Identification and pre-clinical investigation of 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid as a drug for external use to treat psoriasis.

BACKGROUND AND PURPOSE: Psoriasis vulgaris is a refractory skin inflammatory disorder with 80% of the cases belonging to the mild-to-moderate type, which can be controlled by topical treatment. Nevertheless, the drugs for external use have not been upgraded for decades. We modified acetyl-11-keto-beta-boswellic acid (ABKA), a natural compound shown to treat psoriasis animal models, to improve efficacy and solubility for topical use. EXPERIMENTAL APPROACH: Eleven compounds were synthesized using AKBA as a lead compound, and their effects on Th17 cell differentiation were screened. 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid (CKBA) potently inhibited Th17 cell differentiation. Its efficacy in a mouse model of psoriasis was assessed along with its pharmacology and safety profile when topically or systemically delivered to several animal species. KEY RESULTS: CKBA inhibited mouse and human Th17 cell differentiation with an IC50 of 3.28 and 3.61 µM, respectively, and directly targeted acetyl-CoA carboxylase 1 (ACC1). Safety evaluation and toxicity tests suggested that systemically delivered high-dose CKBA for 14 days had no dose-associated adverse effects on the CNS, haematopoietic, cardiovascular, respiratory and digestive systems of cynomolgus monkeys. CKBA ointment permeated the skin and did not irritate or sensitize intact skin. CKBA ointment mediated dose-dependent suppression of imiquimod-induced psoriasis-like skin inflammation with slow absorption and limited bioavailability (<10% in rats and <1% in minipigs). CONCLUSIONS AND IMPLICATIONS: CKBA is safe when topically or systemically delivered to animals. The beneficial effects of CKBA ointment in a mouse model of psoriasis indicate that this is a promising drug candidate for further development as a treatment for psoriasis.

Comparative evaluation of efficacy and safety of calcipotriol versus calcitriol ointment, both in combination with narrow-band ultraviolet B phototherapy in the treatment of stable plaque psoriasis.

BACKGROUND: Vitamin D analogues and NBUVB are both well-recognised modes of therapy in the treatment of chronic stable plaque psoriasis. The objective of this open label intraindividual, left right study was to compare two different vitamin D analogues, calcipotriol and calcitriol, in combination with NBUVB phototherapy in psoriasis. METHODS: Thirty patients with stable plaque psoriasis were enrolled for a 12-week clinical trial. The target lesion on the left side was treated topically with calcitriol ointment, while that on the right side was treated with calcipotriol ointment once daily. The whole body was irradiated with narrow-band ultraviolet B phototherapy (NBUVB) three times per week. Efficacy was assessed by target plaque scoring. RESULTS: Both therapies resulted in a statistically significant reduction in erythema, scaling, thickness, and target plaque score, seen as early as 2 weeks into therapy. However, the calcipotriol combination led to an earlier clearance of plaques and a lesser relapse rate than the calcitriol combination. The number of treatment sessions and cumulative NBUVB doses were significantly lower in the calcipotriol-treated group. CONCLUSION: Both vitamin D analogues appear to be safe, effective, and cosmetically acceptable, with calcipotriol being more efficacious, well tolerated, with a rapid onset of action and a better maintenance of response.

Preparation and pharmaceutical properties of Hangeshashinto oral ointment and its safety and efficacy in Syrian hamsters with 5-fluorouracil-induced oral mucositis.

Chemotherapy-induced oral mucositis (COM) is a common adverse effect of cancer chemotherapy. Several clinical studies reported that repetitive use of mouthwashes containing 2.5-6.25% Hangeshashinto (HST), a Kampo formula, relieves COM, but the effect is insufficient. To solve this problem, we produced an oral ointment of 12% HST extract (considered quantitatively equivalent to 20% commercially available HST), which will increase the local concentrations of its active ingredients and prolong the contact time with COM. In this study, we evaluated the pharmaceutical properties (spreadability and stability) of HST oral ointment. In addition, its safety (oral mucosal irritation) and therapeutic effects on 5-fluorouracil-induced oral mucositis were evaluated in male Syrian hamsters. The HST ointment showed good spreadability and stability for more than 8 weeks at 4 °C. In the oral mucosal irritation test, topical application of HST ointment (0.2 g) three times per day for 14 days had no adverse effect on the oral mucosa of hamsters. In hamsters treated with 5-fluorouracil (60 mg/kg) twice, COM was induced by a submucosal injection of 5% acetic acid into the cheek pouch. When HST ointment (50 µg) was topically applied to the mucositis area once per day for 12 days, the area and macroscopic score of mucositis were significantly decreased, and the depth of the wound tended to be reduced compared with the lactose ointment-treated control animals. These findings suggest that HST oral ointment shows good properties in spreadability, stability, and safety, and elicits a therapeutic effect in an animal model of COM.

Combination of available topical beta-blockers and antibiotic ointment for epidermal growth factor receptor tyrosine kinase inhibitor-induced paronychia and pseudopyogenic granulomas in Taiwan.

BACKGROUND: Painful paronychia and pseudopyogenic granuloma (PG) are common adverse drug reactions (ADRs) associated with the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat non-small cell lung cancer (NSCLC). Multiple local management approaches have been tested with unsatisfactory results. We have introduced an occlusion therapy technique through which available topical drugs for longer than 2 years. METHODS: Based on the cancer registry and case management system of our hospital, from July 2019 to July 2020, we retrospectively enrolled patients with NSCLC who were treated with EGFR-TKIs and received applications of 0.5% timolol ophthalmic solution (TIMOPTOL XE 0.5%®) combined with a neomycin/tyrothricin ointment (Biomycin®) using the occlusion method to treat paronychia or PG. RESULTS: A total of 22 patients were enrolled, with a mean age of 66.5 years, most of whom were women (72.7%). Periungual lesion-related pain was reported by all patients, and periungual bleeding and PG were reported in 14% (3/22) and 64% (14/22) of patients, respectively. After the occlusion therapy application of timolol ophthalmic solution combined with neomycin/tyrothricin ointment twice daily, the overall response rate was 83.3%, including complete response in 18% (4/22) of cases and partial response in 68% (15/22) of cases. CONCLUSION: We presented an occlusion method using available topical beta-blockers and antibiotic ointment for EGFR-TKI-induced paronychia and PG in Taiwan. The result is favorable. Further randomized control trial is urgent to validate our findings.

Iodine-containing ointment-induced hypothyroidism in a patient with anorexia nervosa and sacral decubitus ulcer: a case report with literature review.

We present a case of a 58-year-old woman with anorexia nervosa and a sacral decubitus ulcer who developed hypothyroidism because of an iodine-containing ointment. Considering the absence of autoimmune thyroid diseases, the development of hypothyroidism after the use of an iodine-containing ointment, and the recovery of thyroid function after the discontinuation of the ointment, we presumed that her hypothyroidism was induced by the iodine-containing ointment. Although the hypothyroidism improved after discontinuing the iodine-containing ointment, she developed aspiration pneumonia and required long-term hospitalization. Many patients with autoimmune thyroid diseases develop hypothyroidism after excessive iodine intake. However, anorexia nervosa may have exacerbated the iodine-induced hypothyroidism in our patient. To the best of our knowledge, no previous study has reported a case of hypothyroidism caused by iodine-containing ointment in a patient with anorexia nervosa. Hence, physicians must pay careful attention to a patient's background factors to ensure the early diagnosis of hypothyroidism due to iodine-containing ointments.

Inhibition of JAK1/STAT3 pathway by 2-methoxyestradiol ameliorates psoriatic features in vitro and in an imiquimod-induced psoriasis-like mouse model.

Psoriasis is characterized by hyperproliferative keratinocytes, dilated capillaries and leukocyte infiltration. 2-Methoxyestradiol (2-ME) has shown significant inhibition on proliferation, angiogenesis and inflammation. To evaluate the anti-psoriatic potential of 2-ME, psoriasis-like dermatitis was induced by topical application of imiquimod (IMQ) on the dorsal skin of C57BL/6 mice for seven consecutive days, followed by treatment of vehicle or 2-ME ointment from Day 4 on. The psoriasis area and severity index (PASI) was assessed daily. On Day 8, skin histology and spleen index were assessed. The effects of 2-ME on the proliferation, apoptosis, cell cycle, vascular endothelial growth factor A (VEGFA), and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways of HaCaT cells stimulated by interleukin-17 (IL-17A) were detected, together with its effect on the proliferation, tube formation and VEGF receptor expression of human umbilical vein endothelial cells (HUVECs). We found that topical 2-ME treatment significantly improved IMQ-induced psoriasis-like dermatitis and decreased the PASI scores, the activation of STAT3 in the skin (P < 0.05), and the spleen index in mice (P < 0.01). In vitro, 2-ME inhibited the proliferation of HaCaT cells by inducing apoptosis and G2/M phase arrest (P < 0.01). Moreover, 2-ME suppressed IL-17A-induced VEGFA (2.5 µM: P < 0.05; 5 µM: P < 0.01) and phosphorylation of STAT3 by blocking p-JAK1 in HaCaT cells and prevented tube formation (P < 0.01) and proliferation by targeting VEGF receptors 1 (VEGFR1) and 2 (VEGFR2) in HUVECs. We conclude that 2-ME alleviated psoriasis in vivo and in vitro by inhibiting JAK1/STAT3 pathway and was a promising therapeutic agent for psoriasis.

Lip mesotherapy with dexpanthenol in the treatment of isotretinoin-induced cheilitis.

INTRODUCTION: Cheilitis is the most common mucocutaneous side effect of isotretinoin (ISO). Dexpanthenol (DXP) increases fibroblast proliferation and re-epithelialization in wound healing. We aimed to investigate the effect of DXP-mesotherapy in ISO-induced cheilitis in this study. METHODS: This study was conducted on patients who had been using ISO (0.5-1 mg/kg/day) for at least 2 months. Twenty-five patients who administered DXP-mesotherapy (mesotherapy group) and 33 patients without the procedure (control group, only ointment) participated in this study. All patients were prescribed only hamamelis virginiana distillate in ointment form as a lip balm. The efficacy of the treatment was interpreted by the change in lip balm use frequency, quality of life, and Isotretinoin Cheilitis Grading Scale (ICGS). RESULTS: There was a statistically significant decrease in all ICGS-subgroups scores in the mesotherapy group after 1 month compared with the baseline (p = <0.001), although in the controls, erythema, crust, and fissure scores significantly increased (p = 0.001, p = 0.002).While there was no difference between the groups in terms of ICGS total scores at baseline, there was a significant difference after 1 month in favor of the mesotherapy group (p < 0.001). In the mesotherapy group, lip balms were needed significantly less frequently and there was a significant improvement in quality of life compared with both the control group and at baseline after 1 month (both; p < 0.001). On the other hand, the control patients suffered more from cheilitis and dryness than at baseline (p < 0.001). CONCLUSION: Dexpanthenol-mesotherapy seems to be a safe, and so effective method in management of ISO-related cheilitis.

Efficacy of nano-modified Runji ointment in the treatment of mild and moderate psoriasis with blood dryness syndrome: a study protocol for a double-blind randomized controlled trial.

INTRODUCTION: Psoriasis is a common, recurrent, immune skin disease, which seriously affects patients' quality of life. In clinical practice, modified Runji ointment can effectively treat mild-to-moderate psoriasis with blood dryness syndrome, but there is a lack of high-quality evidence-based medical evidence. This trial aims to evaluate the efficacy and safety of nano-modified Runji ointment in the treatment of mild-to-moderate psoriasis with blood dryness syndrome. METHODS/DESIGN: This study will be a randomized double-blind placebo-controlled trial. A total of 80 patients will be recruited and randomly divided into an intervention group (nano-modified Runji ointment group) and a placebo group at a ratio of 1:1. All included patients will receive 8 weeks of nano-modified Runji ointment or placebo ointment respectively, twice a day. The primary outcome will be the change in psoriasis area and disease severity index score at week 8 compared to baseline. The secondary outcomes will be rash area score, pruritus score, Dermatology Life Quality Index score, traditional Chinese medicine symptom score and adverse events. DISCUSSION: This study may provide high-quality evidence for the efficacy of nano-modified Runji ointment in the treatment of mild to moderate psoriasis with blood dryness syndrome. The results of this study will be published in peer-reviewed journals. TRIAL REGISTRATION: ChiCTR, ChiCTR2000034292. Registered July 1, 2020, https://www.chictr.org.cn/edit.aspx?pid=55884&htm=4.

Múltiples úlceras perianales en relación con el uso de una pomada antihemorroidal con acetónido de triamcinolona, lidocaína y pentosano polisulfato sódico como principios activos: una serie de 11 pacientes españoles / Multiple Perianal Ulcers Related to Use of a Hemorrhoidal Ointment With the Active Ingredients Triamcinolone Acetonide, Lidocaine, and Pentosan Polysulfate Sodium: A Series of 11 Spanish Patients

La aparición de úlceras perianales en relación con una pomada antihemorroidal es una condición nunca antes reportada en la literatura. Presentamos una serie de 11 casos de 10 hospitales españoles con diagnóstico de úlceras perianales tras la aplicación de una misma pomada antihemorroidal con acetónido de triamcinolona, lidocaína y pentosano polisulfato sódico como principios activos. No se ha podido identificar ninguna condición previa o enfermedad concomitante que pudiera justificar un diagnóstico etiológico alternativo y tras retirar la pomada antihemorroidal se ha evidenciado una resolución completa de las úlceras en un periodo medio de 8 semanas. Esta serie de casos evidencia el potencial efecto dañino de un producto farmacéutico no sujeto a prescripción ni seguimiento médico y la necesidad de interrogar por el uso de agentes tópicos ante la aparición de úlceras perianales (AU)

The development of perianal ulcers related to the use of a hemorrhoidal ointment has not been reported in the literature. We describe a series of 11 patients who were treated for perianal ulcers in 10 Spanish hospitals after they used the same ointment containing the active ingredients triamcinolone acetonide, lidocaine, and pentosan polysulfate sodium. No prior or concomitant conditions suggesting an alternative cause for the condition could be identified, and after the patients stopped using the ointment, their ulcers cleared completely in 8 weeks on average. This case series shows the damage that can be caused by an over-the-counter pharmaceutical product used without medical follow-up. It also illustrates the need to ask patients with perianal ulcers about any topical agents used before the lesions appeared (AU)

Estudo ex vivo da elevação do pH em superfície radicular externa após agitação ultrassônica de diferentes pastas de hidróxido de cálcio / Assessment of pH increase in the external root surface after ultrasonic agitation of different calcium hydroxide pastes: Ex vivo study

Objetivo: O presente estudo teve por objetivo avaliar, ex vivo, a capacidade de elevação do pH da superfície radicular externa de diferentes pastas de hidróxido de cálcio (HC) utilizadas como medicação intracanal, além da influência da ativação ultrassônica (AUS) durante aplicação no interior do canal radicular. Métodos: Foram utilizados 100 incisivos humanos superiores unirradiculares, que tiveram os canais radiculares modelados e divididos aleatoriamente em seis grupos experimentais (n=15), de acordo com a pasta de HC, tendo como variáveis as medicações utilizadas e a ativação da pasta com AUS no momento da aplicação, além de um grupo controle (n=10): Pasta Calen; HC+clorexidina 2% gel (CX2%); e HC + água destilada. Os dentes foram mantidos imersos em água deionizada e as medidas do pH, verificadas nos períodos de 7, 14, 21 e 28 dias, com auxílio de pHmetro. Resultados: De acordo com os dados obtidos, verificou-se elevação do pH nos períodos de 7 e 14 dias em todos os grupos. Apenas os grupos em que foi utilizada a associação do HC com CX2% apresentou evolução com aumento significativo do pH ao longo dos períodos analisados (p<0,05). A ativação das pastas com AUS proporcionou incremento significativo dos valores de pH (p<0,05). Conclusão: De acordo com a metodologia empregada, pode-se concluir que todas as pastas utilizadas promovem elevação do pH no tecido dentinário, e a ativação das pastas com AUS influencia significativamente na elevação do pH no tecido dentinário (AU).

Objective: The aim of the present study was to evaluate, ex-vivo, the pH elevation capacity on the external root surface of different calcium hydroxide (HC) pastes, utilized as intracanal medication, it was also evaluated the influence of the ultrasonic activation at the application within the root canal. Methods: 100 human single root superior incisors were used, which had their root canals shaped and randomly divided into 6 experimental groups (n=15) according to the following HC pastes: Calen; HC + Chlorhex- idine 2% gel (CX2%); HC + distilled water, utilizing the medications and the ultrasonic activation of the paste at the time of the application as variables and 1 control group (n=10). The teeth were kept immersed in deionized water and the pH parameters were verified in 7, 14, 21 and 28 days with a pH measurement machine. Results: According to the data obtained, pH was elevated in the first week in all groups. Only the groups which the association of HC with CX2% was made, did show a significant increase in the pH level over the analyzed periods (p < 0,05). The activation of the pastes with US provided a significant increase in pH values (p < 0,05). Conclusion: According to the methodology used, we can conclude that all the HC pastes used, promote pH elevation in dentin tissue. And the acti- vation of the pastes with US significantly influences the pH increase in dentin tissue

Sinecatechins ointment as a potential novel treatment for usual type vulval intraepithelial neoplasia: a single-centre double-blind randomised control study.

OBJECTIVE: To compare the safety and efficacy of 10% sinecatechins (Veregen® ) ointment against placebo in the treatment of usual type vulvar intraepithelial neoplasia (uVIN). DESIGN: A Phase II double-blind randomised control trial. SETTING: A tertiary gynaecological oncology referral centre. POPULATION: All women diagnosed with primary and recurrent uVIN. METHODS: Eligible patients were randomised 1:1 to receive either sinecatechins or placebo ointment (applied three times daily for 16 weeks) and were followed up at 2, 4, 8, 16, 32 and 52 weeks. MAIN OUTCOME MEASURES: The primary outcome measure, recorded at 16 and 32 weeks, was histological response (HR). Secondary outcome measures included clinical (CR) response, toxicity, quality of life and pain scores. RESULTS: There was no observed difference in HR between the two arms. However, of the 26 patients who were randomised, all 13 patients who received sinecatechins showed either complete (n = 5) or partial (n = 8) CR, when best CR was evaluated. In placebo group, three patients had complete CR, two had partial CR, six had stable disease and two were lost to follow up. Patients in the sinecatechins group showed a statistically significant improvement in best observed CR as compared with the placebo group (P = 0.002). There was no difference in toxicity reported in either group. CONCLUSION: Although we did not observe a difference in HR between the two treatment arms, we found that 10% sinecatechins application is safe and shows promise in inducing clinical resolution of uVIN lesions and symptom improvement, thus warranting further investigation in a larger multicentre study. TWEETABLE ABSTRACT: A randomised control study indicating that sinecatechins ointment may be a novel treatment for uVIN.

Iatrogenic Cushing Syndrome And Hypertension In An Infant Girl Due To Use Of Nappy Rash Cream Containing A Potent Topical Steroid.

Eleven months old female patient presented to paediatric out patient with parents concerned about her facial swelling. Upon examination child's weight and height for age were normal on her percentiles, she had a cushingoid facies with plethoric cheeks (Figure-1,2) though generalized oedema was absent and there was centripetal obesity with some muscle wasting (Figure-3,4). Systemic examination was normal excluding blood pressure which was high for her age. Electrolytes and cortisol levels were normal. On further inquiry it was revealed that she had been using a nappy rash cream containing a potent steroid, i.e., fluticasone for 2 months and this was identified as a cause for her cushingoid features.