pep005 and Condylomata-Acuminata

Anogenital warts (AGWs) are a common therapeutic challenge. All therapies are associated with burning, pain, and frustrating high rate of recurrence. The search for a new alternative continues. Recently, a diterpene ester extracted from the Euphorbia peplus plant (ingenol mebutate [IM]) has been shown to possess activity against AGWs.. This study aimed to compare and evaluate the therapeutic efficacy and safety of topical 0.05% ingenol gel with another herbal extract medication (topical 25% podophyllin solution) in treatment of AGWs.. This was a comparative single blinded nonrandomized, 2-arm trial of ingenol 0.05% gel versus podophyllin solution 25% administered up to 6 times to patients with AGWs. To evaluate the therapeutic efficacy, the complete clearance rate and recurrence rate were assessed 1 and 12 weeks after last treatment, respectively. Safety was assessed by occurrence and severity of pain and local skin reaction (LSR).. Of 31 and 36 patients in the IM group and podophyllin group who completed the study, initial complete resolution was observed in 20 (64.5%) and 14 (38.9%) patients, respectively (P = 0.03). The initial clearance was faster in the IM group (2.00 ± 0.91 weeks) compared with the podophyllin group (4.21 ± 1.05 weeks, P = 0.00). After 3 months, recurrence was seen in 13 (65.0%) of 20 patients in the IM group and 6 (42.8%) of 14 in the podophyllin group (P = 0.20). The number of patients with complete resolution after 3 months was not different between the 2 groups (7/31 in the IM group and 8/36 in the podophyllin group, P = 0.97). The mean ± SD severity scores for LSR and pain in the IM group were 6.65 ± 1.76 and 6.13 ± 2.57, respectively, which was significantly higher than their scores (3.39 ± 1.57 and 2.58 ± 1.38) in the podophyllin group (P = 0.00).. Ingenol mebutate 0.05% gel is effective as podophyllin 25% solution in treating AGWs, with further benefit of being much more rapid. However, high recurrence rate, sever pain, and LSR limit its use.

Topics: Adult; Anus Diseases; Condylomata Acuminata; Diterpenes; Female; Gels; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Podophyllin; Prospective Studies; Treatment Outcome

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.

Topics: Condylomata Acuminata; Diterpenes; Humans; Keratosis, Actinic; Necrosis; Papillomaviridae; Papillomavirus Infections; Skin Abnormalities; Warts

Topics: Administration, Cutaneous; Adult; Anus Diseases; Condylomata Acuminata; Diterpenes; Female; Human papillomavirus 16; Human papillomavirus 31; Human papillomavirus 6; Humans; Male; Middle Aged; Papillomaviridae; Penile Diseases; Treatment Outcome; Vulvar Diseases; Young Adult

Topics: Adolescent; Adult; Condylomata Acuminata; Diterpenes; Gels; Humans; Male; Papillomaviridae; Penile Diseases; Treatment Outcome

Anogenital warts (AGW) can cause physical discomfort and decreased quality of life. Recent case reports suggest that ingenol mebutate gel might be an effective treatment of AGW.. To explore primarily the safety, and secondarily the efficacy of ingenol mebutate gel 0.05% in patients with AGW.. This was an exploratory, open-label, 1-arm trial of ingenol mebutate gel 0.05% administered up to three times to patients with AGW. Safety was assessed by occurrence and severity of local skin reactions (LSRs) and treatment-related adverse events (AEs). Efficacy was assessed by complete clearance and reduction in AGW count 14 days after last treatment, and recurrence 12 weeks after clearance.. Of 41 patients enrolled, 40 received treatment and 26 completed the trial. Patients had a median AGW count of 11.0 and AGW duration of 3.0 years at baseline. All patients experienced transient LSRs following treatment with a maximum composite LSR score of 7.5 (on a scale from 0 to 18). A total of 93% of patients reported treatment-related AEs, most frequently pain (85%) and procedural complications (35%) due to smearing of the gel. 78% of patients took mild analgesics for the pain, typically for 1-2 days following treatment. The majority of AEs were of moderate-to-severe intensity. Seventeen of 39 patients (43.6%) had complete clearance 14 days after last treatment, and AGW count was reduced by 90.9%. There was a tendency towards lower clearance rate in patients with longer duration of AGW. Eight of 14 patients (57.1%) had AGW recurrence 12 weeks after clearance.. Ingenol mebutate gel was associated with a high number of AEs and withdrawals due to painful local and adjacent skin reactions. Furthermore, it showed promising efficacy in reducing AGW despite a difficult-to-treat population. Optimization of the formulation is warranted to improve the safety profile of the treatment.

Topics: Adult; Aged; Antineoplastic Agents; Anus Diseases; Blister; Condylomata Acuminata; Diterpenes; Edema; Erythema; Female; Gels; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Middle Aged; Pain; Prospective Studies; Recurrence; Skin Ulcer; Treatment Outcome; Young Adult

Recently, it has been reported that ingenol mebutate (IM) is an effective treatment option for anogenital warts (AGW), inducing fast wart necrosis within 24 hours in vivo. With regard to its mode of action, IM is thought to act both as an inducer of direct cytotoxic effects and immunologic mechanisms. To distinguish whether the wart necrosis is mainly caused by cytotoxic effects, or whether immune mechanisms are leading, we used time-lapse imaging to analyse IM-treated warts ex vivo over 24 hours. Ex vivo IM-treated warts, which have been detached from the immune system, did not show destructive necrosis, pointing towards a primarily immune-driven mode of action of IM in the treatment of AGW.

Topics: Antineoplastic Agents; Condylomata Acuminata; Diterpenes; Humans; Immunity; Necrosis; Time-Lapse Imaging; Tissue Culture Techniques

Therapeutic options of anogenital warts (AGW) at the urethral meatus are limited and often require effortful and time-consuming procedures under general anesthesia. Here, we present two cases of AGW at the urethral meatus, which we have successfully treated with low-dose topical ingenol mebutate gel.

Topics: Adult; Anus Diseases; Condylomata Acuminata; Diterpenes; Human papillomavirus 11; Human papillomavirus 6; Humans; Male; Papillomavirus Infections; Treatment Outcome; Warts

Ingenol mebutat (IM)-gel is effective for the topical treatment of epithelial tumors, including actinic keratoses (AKs) or anogenital warts (AGW). AK patients treated with IM develop intensified inflammatory reactions on sights of prior clinical visible or palpable AKs as compared to the surrounding actinically damaged skin, suggesting the induction of a tumor cell-directed inflammation. AGW patients treated with IM develop even stronger inflammatory reactions with large erosions, suggesting a directed inflammatory response against HPV-infected keratinocytes. Of note, even widespread erosions heal very fast without any superinfections. Here, we set out to elucidate underlying molecular and cellular mechanisms of these clinical observations.. The effects of IM (10. Ingenol mebutat significantly and dose-dependently induced the expression of proinflammatory chemokines (CXCL8, CCL2) and AMP (RNase7, HBD3) in HEK and epithelial cancer cell lines. A significantly stronger induction of CXCL8 and CCL2 was observed in our tested tumor cells as compared to HEK. We did not observe any significant effect of IM on HEK migration, respectively wound healing responses in vitro for any tested concentration (10. Our data suggest that tumor cells are more susceptible to IM as compared to differentiated HEK. This is evident by a stronger IM-mediated induction of proinflammatory chemokines in tumor cells, which may result in a tumor cell-directed inflammatory response and rapid tumor destruction. In addition, IM induces AMP in keratinocytes and seems not to severely interfere with keratinocyte migration, which contributes to a fast and uncomplicated wound healing. Surprising is a selective inhibition of keratinocyte migration by IM at the concentration of 10

Topics: Administration, Topical; Antimicrobial Cationic Peptides; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokines; Condylomata Acuminata; Diterpenes; Gene Expression Regulation; HEK293 Cells; Humans; Inflammation; Keratinocytes; Keratosis, Actinic; Neoplasms; Papillomaviridae; Wound Healing

Topics: Condylomata Acuminata; Diterpenes; Humans; Male

Topics: Adult; Aged; Anus Diseases; Condylomata Acuminata; Diterpenes; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Male; Middle Aged; Young Adult

Condylomata acuminata (CA) are one of the most common sexually transmitted infections in the sexually active population. Due to the stigmatizing character of the disease and the high rate of relapse after therapy, CA may significantly affect patients' quality of life. Here, we report the case of successful treatment of multiple CA of the penis and scrotum in a 53-year-old man with ingenol mebutate gel.

Topics: Condylomata Acuminata; Diterpenes; Humans; Male; Middle Aged; Penile Diseases; Treatment Outcome