A New Topical Candidate in Acne Treatment: Characterization of the Meclozine Hydrochloride as an Anti-Inflammatory Compound from In Vitro to a Preliminary Clinical Study.

Acne is a chronic inflammatory multifactorial disease involving the anaerobic bacterium Cutibacterium acnes (C. acnes). Current acne treatments are associated with adverse effects, limiting treatment compliance and use. We showed that meclozine, an anti-histaminic H1 compound, has anti-inflammatory properties. In Vitro, meclozine reduced the production of CXCL8/IL-8 and IL-1ß mRNA and protein by C. acnes-stimulated human keratinocytes and monocytes. No cell toxicity was observed at the IC50. Meclozine prevented the phosphorylation of ERK and JNK. In Vivo, 1% meclozine gel significantly decreased C. acnes-mouse ear induced inflammation by 26.7% (p = 0.021). Ex vivo experiments on human skin explants showed that meclozine decreased the production of GM-CSF, IL-1ß and TNF-α at transcriptional and translational levels. In a randomized, double-blind, placebo-controlled proof-of-concept clinical trial on 60 volunteers, 2% meclozine pharmaceutical gel decreased by 20.1% (p < 0.001) the ASI score in the treated group after 12 weeks of treatment. No adverse event was reported. Together, these results indicate that meclozine is a potent topical anti-inflammatory compound of potential value for acne treatment.

Primaquine as a Candidate for HHV-8-Associated Primary Effusion Lymphoma and Kaposi's Sarcoma Treatment.

Human Herpesvirus 8 (HHV-8) is associated with three main severe orphan malignancies, Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL), which present few therapeutic options. We identified the antimalarial primaquine diphosphate (PQ) as a promising therapeutic candidate for HHV-8-associated PEL and KS. Indeed, PQ strongly reduced cell viability through caspase-dependent apoptosis, specifically in HHV-8-infected PEL cells. Reactive oxygen species (ROS)- and endoplasmic reticulum (ER) stress-mediated apoptosis signaling pathways were found to be part of the in vitro cytotoxic effect of PQ. Moreover, PQ treatment had a clinically positive effect in a nonobese diabetic (NOD)/SCID xenograft PEL mouse model, showing a reduction in tumor growth and an improvement in survival. Finally, an exploratory proof-of-concept clinical trial in four patients harboring severe KS was conducted, with the main objectives to assess the efficacy, the safety, and the tolerability of PQ, and which demonstrated a positive efficacy on Kaposi's sarcoma-related lesions and lymphedema.

Harnessing Redox Disruption to Treat Human Herpesvirus 8 (HHV-8) Related Malignancies.

Reprogrammed metabolism is regarded as a hallmark of cancer and offers a selective advantage to tumor cells during carcinogenesis. The redox equilibrium is necessary for growth, spread and the antioxidant pathways are boosted following Reactive Oxygen Species (ROS) production to prevent cell damage in tumor cells. Human herpesvirus 8 (HHV-8), the etiologic agent of Kaposi sarcoma KS and primary effusion lymphoma (PEL), is an oncogenic virus that disrupts cell survival-related molecular signaling pathways leading to immune host evasion, cells growths, angiogenesis and inflammatory tumor-environment. We recently reported that primaquine diphosphate causes cell death by apoptosis in HHV-8 infected PEL cell lines in vivo and exhibits therapeutic anti-tumor activity in mice models and advanced KS. Our findings also suggest that the primaquine-induced apoptosis in PEL cells is mostly influenced by ROS production and targeting the redox balance could be a new approach to treat HHV-8 related diseases. In this review, we summarized the knowledge about the influence of ROS in cancer development; more specifically, the proof of evidence from our work and from the literature that redox pathways are important for the development of HHV-8 pathologies.

Prevalence of cervical HPV infection, sexually transmitted infections and associated antimicrobial resistance in women attending cervical cancer screening in Mali.

OBJECTIVES: To assess the prevalence of sexually transmitted infections (STIs), antimicrobial resistance and cervical lesions among women from Sikasso, Mali. METHODS: Women infected with human immunodeficiency virus (HIV) (n=44) and HIV-negative women (n=96) attending cervical cancer screening were included. Screening for human papillomavirus (HPV), Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) was performed using polymerase chain reaction assays, and herpes simplex virus (HSV-1/2) serological status was assessed using enzyme-linked immunosorbent assays. Antibiotic resistance tests were performed for MG- and NG-positive cases. RESULTS: A high prevalence of high-risk HPV (hrHPV) infection (63%) was found. This was associated with cervical lesions in 7.5% of cases. An unusual distribution was found, with HPV31, HPV56 and HPV52 being the most prevalent. The hrHPV distribution differed by HIV status, with HIV-positive cases having HPV35/31/51-52-56 and HIV-negative cases having HPV31/56/52. The seroprevalence of HSV-2 was 49%, and the prevalence of other STIs was as follows: CT, 4%; MG, 9%; NG, 1%; and TV, 7%. Five of nine MG-positive specimens and the NG strains obtained were resistant to fluoroquinolone. CONCLUSIONS: These results showed high prevalence of hrHPV and fluoroquinolone resistance in several NG and MG strains. Further studies are required to confirm these data in Mali, and to improve prevention, screening and management of cervical cancer and other STIs in women.