An overview of cyclopropenone derivatives as promising bioactive molecules.

Cyclopropenone is a valuable electrophilic reagent that can react with electrophilic reagents, nucleophilic reagents, free radicals, organic metals, etc. Furthermore, cyclopropenone derivatives have shown significant biological activity in various diseases, such as triple-negative breast cancer (TNBC), melanoma, and alopecia areata (AA). The cyclopropenone analogue diphenylcyclopropenone (DPCP) has been approved for the treatment of AA. Given the potential therapeutic benefits of cyclopropenone derivatives, this review aims to systematically summarize the structures, synthesis routes, and potential pharmacological functions of cyclopropenone analogues in the hope of offering novel insights for further rational design of more drugs based on the cyclopropenone skeleton for the treatment of human diseases.

Diphenylcyclopropenone and platelet-rich plasma in the management of severe or recalcitrant alopecia areata.

BACKGROUND: Alopecia areata (AA) is a common disease characterized by hair loss with an autoimmune background. There are many lines of therapy, but no standard line for all cases. Consequently, treating severe forms of AA is challenging. OBJECTIVE: This study aimed to compare the efficacy and safety of the combination of diphenylcyclopropenone (DPCP) and platelet-rich plasma (PRP) with DPCP alone in treating patients with severe or refractory AA. PATIENTS AND METHODS: Our randomized clinical trial was conducted on patients with severe and recalcitrant AA. Group A included 13 patients who received only DPCP, while Group B included 11 patients who received both DPCP and PRP. After sensitization in both groups of patients, DPCP was applied to half the scalp weekly. In addition, PRP injection in all scalp was performed once a month in group B. The patients in both groups completed the study for six months. RESULTS: The regrowth scale results were 53.85% and 54.5% for groups A and B, respectively. Although the response rate of group B was higher than that of group A, there is no statistically significant difference between the two groups. CONCLUSION: From our clinical trial, it can be concluded that DPCP alone or combined with PRP is an effective and safe method for treating severe or recalcitrant AA.

Effectiveness and safety of topical application of diphenylcyclopropenone versus podophyllin in treatment of genital warts.

BACKGROUND: Many therapeutic modalities are available for treating genital warts; however, the effectiveness of both diphenylcyclopropenone and podophyllin is still controversial. AIM: To evaluate the effectiveness and safety of diphenylcyclopropenone and podophyllin in treating genital warts. METHODS: This study included 57 patients, divided randomly into two groups. Group (A): diphenylcyclopropenone (n = 29). Group (B): podophyllin 25% (n = 28). In group (A), sensitization was done with 2% diphenylcyclopropenone. Then, after 1 or 2 weeks, treatment started with a weekly application of diphenylcyclopropenone solutions ranging between 0.001 and 1% until clearance, or for a maximum of 10 sessions. In group (B), podophyllin 25% was applied weekly until clearance or for a maximum of 6 weeks. RESULTS: Higher clearance was achieved in group A, with 19 of 29 (65.5%) patients, than in group B, with 9 of 28 (32.1%) (p-value = 0.004). Also, effectiveness increases with young age in group A. Shorter wart duration was associated with better response in both groups (p-value = 0.005). No serious adverse effects occurred in either group. No recurrence was detected in group A, while seven patients (77.8%) had recurrence in group B after 1 year of follow up. CONCLUSION: Diphenylcyclopropenone shows a higher success rate than podophyllin in treating genital warts and a lower recurrence rate.

Treatment Response to Diphenylcyclopropenone in Patients with Alopecia Totalis/Universalis.

Introduction: Alopecia totalis (AT) and Alopecia universalis (AU) are forms of Alopecia areata (AA) which represent the strongest predictor of poor prognosis since spontaneous regrowth is <10%. Topical immunotherapy agent, diphenylcyclopropenone (DPCP) has shown clinical efficacy with limited side effects in severe forms of AA. However, its specific role in AT/AU characterized by complete hair loss over the scalp can help highlight the efficacy of the drug with fewer confounders. Methodology: Data were collected from 18 patients diagnosed with AT/AU and treated with topical immunotherapy with DPCP as per protocol by Happle et al. Baseline Severity of Alopecia Tool (SALT) score and subclass was recorded. In the case of AU, baseline body hair loss score was also recorded. Patients were reassessed after 6 months of treatment in terms of change in SALT score and hair regrowth was assessed using the Global Assessment Score. The side effects during treatment were also assessed and recorded. Results: Eighteen patients of whom eleven (61.1%) were diagnosed as AU and seven (38.9%) as AT were treated. The mean age was 21.6, with a male: female ratio of 3:2. The comorbidities noted were atopy in six (33.3%), atopy and hypothyroidism in one (5.5%), Down's syndrome in two (11.1%), and hypothyroidism alone in one (5.5%) patient. The mean duration of disease at the time of presentation was 3 years and all patients had remained refractory to various other modalities of treatment. All patients had a baseline SALT score of 100 corresponding to S5. After 6 months of treatment, 27.7% of patients did not show any response (SALT score S5), 16.6% had a score of S4, 11.1% had a score of S3, 11.1% had a score of S2, 22.2% had a score of S1, and 11.1% had a score of S0. On assessing improvement in body hair loss score, 36.3% of patients showed no improvement, 36.3% showed partial improvement, and 27.2% of patients showed complete body hair regrowth. About 55.5% of patients developed notable side effects that included severe local reactions, cervical lymphadenopathy, acne and pigmentation at the site of application as well as untreated sites. Conclusion: The AT/AU subtypes of AA, was amenable to treatment with contact immunotherapeutic agent DPCP with a >75% hair regrowth in 33.3% of patients. The castling phenomenon was seen in 63.6% of AU patients. The adverse effects noted were not severe enough to deter treatment.

Randomized controlled trial to compare the effectiveness and safety of low dose dexamethasone oral mini-pulse versus diphenylcyclopropenone contact sensitisation in severe pediatric alopecia areata.

Oral mini pulse (OMP) corticosteroids and diphencyclopropenone (DPCP) contact sensitisation are commonly used treatment modalities in severe cases of Alopecia areata (AA) in children but with scarce studies comparing the two modalities in children. In this study we aimed to compare the effectiveness and safety of dexamethasone OMP with DPCP contact sensitization in severe non progressive AA in children. This randomized open label study was undertaken in 30 children less than 18 years of age with extensive non progressive AA divided in two groups. Group I included 15 patients who received dexamethasone (5 mg/week) OMP as five tablets of 0.5 mg dexamethasone (i.e., 2.5 mg dexamethasone) on two consecutive days in a week. Group II included 15 patients who were treated with DPCP contact sensitization. The treatment was continued in all patients for 24 weeks. Patients were followed up every 4 weeks and records were maintained. Response rate was 100% in OMP group and 53.3% in DPCP group at 24 weeks. In Group I, complete regrowth was seen in 20% patients, and cosmetically acceptable regrowth in 66.7% while in Group II, complete regrowth was not seen in any of the patients, and cosmetically acceptable regrowth in 20% (p = 0.001). Hair regrowth started at mean duration of 7.7 weeks in Group I, while 11.3 weeks in Group II. Response rate of treatment with dexamethasone OMP leads to a significantly faster and better hair regrowth compared to DPCP contact immunotherapy in non-progressive extensive AA in children.

Use of Contact Immunotherapy in the Treatment of Skin Diseases Other than Alopecia Areata.

For decades, contact immunotherapy with dinitrochlorobenzene, diphencyprone, and squaric acid dibutylester has played an important role in both clinical practice and scientific research. It is listed as the first-line treatment for extensive alopecia areata and was more recently approved for melanoma treatment as an orphan drug in the USA. Moreover, owing to the relative low cost and safety, topical immunotherapy has also been used in many infectious, neoplastic, and inflammatory dermatological diseases. It is especially valuable in vulnerable groups, for cosmetic/pain sensitive areas, or for multiple lesions. In this review, we summarize the current evidence supporting the use of contact immunotherapy for treatment of skin diseases, from articles collected from PubMed database. Owing to space limitation and already numerous studies focusing on alopecia areata, we include only skin diseases other than alopecia areata. In addition to diseases that have been reported to be treated by contact immunotherapy, the hypothesized mechanism, prognosis prediction, efficacy, and safety of these topical agents are discussed.

Topical diphenylcyclopropenone plus topical 0.5% anthralin versus topical diphenylcyclopropenone alone for the treatment of chronic extensive alopecia areata: A split-scalp, double-blind, controlled study.

Background: The combination of diphenylcyclopropenone (DCP) and anthralin may demonstrate synergistic effects in the treatment of chronic extensive alopecia areata (AA). Objective: The objective of the study was to compare the efficacy of the combination therapy of topical DCP and topical 0.5% anthralin versus topical DCP alone for the treatment of chronic extensive AA. Materials and Methods: Ten patients were included in the study. Of these, 1, 2, and 7 patients were diagnosed with alopecia totalis, severe AA (>50% hair loss), and alopecia universalis, respectively. For each patient, one side of the scalp was treated with a DCP solution and 0.5% anthralin for 6 months, while the other side was treated with DCP and a cream base for the same duration. The clinical responses were assessed at baseline and then monthly until the end of the 6-month study period using the Severity of Alopecia Tool score. The side effects were evaluated at each follow-up visit. Results: The difference in the efficacies of the combination treatment and DCP alone was not statistically significant (P = 0.59). Regarding the side effects, DCP plus 0.5% anthralin caused significantly more excessive dermatitis than DCP alone (7 patients vs. 2 patients; P = 0.02). Eight patients reported temporary hyperpigmentation at the combination-treatment site, whereas no hyperpigmentation was reported at the DCP-alone site of any patient (P < 0.001). Conclusions: The combination of DCP and 0.5% anthralin was not superior to DCP alone for the treatment of chronic extensive AA. An increase in side effects - excessive dermatitis and hyperpigmentation - was observed in the combination-treatment group.

Topical immunotherapy treatment of alopecia areata with diphenylcyclopropenone: Regulatory T cells as biomarkers for treatment response.

Treatment of alopecia areata is often challenging, especially for patients with extended disease. Contact immunotherapy with diphenylcyclopropenone (DPCP) has been reported as an effective topical treatment but the exact immunologic mechanism of diverting the immune response is still unknown. We investigated the efficacy of topical immunotherapy with DPCD in acute, intermediate, and chronic lesions of AA and the response rate was associated with perifollicular infiltrate of T regulatory cells. Approximately two-thirds of our patients (67.5%) had a response rate > 50% after 6 months of DPCP therapy. Patients with acute and intermediate onset of the disease were more likely to respond to the therapy. Although responders demonstrated FOXP3+ positive lymphocytes in immunohistochemistry, this association could not be confirmed by statistical significance (p = 0.052). In patients with multiple lesions, that had different chronological onset, the lesions with more recent onset responded faster than lesions of longer duration.

Economic Impact of Home-Use versus Office-Use Diphenylcyclopropenone in Extensive Alopecia Areata.

Introduction: Diphenylcyclopropenone (DPCP) is the medication of choice for the treatment of severe alopecia areata (AA) according to AA treatment guidelines. Precise initiation and application are important factors for successful treatment. However, it is difficult for patients who live far away to visit their doctor weekly. Methods: We conducted a retrospective cohort study to assess the cost, effectiveness, and side effects of DPCP treatment between office-use DPCP (O-DPCP) and home-use DPCP (H-DPCP) in severe AA patients. A cost-effectiveness analysis was performed from the perspective of healthcare providers and patients using real-world data and the national cost statistics for hospital services comparing O-DPCP and H-DPCP in patients with severe AA at 24, 36, and 48 weeks. Results: Two groups of 41 patients treated with O-DPCP and H-DPCP were enrolled. There was no significant difference in the proportion of patients who showed a favorable outcome (≥50% improvement) with minimal side effects between both groups at 24 (O-DPCP 43.9% vs. H-DPCP 26.8%, p = 0.11), 36 (O-DPCP 58.5% vs. H-DPCP 43.9%, p = 0.19), or 48 weeks (O-DPCP 63.4% vs. H-DPCP 56.1%, p = 0.49). The cost of H-DPCP was half of the cost of O-DPCP. Discussion/Conclusion: H-DPCP is a cost-effective and time-efficient alternative treatment option for severe AA patients.

A prospective comparative study of two regimens of diphenylcyclopropenone (DPCP) in the treatment of alopecia areata.

BACKGROUND: Alopecia areata (AA) is a chronic disorder and the best treatment regimen for it is unknown. Currently, one of the best documented treatment modalities for AA is topical immunotherapy. AIM: To evaluate the safety and efficacy of a novel method (multi-concentration patch test) versus standard protocol for topical immunotherapy. METHODS: A prospective randomized clinical trial was conducted on 30 patients with Alopecia areata, half of them received DPCP with a novel method using multi-concentration patch test to determine the optimal initiating concentration of DPCP (case group) and the other half experienced immunotherapy according to the standard protocol (control group). Percentage of hair regrowth after 6 months of treatment and the incidence of drug-related adverse effects were evaluated and compared between the two groups. (IRCT registration code: IRCT20141209020250N5). RESULTS: Absolute and relative hair regrowth percentages were reported 25% and 41.49% in case group and 8.2% and 14.21% in control group respectively. Considerable response (more than 75% hair regrowth) was observed in 4 (26.6%) patients in case and 1 (6.6%) patient in control group. The clinical response was initiated about 7 weeks sooner in case compared to the control group (14 versus 7.38 weeks, P: 0.001). Overall, clinical response was higher in patients received new protocol, compared to control group. Moreover, patients who experienced new protocol had a higher level of treatment satisfaction in comparison with patients having standard protocol (P: 0.012). CONCLUSION: This study revealed the effectiveness and safety of the novel multi-concentration patch test DPCP therapy for AA and its priority to conventional method, at least in terms of shortened duration of DPCP immunotherapy.

Is the severity of initial sensitization to diphenylcyclopropenone in alopecia areata patients predictive of the final clinical response?

Immunotherapy by diphenylcyclopropenone (DPCP) is generally started with 2% DPCP sensitization, however in recent years studies have questioned the necessity of sensitization that may cause patients severe reactions and troubles at the onset of therapy. The purpose of the present study was to evaluate the association between the severity of initial reaction to 2% DPCP sensitization in AA patients and clinical response. In this retrospective study, 110 AA patients who continued therapy for at least 6 months were enrolled. Hair loss and hair regrowth rates were calculated based on the Severity of Alopecia Tool (SALT) scoring system. Initial reaction to 2% DPCP sensitization after 2 weeks was graded as negative reaction (absence of any reaction), doubtful reaction (mild erythema, pruritus, and irritation for minutes after test), weak (erythema, mild edema, and scaling), and strong to extreme reaction (vesicles, bullae, ulcer, and discharge). The degrees of the initial reaction to 2% DPCP after 2 weeks were negative reaction 13 (11.81%), doubtful reaction 40 (36.36%), weak reaction 33 (30%), and strong to extreme reaction 24 (21.81%). Patients were divided into two groups: (A) patients with less than 12-month therapy (75 of 110), (B) patients with more than 12-month therapy (35 of 110). Initial reaction to 2% DPCP sensitization was not correlated with hair regrowth rate in either group (group A: Spearman's rho = 0.194, p = 0.095; group B: Spearman's rho = 0.063 p = 0.720). After 12-month treatment with DPCP, hair regrowth rate was significantly greater than 6-months therapy (group A: 17.03 ± 37.78, group B: 49.26 ± 36.34; p = 0.003). The severity of hair loss at the onset of treatment was significantly associated with the response rate in both groups (p-value <0.002). Based on our results, it is the initial severity of the disease and not the initial reaction to 2% DPCP sensitization that predicts the clinical response to DPCP immunotherapy.

A randomized trial of diphenylcyclopropenone (DPCP) combined with anthralin versus DPCP alone for treating moderate to severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is a chronic autoimmune disorder. Finding the best treatment regimen for it remains a challenge. Currently, one of the best documented treatment modalities for AA is topical immunotherapy. AIM: To evaluate the safety and efficacy of combined DPCP and anthralin versus standard protocol (DPCP alone). METHODS: A prospective randomized clinical trial was conducted on 50 patients with Alopecia areata who received DPCP alone (group D) or in combination with anthralin (group D/A). Percentage of hair regrowth after 6 months of treatment and the incidence of drug-related adverse effects were evaluated and compared between the two groups. RESULTS: Complete hair regrowth was observed among three patients in each group (18.75% in Group D and 15.79% in Group D/A) after 6 months. Moreover, 25% and 31% of patients in group D and 21% and 47% of patients in group D/A had > 75% and > 50% hair regrowth respectively at the end of the study (P-value: 0.696). In addition, earlier age of onset, chronicity of lesions, nail involvement, facial hair loss and extensive lesions at baseline were associated with poor clinical outcome. CONCLUSION: DPCP and anthralin was as effective as DPCP alone and anthralin did not add to the effect of DPCP in treating AA.

Application of Topical Immunotherapy in the Treatment of Alopecia Areata: A Review and Update.

Treatment of extensive or recalcitrant alopecia areata (AA) is a major clinical challenge. Even after thorough investigation of several medications, its treatment outcomes have remained unsatisfactory. While there is no US Food and Drug Administration-approved medication for AA yet, topical immunotherapy has been a well-documented treatment option. Dinitrochlorobenzene, squaric acid dibutylester, and diphenylcyclopropenone are three substances that have demonstrated efficacy in the treatment of extensive or recalcitrant AA. Despite being commonly used, the mechanism underlying topical immunotherapy is not well-elucidated and a wide range of clinical efficacies have been reported in the literature. The aim of this review was to summarize and update the pharmacology, mechanism of action, therapeutic efficacy, and tolerability of topical immunotherapy in the treatment of AA.

Diphenylcyclopropenone plays an effective therapeutic role by up-regulating the TSLP/OX40L/IL-13 pathway in severe alopecia areata.

Topical immunotherapy with diphenylcyclopropenone (DPCP) is considered to be the most effective treatment of severe AA. However, the mechanism is unclear and an early predictor for the efficacy needs to be explored. The TSLP/OX40L/IL-13 pathway is an important pathway to initiate and maintain Th2 immune responses. Our previous work suggests this pathway may play a role in severe AA treated with DPCP. Thus, to further investigate the mechanism of TSLP/OX40L/IL-13 pathway in severe AA treated with DPCP and explore the predictor for the efficacy of DPCP therapy, we conducted a prospective study to compare expression levels of TSLP, OX40L, Th2 cytokines IL-4, IL-5 and IL13, and Th1 cytokine IFN-γ in severe AA patients before and after the treatment. Results showed that 21 AA patients were responsive (responders) to the DPCP therapy and 12 were not responsive (non-responders). Responders had lower levels of TSLP, OX40L and IL-13 than non-responders before the treatment. After the DPCP treatment, TSLP, IL-5 and IL-13 increased and IFN-γ decreased in responders while there were no changes of TSLP, IL-4, IL-13 and IFN-γ in non-responders. Our data suggest that the TSLP/OX40L/IL-13 pathway is down-regulated in some severe AA patients and DPCP might play a therapeutic role by up-regulating the pathway in these severe AA patients. The TSLP/OX40L/IL-13 pathway could be a predictor of response to the DPCP therapy for severe AA patients.

Immunomodulatory effects of topical diphencyprone for the treatment of acute urban cutaneous leishmaniasis.

BACKGROUND AND OBJECTIVE: Efficacious and safe treatments are lacking for cutaneous leishmaniasis (CL). This study investigates the efficacy of adding diphencyprone immunotherapy to conventional meglumine antimoniate (MA) treatment for acute urban CL. METHODS: This randomized controlled pilot study included 46 patients with acute CL. They were randomly allocated to receive either combination of diphencyprone immunotherapy with intralesional MA (intervention; N = 23) or intralesional MA alone (control; N = 23) weekly. The size and duration of lesions were measured at the baseline and after that at 4th, 8th, 12th, and 24th weeks. Data were analyzed in SPSS and p < .05 was considered significant. RESULTS: The groups showed no significant difference in duration of lesions, but number of injections was significantly higher in the control group compared with the intervention group (p < .001). Size and induration of lesions was significantly reduced in both groups during the course of study (p < .001). The intervention group showed significantly lower induration of lesions in 4th, 8th, and 12th week compared with controls (p < .05). CONCLUSION: Combination of diphencyprone with MA resulted in earlier resolution of acute CL lesions with a relatively acceptable rate of adverse effects, compared with intralesional MA alone.

Utility of Dermoscopic Evaluation in Predicting Clinical Response to Diphencyprone in a Cohort of Patients with Alopecia Areata.

BACKGROUND: Alopecia areata (AA) is a chronic and inflammatory disease of hair follicles, causing nonscarring alopecia. While the various types of treatment have been investigated, the definite cure for AA has not been established yet. OBJECTIVES: The objective of this study is to evaluate the clinical and dermoscopic features of patients with AA to identify the factors with prognostic values in diphenylcyclopropenone (DPCP) response rate. METHODS: Eighty patients with AA were included, and baseline hair loss was calculated based on the severity alopecia tool (SALT) score. The characteristic dermoscopic features of AA were evaluated by two skilled dermatologists separately at baseline, 12 and 24 weeks afterward. RESULTS: The mean SALT score in the 1st, 12th, and 24th week was 77 ± 24.7, 80 ± 27, and 71 ± 35.6, respectively, which were not significantly different over this time period (P = 0.085). SALT score correlated negatively with the short vellus hair/field (ρ = -0.361, P = 0.02), broken hair/field (ρ = -0.317, P = 0.044), and tapering hair/field (ρ = -0.388, P = 0.012) in the 1st week. Forty-one patients continued treatment courses over 24 weeks. Six patients had good response, 11 achieved partial response, and 24 had no hair regrowth. Statistically significant correlation was observed between treatment response and duration of disease (P = 0.04), frequency of relapses (P = 0.033), type of alopecia, and number of black dots (P = 0.028). The mean for all dermoscopic findings showed descending process during our three follow-up sessions which was statistically significant for black dot (P = 0.015) and broken hair (P = 0.006). CONCLUSION: The number of black dot per field initially was negatively correlated to DPCP therapy and the frequency of dermoscopic findings reduced during the treatment process.

Limited efficacy of diphenylcyclopropenone in the treatment of alopecia areata: Experience from a Tertiary Healthcare Institution in Singapore.

Alopecia areata (AA) is a common cause of nonscarring hair loss. Diphenylcyclopropenone (DPCP) is a form of contact immunotherapy used in the treatment of AA. We retrospectively reviewed all patients who were diagnosed with AA over a 4-year period (1st January 2012 to 31st December 2015) and who have received DPCP. Forty patients were studied in total. The mean duration of disease prior to the study was 195 days. Patients received a mean number of 14.91 sessions (range: 1-65). The mean number of sessions required before clinical response was seen was 2.33 sessions, corresponding to 0.001% DPCP. Based on the modified Global Assessment Grading System, 33.5% (n = 11) of the patients experienced less than 25% improvement, 48.5% (n = 16) experienced 25%-74% improvement and 18.3% (n = 6) experienced more than 75% improvement. One patient had severe sensitisation reaction amounting to near erythroderma which resolved completely upon cessation of DPCP therapy. No other adverse reactions were noted in the cohort. DPCP remains a valuable tool in a dermatologist's armamentarium in treating alopecia areata as it is safe, well-tolerated, and shows limited efficacy.