis induction. Skin severity score, TEWL, number of mast cells and serum IgE concentration statistically increased in WIT but not in WOT after dermatitis induction. Histological changes coincided with the skin severity score in WIT, while no changes were observed in WOT. In the therapeutic study, skin severity score in WOT but not in WIT statistically decreased after cutting off the hind toenails. TEWL and numbers of mast cells in WOT were statistically lower compared with findings in WIT. Thus scratching up the skin with toenails seemed to be the most important factor leading to dermatitis in NC mice.     

Effects of betamethasone,sulindac and quinacrine drugs on the inflammatory neoangiogenesis response induced by polyurethane sponge implanted in mouse

In this study, we showed the effect of the betamethasone, sulindac and quinacrine alone or combined, on the inflammatory angiogenesis promoted by polyurethane sponge on mice. The main finding reported here is that the formation of new blood vessels was strongly inhibited by low concentration of betamethasone, sulindac or quinacrine, whether alone or in combination. It is known that steroidal anti-inflammatory drugs inhibit the enzymes required for the production of prostaglandins through a nuclear glucocorticoid receptor (GR) mediated mechanism. This mechanism may occur in endothelial cells as well. Considering that activity of cyclo-oxigenases 1 and 2 is inhibited by sulindac, and that these enzymes are located in the stromal tissue, we propose that the anti-angiogenic effect of these agents may occur via inhibition of both COX isoforms. On the other hand, quinacrine inhibited PLA2 activity, and we propose here that the anti-angiogenic effect occurs via inhibition of the enzyme PLA2. The potentiated effect of the association of betamethasone, sulindac and quinacrine may have some therapeutic benefit in the control of pathological angiogenesis. Further studies are required to validate these propositions.     

Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee – A randomized double blind placebo controlled trial

Osteoarthritis is a common, chronic, progressive, skeletal, degenerative disorder, which commonly affects the knee joint. Boswellia serrata tree is commonly found in India. The therapeutic value of its gum (guggulu) has been known. It posses good anti-inflammatory, anti-arthritic and analgesic activity. A randomized double blind placebo controlled crossover study was conducted to assess the efficacy, safety and tolerability of Boswellia serrata Extract (BSE) in 30 patients of osteoarthritis of knee, 15 each receiving active drug or placebo for eight weeks. After the first intervention, washout was given and then the groups were crossed over to receive the opposite intervention for eight weeks. All patients receiving drug treatment reported decrease in knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was decreased. Radiologically there was no change. The observed differences between drug treated and placebo being statistically significant, are clinically relevant. BSE was well tolerated by the subjects except for minor gastrointestinal ADRs. BSE is recommended in the patients of osteoarthritis of the knee with possible therapeutic use in other arthritis.     

Relative potency in acute and chronic suppressive effects of prednisolone and betamethasone on the hypothalamic-pituitary-adrenal axis in man

The relative potency in the hypothalamic-pituitary-adrenal (HPA) suppression of both prednisolone and betamethasone was examined in an acute study with normal volunteers and in a chronic study with glucocorticoid-treated patients. Circadian rhythm of plasma cortisol was studied after a single dose administration of 5 to 30 mg prednisolone or 0.5 to 3.0 mg betamethasone at 8:00 hr. Morning-rise of plasma cortisol occurred on the morning after the administration of 30 mg or less prednisolone but no morning rise was noted after the administration of 1.0 mg or more betamethasone. Plasma ACTH was slightly elevated on the morning after 30 mg prednisolone administration but showed low levels throughout the night after 3.0 mg betamethasone administration. Plasma cortisol responsiveness to ACTH was examined in patients before and during therapy with either prednisolone or betamethasone. The basal cortisol level was not suppressed and the responsiveness to ACTH remained nearly normal during long-term 5 mg prednisolone therapy, but these were completely suppressed during long-term 5 mg betamethasone therapy. The responsiveness to ACTH was nearly normal in patients receiving alternate-day therapy with prednisolone in such large doses as 50 or 60 mg every other day, but was completely suppressed in patients receiving 1.0 mg betamethasone every other day. The relative potency of betamethasone in acute and chronic suppressive effects on the HPA system seems to be much stronger than that of prednisolone in equivalent doses with comparable anti-inflammatory effects. It is also suggested that the alternate-day therapy with such long-acting steroids as betamethasone are useless in preventing HPA suppression.     

7,8,4′-Trihydroxyisoflavone Attenuates DNCB-Induced Atopic Dermatitis-Like Symptoms in NC/Nga Mice

Atopic dermatitis (AD) is characterized by chronic highly pruritic and relapsing inflammatory skin lesions. Despite its growing prevalence, therapeutic treatments remain limited. Natural immune modulators from herbal extracts or derivatives may be useful for treating AD symptoms. This study examined the effect of 7,8,4′-trihydroxyisoflavone (7,8,4′-THIF), a metabolite of soy isoflavone daidzin, on AD-like symptoms. Repeated epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) was performed on the ear and dorsal skin of NC/Nga mice to induce AD-like symptoms and skin lesions, and 7,8,4′-THIF (200 and 400 nmol) or tacrolimus (100 µg) was applied topically for 3 weeks to assess their anti-pruritic effects. We found that 7,8,4′-THIF alleviated DNCB-induced AD-like symptoms as quantified by skin lesion, dermatitis score, ear thickness, and scratching behavior. Histopathological analysis demonstrated that 7,8,4′-THIF decreased DNCB-induced eosinophil and mast cell infiltration into skin lesions. We also found that 7,8,4′-THIF significantly alleviated DNCB-induced loss of water through the epidermal layer. In addition to reducing the DNCB-induced increase in serum IgE, 7,8,4′-THIF also lowered skin lesion levels of the chemokine thymus and activation regulated chemokine; Th2 cytokines interleukin (IL)-4, IL-5, and IL-13; and Th1 cytokines IL-12 and interferon-γ. These results suggest that 7,8,4′-THIF might be a potential therapeutic candidate for the treatment of atopic dermatitis.     

The Use of Corticosteroid (Dexamethasone) in the Treatment of Acute Laryngotracheitis

Many practitioners have considered that steroids, with their anti-inflammatory properties, should be efficacious in the treatment of acute laryngotracheitis. To examine this theory, 200 consecutive cases of acute laryngotracheitis admitted to The Hospital for Sick Children, Toronto, were included in a double-blind study using dexamethasone-21-phosphate and placebo according to a random selection code. All other therapy was kept constant. Each patient was assessed by one observer according to seven clinical parameters.The results of this study were subjected to statistical analysis and significantly favoured the steroid-treated group in four parameters only. In view of the risks inherent in steroid therapy, this degree of difference is not sufficient to warrant routine use of this drug for patients with acute laryngotracheitis.     

Establishing efficacy of a new experimental treatment in the 'gold standard' design

Provided that there are no ethical concerns, the comparison of an active drug with placebo in a randomized two-arm clinical trial provides the most convincing way to demonstrate the efficacy of a new experimental treatment. However, in a placebo-controlled clinical trial it is not sufficient to demonstrate merely a statistically significant treatment difference. Regulatory authorities strongly recommend to assess additionally whether the observed treatment difference is also of clinical relevance. The inherent issue is the necessity of the a priori definition of what constitutes a clinically relevant difference in efficacy. This problem can be solved in a three-arm study by including an active control group. We address the necessary conditions in the gold standard design which allow the claim of efficacy for the new treatment with particular focus on assay sensitivity.     

Review of the clinical efficacy of flutrimazole gel in the treatment of dandruff and/or seborrheic dermatitis.

The purpose of this article is to review the phase II and phase III clinical trials with the new pharmaceutical gel form of flutrimazole. The aim of the phase II study was to determine the efficacy and tolerance of flutrimazole 1%, 2% and 4% gel when compared to placebo in the treatment of 80 patients with dandruff or seborrheic dermatitis at a dose of three applications per week during one month. Flutrimazole 1% gel had a similar efficacy compared to the other studied concentrations and a superior efficacy when compared to placebo (p < 0.05). All treatments studied had an excellent tolerance. In the phase III study, the efficacy and tolerance of flutrimazole 1% gel was compared to ketoconazole 2% gel in 192 patients with dandruff or seborrheic dermatitis. Flutrimazole gel had a similar efficacy to ketoconazole gel at a dose of three applications per week for 28 days. Both products were well tolerated and no adverse effects were recorded.     

Novel soft steroids: effects on cell growth in vitro and on wound healing in the mouse.

Evaluation of three "soft" steroids is described. The test compounds were compared with the standard anti-inflammatory steroids betamethasone and prednicarbate in two studies. Soft steroids are designed based on the "inactive metabolite approach" to be rapidly inactivated by predictable metabolism after performing their therapeutic function. Consequently, lower circulating (peripheral) levels of potentially harmful steroids result, and undesirable systemic and local side effects are minimized. The soft and standard steroids behaved similarly in an in vitro cell culture model, whereas in a whole animal study the advantages of the soft steroids were evident.     

A highly sensitive LC-MS-MS assay for analysis of midazolam and its major metabolite in human plasma: applications to drug metabolism

Betamethasone is a synthetic corticosteroid designed to exert a marked glucocorticoid activity. As the free alcohol, betamethasone finds widespread clinical applications related to its anti-inflammatory and immunosuppressant activity. In the present study, a fast, sensitive, robust method was developed for the determination and quantification of betamethasone in human plasma by liquid chromatography coupled with tandem mass spectrometry, using photospray ionization in negative mode. Betamethasone was extracted from 0.5 ml human plasma by liquid-liquid extraction (LLE) using chloramphenicol as internal standard. The method has a chromatographic run of 2.5 min using a C(18) analytical column (100 mm x 2.1 mm i.d.) and the linear calibration curve over the range was linear from 0.05 to 50 ng ml(-1) (r(2)>0.993). The between-run precision, based on the relative standard deviation replicate quality controls was 94.1% (0.15 ng ml(-1)), 90.7% (4.0 ng ml(-1)) and 97.2% (40 ng ml(-1)). The between-run accuracy for the above-mentioned concentrations was 11.9, 9.0 and 9.8%, respectively. The method herein described was employed in a bioequivalence study of two formulations of dexchlorpheniramine/betamethasone 2 mg/0.25 mg tablets.     

牛肺磷脂注射液在呼吸窘迫综合征患儿正压通气中的应用

目的:探讨牛肺磷脂注射液联合呼吸机鼻塞式持续正压通气治疗新生儿呼吸窘迫综合征的疗效。方法:98例呼吸窘迫综合征新生儿为研究对象,随机数字法分为两组。对照组应用呼吸机鼻塞式持续正压通气治疗,研究组应用牛肺磷脂注射液联合治疗。结果:研究组有效率高于对照组(P<0.05);治疗前两组患儿的动脉血气指标无明显差异,治疗后,研究组12 h及24 h后的PaO₂、血pH水平高于对照组,PaCO₂水平低于对照组,两组差异有统计学意义(P<0.05);治疗前两组患儿的胸部X线情况对比无明显差异,治疗后,研究组胸部X线各项情况的改善均优于对照组,两组差异有统计学意义(P<0.05);研究组用机时间、住院时间均短于对照组(P<0.05);研究组并发症的发生率低于对照组,两组差异有统计学意义(P<0.05)。结论:牛肺磷脂注射液联合呼吸机鼻塞式持续正压通气治疗新生儿呼吸窘迫综合征效果理想,能够改善患儿的动脉血气指标,提高治疗的效果,缩短患儿的用机及住院时间。     

Randomised, placebo-controlled, double-blind, split-face study on the clinical efficacy of Tricutan on skin firmness.

Tricutan is a combination product of herbal extracts traditionally used for treatment of skin conditions, together with dimethylaminoethanol. The effectiveness of Tricutan in improving skin firmness and elasticity in photoaged facial skin was examined in a randomised, placebo-controlled, double-blind, split-face study in 28 women, 34-67 years old. Treatment with Tricutan and placebo was given for 4 weeks. Skin firmness and elasticity was evaluated using the speed of propagation of ultrasound shear waves in the skin as end point (Reviscometer RVM 600). The study was completed by 25 women. The Tricutan treatment resulted in a significantly reduced propagation speed indicating increased firmness. There was no immediate effect by Tricutan application on propagation speed. At self evaluation the women evaluated the treatment effect of Tricutan to be significantly better than the treatment effect of placebo. The clinical evaluation also showed Tricutan to give a significantly better treatment result than placebo. Tolerance to Tricutan was generally good. However, three women did not complete the study because of mild irritative contact dermatitis. The results show that Tricutan can increase skin firmness both objectively and subjectively. Further studies are warranted, especially to investigate if Tricutan can delay the need for surgical face-lift procedures.     

A型肉毒素与复方倍他米松注射液联用治疗瘢痕疙瘩患者的疗效及安全性研究

目的:分析A型肉毒素与复方倍他米松注射液联用治疗瘢痕疙瘩患者的疗效及安全性。方法:选取2015年1月-2016年8月期间我院收治的90例瘢痕疙瘩患者为研究对象,根据治疗方法将患者随机分为A组、B组和C组各30例。A组给予A型肉毒素治疗,B组给予复方倍他米松注射液治疗,C组给予A型肉毒素联合复方倍他米松注射液治疗。比较三组患者的相关指标改善评分、临床疗效、不良反应发生率和复发率。结果:C组患者体积、痛痒觉、硬度和自我评价的改善评分均高于B组和A组(P0.05),B组的各项指标改善评分和A组相比差异无统计学意义(P0.05)。三组总有效率比较差异有统计学意义,且C组高于B组(P0.05),A组和C组总有效率比较差异无统计学意义(P0.05)。A组不良反应总发生率低于B组和C组,差异有统计学意义(P0.05),B组与C组不良反应总发生率相比,差异无统计学意义(P0.05)。A组和C组治疗后半年、1年瘢痕疙瘩复发率均低于B组(P0.05),但A组和C组比较差异无统计学意义(P0.05)。结论:与单独使用A型肉毒素或复方倍他米松注射液相比,A型肉毒素与复方倍他米松注射液联合使用治疗瘢痕疙瘩能显著提高疗效,降低复发率,且不会增加不良反应发生率,安全性较高,值得进一步推广应用。