Repurposed drug agomelatine is therapeutic against collagen-induced arthritis via iNOS targeting.

BACKGROUND: The most promising biologics tumor necrosis factor α (TNFα) inhibitors are effective in treating rheumatoid arthritis (RA) in only 50-70 % of the cases; thus, new drugs targeting TNFα-mediated inflammation are required. METHODS: Firstly, the drugs that could inhibit FLS proliferation and TNFα induced inflammatory cytokine production were screened. Secondly, treatment effects of the identified drugs were screened in collagen-induced arthritis (CIA) mouse model. Thirdly, the inhibitory effect of the identified drug, agomelatine (AOM), on TNFα induced inflammatory cytokine production and NF-κB activity were confirmed. Fourthly, bioinformatics was applied to predict the binding target of AOM and the binding was confirmed, and the already known inhibitor of target was used to test the treatment effect for CIA mouse model. Finally, the effect of AOM on signaling pathway was tested and on TNFα induced inflammatory cytokine production was observed after inhibiting the target. RESULTS: AOM effectively inhibited TNFα-induced NF-κB activation, NF-κB p65 translocation, and inflammatory cytokines production in vitro and was therapeutic against CIA. The mechanistic study indicated inducible nitric oxide synthase (iNOS) as the binding target of AOM. 1400 W, a known inhibitor of iNOS, could effectively treat CIA by decreasing iNOS activity and the levels of inflammatory cytokines. The inhibitory effect of AOM on TNFα-induced inflammation was further elucidated by 1400 W, or NF-κB p65 inhibitor JSH-23, indicating that AOM is therapeutic against CIA via iNOS/ERK/p65 signaling pathway after binding with iNOS. CONCLUSIONS: AOM is therapeutic against CIA via inhibition of the iNOS/ERK/p65 signaling pathway after binding with iNOS.

In vitro determination of the combination of ciclopirox and terbinafine in the treatment of dermatophytosis.

INTRODUCTION: The cases of dermatophytosis are increasing and they are associated with a higher number of therapeutic failures leading the doctor to prescribe combinations of antifungals as therapy. The objective was to evaluate the interaction of terbinafine and ciclopirox, the most commonly antifungals used in the clinic, in dermatophyte isolates. METHODOLOGY: The minimum inhibitory concentrations (MIC) of ciclopirox and terbinafine were determined by the broth microdilution method according CLSI and the checkerboard assay was used to evaluate the interaction between the antifungal agents. RESULTS: For terbinafine the mic50 was 0.125 ug/mL and mic90 was 0.250 ug/mL. For ciclopirox the values were 2.0 ug/mL for mic50 and 4.0 ug/mL for mic90. No synergistic interaction was observed for the dermatophyte isolates tested. CONCLUSION: These results suggest that the use of terbinafine in combination with ciclopirox, which is widely used in the clinic, may not be a good choice for the treatment of onychomycosis.

Structure-based design and synthesis of sulfonylureas as novel NLRP3 inhibitors for Alzheimer's disease.

Alzheimer's disease (AD) remains an incurable neurodegenerative condition that poses a threat to humanity. Immune signaling in the brain, particularly the NLR family pyrin domain containing 3 (NLRP3), is currently targeted for AD treatment. Based on the crystal structure of the NACHT domain of NLRP3 and its renowned inhibitor MCC950, we designed and synthesized nineteen sulfonylurea compounds and evaluated their capacity to inhibit caspase-1 and interleukin-1ß (IL-1ß). Of these, nine were selected for measuring their IC50 for caspase-1 and cytotoxicity analysis. Finally, three compounds were chosen to assess their inhibitory effect on IL-1ß in mice. The results showed that compound 5m had a superior ability to reduce IL-1ß levels in the brain compared to MCC950 at a lower dosing concentration, indicating that 5m has the potential to penetrate the blood-brain barrier (BBB) and inhibit inflammation both in vitro and in vivo. Docking studies of compound 5m on NLRP3 revealed a binding mode similar to MCC950. These findings suggest that compound 5m holds promise as an NLRP3 inhibitor for AD treatment.

Comparative Effectiveness of Alternative Treatment Approaches to Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis: An Observational Trial Emulation.

RATIONALE & OBJECTIVE: Optimal approaches to treat secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis (HD) have yet to be established in randomized controlled trials (RCTs). STUDY DESIGN: Two observational clinical trial emulations. SETTING & PARTICIPANTS: Both emulations included adults receiving in-center HD from a national dialysis organization. The patients who had SHPT in the period between 2009 and 2014, were insured for≥180 days by Medicare as primary payer, and did not have contraindications or poor health status limiting theoretical trial participation. EXPOSURE: The parathyroid hormone (PTH) Target Trial emulation included patients with new-onset SHPT (first PTH 300-600pg/mL), with 2 arms defined as up-titration of either vitamin D sterols or cinacalcet within 30 days (lower target) or no up-titration (higher target). The Agent Trial emulation included patients with a PTH≥300 pg/mL while on≥6µg weekly of vitamin D sterol (paricalcitol equivalent dose) and no prior history of cinacalcet. The 2 arms were defined by the first dose or agent change within 30 days (vitamin D-favoring [vitamin-D was up-titrated] vs cinacalcet-favoring [cinacalcet was added] vs nondefined [neither applies]). Multiple trials per patient were allowed in trial 2. OUTCOME: The primary outcome was all-cause death over 24 months; secondary outcomes included cardiovascular (CV) hospitalization or the composite of CV hospitalization or death. ANALYTICAL APPROACH: Pooled logistic regression. RESULTS: There were 1,152 patients in the PTH Target Trial (635 lower target and 517 higher target). There were 2,726 unique patients with 6,727 patient trials in the Agent Trial (6,268 vitamin D-favoring trials and 459 cinacalcet-favoring trials). The lower PTH target approach was associated with reduced adjusted hazard of death (HR, 0.71 [95% CI, 0.52-0.93]), CV hospitalization (HR, 0.78 [95% CI, 0.63-0.98]), and their composite (HR, 0.74 [95% CI, 0.61-0.89]). The cinacalcet-favoring approach demonstrated lower adjusted hazard of death compared to the vitamin D-favoring approach (HR, 0.79 [95% CI, 0.62-0.99]), but not of CV hospitalization or the composite outcome. LIMITATIONS: Potential for residual confounding; low use of cinacalcet with low power. CONCLUSIONS: SHPT management that is focused on lower PTH targets may lower mortality and CV disease in patients receiving HD. These findings should be confirmed in a pragmatic randomized trial. PLAIN-LANGUAGE SUMMARY: Optimal approaches to treat secondary hyperparathyroidism (SHPT) have not been established in randomized controlled trials. Data from a national dialysis organization was used to identify patients with SHPT in whom escalated treatment may be indicated. The approach to treatment was defined based on observed upward titration of SHPT-controlling medications: earlier titration (lower target) versus delayed titration (higher target); and the choice of medication (cinacalcet vs vitamin D sterols). In the first trial emulation, we estimated a 29% lower rate of death and 26% lower rate of cardiovascular disease or death for patients managed with a lower versus higher target approach. Cinacalcet versus vitamin D-favoring approaches were not consistently associated with outcomes in the second trial emulation. This observational study suggests the need for additional clinical trials of SHPT treatment intensity.

A dermocosmetic regimen is able to mitigate skin sensitivity induced by a retinoid-based fixed combination treatment for acne: Results of a randomized clinical trial.

INTRODUCTION: Topical retinoids cause retinoid-induced skin discomfort (RISD) mainly during the first weeks of use leading to noncompliance and premature treatment discontinuation. A dermocosmetic (DC) may help to reduce treatment-related signs and symptoms and improve adherence. OBJECTIVES: To assess the benefit of a DC regimen compared to a routine skin care regimen (RC) by reducing RISD signs and symptoms induced by a retinoid/benzoyl peroxide fixed-drug combination in subjects with acne. MATERIALS AND METHODS: Double-blind, randomized, comparative study in subjects ≥16 years with mild to moderate acne candidates to a topical adapalene/BPO fixed drug combination (A/BPO). Evaluations took place at Day 0, 7, 14, 28, and 84 and included erythema, desquamation, burning, itching and stinging and RISD (SD, a composite score of local treatment-related signs and symptoms and acne severity. Subjects used daily the DC or RC together with the fixed combination for 84 days. RESULTS: Eighty-eight subjects were included, the mean age was 21 years; 84% were females. At Day 0 the SD score was 0.8 in both groups. A statistically significant difference in terms of skin sensitivity with DC compared to RC (1.6 points, vs. 2.4 points p < 0.05) was observed at Day 14. Clinical sign and symptom scores were more reduced with DC than with RC at all time points. Acne severity improved in both groups. CONCLUSION: DC significantly reduces A/BPO-related RISD compared to RC, especially during the first 14 days of treatment, without interfering with the clinical efficacy of the treatment, thus helping to maintain treatment adherence.

Comparing the Efficacy for Pulse Versus Continuous Dose Terbinafine Therapy in Patients With Onychomycosis.

Recently, treatment outcomes in patients with toenail onychomycosis have improved considerably due to more effective oral antifungal medications such as terbinafine and itraconazole. These medications can either be used continuously for several weeks at a lower dose or intermittently (pulsed) at a higher dose. Previous literature comparing pulse and continuous therapy has generated mixed results.  Our study aims to compare the efficacy, in terms of clinical cure rate, of continuous vs pulse dose terbinafine regimens for toenail onychomycosis. Sixty patients with onychomycosis of Fitzpatrick skin types IV to VI, between 15 and 65 years of age, were divided into a continuous treatment group receiving 250 mg terbinafine once daily for 12 weeks and a pulse treatment group receiving 250 mg twice daily terbinafine for 1 week repeated every 4 weeks for 12 weeks. Each patient was followed up at weeks 4, 8, and 12.  Efficacy of the continuous treatment group was significantly greater at 76.67% compared with 26.67% in the pulse treatment group. Thus, we conclude that the clinical cure rate of a continuous dose regimen of terbinafine is a superior treatment option for toenail onychomycosis. However, we also suggest further studies including combinations of multiple agents and hybrid regimen models for the optimal onychomycosis treatment.   J Drugs Dermatol. 2023;22(10):     doi:10.36849/JDD.7323R1.

Improved effectiveness of an increased dose of griseofulvin for treating Tinea capitis among refugee children in Israel: A retrospective cohort study.

BACKGROUND: Tinea capitis (TC), a fungal infection that occurs in children, is primarily caused by dermatophytes such as Trichophyton and Microsporum species. For Trichophyton species, treatment with terbinafine is considered more effective than griseofulvin treatment. Specific populations, such as refugee children, are more susceptible to TC. OBJECTIVE: This study aimed to describe and compare the response to treatment among Israeli and refugee children with TC. PATIENTS/METHODS: We retrospectively reviewed data collected on refugee and Israeli children with TC between January 2004 and January 2020. RESULTS: Overall, 3358 children with TC (refugees: 1497; Israelis: 1861) were identified. Among these, 86% of the refugee children had TC caused by Trichophyton violaceum, 65% of the Israeli children had TC caused by Microsporum canis and 83% of all children were treated with griseofulvin. Overall, 14% of the refugees showed a partial response to a griseofulvin dose of ≤25 mg/kg/day; however, they showed a complete response upon increasing the dose to ≥30 mg/kg/day. No significant adverse effects were observed. CONCLUSION: The over-crowded day care centres and dense living make refugee children more susceptible to TC than the general population, and griseofulvin dosage adjustment is necessary. TC, due to Trichophyton species, could benefit from receiving an increased dose of griseofulvin in a suspension form, which is cheaper than terbinafine.

Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y14 Receptor Antagonists.

P2Y14 receptor (P2Y14R) is activated by extracellular UDP-glucose, a damage-associated molecular pattern that promotes inflammation in the kidney, lung, fat tissue, and elsewhere. Thus, selective P2Y14R antagonists are potentially useful for inflammatory and metabolic diseases. The piperidine ring size of potent, competitive P2Y14R antagonist (4-phenyl-2-naphthoic acid derivative) PPTN 1 was varied from 4- to 8-membered rings, with bridging/functional substitution. Conformationally and sterically modified isosteres included N-containing spirocyclic (6-9), fused (11-13), and bridged (14, 15) or large (16-20) ring systems, either saturated or containing alkene or hydroxy/methoxy groups. The alicyclic amines displayed structural preference. An α-hydroxyl group increased the affinity of 4-(4-((1R,5S,6r)-6-hydroxy-3-azabicyclo[3.1.1]heptan-6-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-naphthoic acid 15 (MRS4833) compared to 14 by 89-fold. 15 but not its double prodrug 50 reduced airway eosinophilia in a protease-mediated asthma model, and orally administered 15 and prodrugs reversed chronic neuropathic pain (mouse CCI model). Thus, we identified novel drug leads having in vivo efficacy.

Cost-effectiveness analysis of cinacalcet vs. paricalcitol in the treatment of hyperparathyroidism secondary to chronic kidney disease.

INTRODUCTION: For the reduction of PTH levels, two classes of drugs are available in the Brazilian market: non-selective and selective vitamin D receptor activators and calcimimetics. Among the mentioned drugs, the SUS provides oral calcitriol, paricalcitol and cinacalcet. OBJECTIVES: Develop cost-effectiveness (CE) and budgetary impact (BI) analysis of cinacalcet versus paricalcitol for patients on dialysis with SHPT, from the perspective of SUS. METHODOLOGY: A decision tree model was constructed for CE analysis, which considered the outcome of avoided parathyroidectomy and a time horizon of 1 year. As for the BI analysis, two scenarios were considered, one of which was measured demand and other epidemiological, based on data from the Brazilian Society of Nephrology (BSN). RESULTS: The CE analysis showed that the use of cinacalcet results in one-off savings of R$1,394.64 per year and an incremental effectiveness of 0.08, in relation to avoided parathyroidectomy. The incremental CE ratio (ICER) was - R$ 17,653.67 per avoided parathyroidectomy for cinacalcet, as it was more effective and cheaper compared to paricalcitol. As for the BI analysis, it was estimated that the incremental BI with the expansion of the use of cinacalcet in the SUS will be between - R$ 1,640,864.62 and R$ 166,368.50 in the first year, considering the main and the epidemiological scenarios. At the end of 5 years after the expansion of use, an BI was estimated between - R$ 10,740,743.86 and - R$ 1,191,339.37; considering the same scenarios. CONCLUSION: Cinacalcet was dominant to avoid parathyroidectomies, being cost-effective.

Synthesis and evaluation of naphthalene derivatives as potent STAT3 inhibitors and agents against triple-negative breast cancer growth and metastasis.

PURPOSE: Triple-negative breast cancer (TNBC) represents the worst prognostic subtype of breast cancer and lacks targeted therapeutic drugs. Signal transducer and activator of transcription 3 (STAT3) is overexpressed and constitutively activated in TNBCs and associated with poor patient outcomes. However, no agents targeting STAT3 have been successfully developed and marketed. Selective Estrogen Receptor Modulators (SERMs) have been reported as potential inhibitors of the IL-6/STAT3 signaling pathway. Naphthalene compounds have good pharmacological activity and significant anti-cancer activity. In this study, we synthesized a new series of naphthalene derivatives with the general structure of SERM and evaluated their effects on TNBC and STAT3 signals. METHODS: A new series of compounds based on the scaffold of SERMs and an amino group were designed and screened based on the structure-activity relationship by MTT assay. The binding activity of SMY002 to STAT3 was predicted and validated by docking and SPR. The STAT3 signaling target and anti-cancer effects of SMY002 were evaluated with three TNBC cell lines and the mice transplanted tumor model. RESULTS: Among the compounds, SMY002 displayed the most potent activity, which could directly interact with STAT3 SH2-domain, and strongly inhibit the phosphorylation, dimerization, nuclear distribution, transcriptional activity, and target genes expression of STAT3. Furthermore, SMY002 markedly suppressed migration, invasion, survival, growth, and metastasis of TNBC cells in vitro and in vivo via down-regulating the expression of Cyclin D1 and MMP9. CONCLUSIONS: SMY002 can significantly inhibit the growth and metastasis of TNBC cells by targeting the STAT3 signal.

Predictive factors requiring high-dose evocalcet in hemodialysis patients with secondary hyperparathyroidism.

The dosage of evocalcet required to control serum parathyroid hormone (PTH) levels varies among secondary hyperparathyroidism (SHPT) patients. This post hoc analysis evaluated the dose-dependent efficacy of evocalcet on serum intact PTH (iPTH) levels, corrected calcium (Ca) and phosphate (P) levels, and safety, in an evaluation period (week 28 to week 30) by stratifying the previous phase 3 data with the final evocalcet dosages (low 1-2 mg [131 patients], medium 3-4 mg [90 patients], high 5-8 mg [92 patients]), and identified pre-treatment patient characteristics predicting the use of higher final evocalcet dosages via univariate and multivariate logistic regression models. At the end of the study at week 30, the median serum iPTH level was higher and the achievement ratio for the target range of Japanese Society for Dialysis Therapy (60-240 pg/mL) was lower in the final high-dose subgroup (216 pg/mL and 58%, respectively) than in the other subgroups (low: 149 pg/mL and 79%; medium: 149 pg/mL and 73%, respectively). Among the three subgroups, the mean serum corrected Ca and P levels demonstrated similar trends, and similar ratio of patients achieved the target range (corrected Ca, 8.4-10 mg/dL; P, 3.5-6.0 mg/dL) from week 28 to week 30. No dose-dependent safety concerns were identified. Younger age, prior cinacalcet use, higher serum levels of iPTH and corrected Ca, procollagen type 1 N-terminal propeptide, intact fibroblast growth factor-23, and larger maximum parathyroid gland volume were significantly associated with final high-dose evocalcet (p < 0.05 in all cases). Patients requiring final high-dose evocalcet had pre-treatment characteristics indicating severe SHPT, leading to a lower final achievement rate for the target PTH levels of Japanese Society for Dialysis Therapy. Therefore, the early initiation of evocalcet treatment for SHPT is critical. Trial registration: This trial was registered as follows: ClinicalTrials.gov: NCT02549391 and JAPIC: JapicCTI-153013.

Adapalene/benzoyl peroxide gel 0.3%/2.5% for acne vulgaris

Acne vulgaris is typically treated with a combination of a topical retinoid plus an antimicrobial agent, as recommended by national and international evidence-based guidelines around the globe. Adapalene, a synthetic topical retinoid, is available in two concentrations (0.1% and 0.3%) and in once-daily fixed-dose combinations with benzoyl peroxide (BPO) 2.5%. Adapalene 0.3%/BPO 2.5% is approved for use for moderate-to-severe acne with proven efficacy, good safety and tolerability across a spectrum of patient variables (different ages, genders, and skin types) and disease severity. While some patients experience issues with transient tolerability during retinoid and BPO therapy, it is our clinical experience that good patient education to set expectations and provide strategies to minimize irritation can overcome the majority of issues. This article reviews the data supporting the use of adapalene 0.3%/2.5% in practice, including the complementary mechanism of action of adapalene and BPO, clinical data from a range of settings, and key aspects of patient education.

Synthesis, Leishmanicidal, Trypanocidal, Antiproliferative Assay and Apoptotic Induction of (2-Phenoxypyridin-3-yl)naphthalene-1(2H)-one Derivatives.

The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8−23 were obtained using the classical base-catalyzed Claisen−Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments.

[Evaluation of the efficacy of dapoxetine in primary and secondary forms of premature ejaculation].

OBJECTIVE: to compare the efficacy of dapoxetine in treatment of primary and secondary premature ejaculation. MATERIALS AND METHODS: The study included 60 patients with premature ejaculation (PE). Depending on the form of premature ejaculation they were divided into two groups: 27 patients with primary PE (group 1) and 33 patients with secondary PE (group 2). Patients were recommended to take dapoxetine 30 mg 1 hour before intercourse. A follow-up visit was scheduled on day 30 after receiving the drug. The intravaginal ejaculation latency time (IELT) and the Premature ejaculation diagnostic tool (PEDT) score were evaluated before dapoxetine was given and after 30 days from the start of the study. The significance of differences between baseline and follow-up values were compared using Wilcoxons test. In both groups, the proportion of patients with an incomplete response (IELT less than 2 minutes, PEDT more than 10) to symptomatic therapy with dapoxetine was evaluated. The proportion of patients with incomplete response to therapy was compared using the chi-square test. RESULTS: The median IELT among all patients before starting therapy was 63 seconds (interquartile interval [IQR]: 28.75-94). After one month of therapy median IELT increased to 119 seconds (IQR: 58.75-321.75). Median PEDT score was 16 (IQR: 13-19) at baseline and 7 (IQR: 4-12) at follow-up. In group 1, the median IELT increased from 57 to 83 seconds (p = 0.02088), and in group 2, the median IELT increased from 70 to 173 seconds (p<0.00001). The mean PEDT score decreased to 7 in both groups (p<0.00001). Incomplete response to therapy was observed in 66.7% of patients in group 1 and in 39.4% of patients in group 2. The difference between two groups was statistically significant (p=0.035456). CONCLUSION: Symptomatic therapy with dapoxetine has a positive effect on the intravaginal ejaculation latency time and patient satisfaction in both primary and secondary premature ejaculation. However, the incidence of incomplete response to therapy is higher in patients with primary premature ejaculation, which may be due to characteristic differences in the pathogenesis of primary and secondary premature ejaculation.

Evocalcet with vitamin D receptor activator treatment for secondary hyperparathyroidism.

This ad hoc analysis of a previously conducted phase 3 head-to-head comparison study of evocalcet and cinacalcet in secondary hyperparathyroidism patients undergoing maintenance hemodialysis evaluated the efficacy and safety of combined once-daily oral evocalcet and intravenous vitamin D receptor activator treatment stratified by weekly vitamin D receptor activator dose (117, 45, and 91 patients in no, low [< 1.5 µg], and high [≥ 1.5 µg] dose groups, respectively). Effects of vitamin D receptor activator were assessed on the basis of intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels; percent changes from baseline; proportions of patients who achieved target intact parathyroid hormone, corrected calcium, and phosphorus at Weeks 28-30; and adverse drug reactions. Intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels decreased in all groups; phosphorus and fibroblast growth factor-23 levels remained high in the high dose group. In the low and high dose groups, greater proportions of patients achieved the corrected calcium target compared with the no dose group (p = 0.043). Ratios of intact-to-C-terminal fibroblast growth factor-23 decreased in all groups. In low and high dose groups, hypocalcemia was less common than in the no dose group (p = 0.014). Evocalcet with concomitant vitamin D receptor activator demonstrated benefits such that more patients achieved the corrected calcium target and exhibited decreased fibroblast growth factor-23 synthesis; the incidence of hypocalcemia also decreased. Clinical trial registration: ClinicalTrials.gov (NCT02549391) and JAPIC (JapicCTI-153013).

Review of the alternative therapies for onychomycosis and superficial fungal infections: posaconazole, fosravuconazole, voriconazole, oteseconazole.

Terbinafine and itraconazole are the most commonly used oral antifungals to treat onychomycosis and superficial dermatomycoses. Recently, poor response to oral terbinafine has been reported. We have summarized the most appropriate dosing regimens of posaconazole, fosravuconazole, voriconazole, and oteseconazole (VT-1161) to treat onychomycosis and superficial fungal infections. A structured search on PubMed and Google Scholar was conducted. Additionally, the bibliographies of selected articles were searched to identify relevant records. The number of records identified from the searches was 463, with 50 articles meeting the inclusion criteria for review. None of the new azoles are US FDA approved for onychomycosis treatment; however, an increasing number of studies have evaluated these agents. The efficacies (complete cure and mycologic cure) of the antifungal agents for dermatophyte great toenail onychomycosis treatment are terbinafine 250 mg/day × 12 weeks (Phase III trial) (38%, 70%), itraconazole 200 mg/day × 12 weeks (Phase III trial) (14%, 54%), posaconazole 200 mg/day × 24 weeks (Phase IIB) (54.1%, 70.3%), fosravuconazole 100 mg/day ravuconazole equivalent × 12 weeks (Phase III) (59.4%, 82.0%), and oteseconazole 300 mg/day loading dose × 2 weeks (Phase II), followed by 300 mg/week × 10 weeks (maintenance dose) (45%, 70%). Guidelines for monitoring are also presented.

The Novel Dual Topoisomerase Inhibitor P8-D6 Shows Anti-myeloma Activity In Vitro and In Vivo.

P8-D6 is a novel dual inhibitor of human topoisomerase I (TOP1) and II (TOP2) with broad pro-apoptotic antitumor activity. NCI-60 screening revealed markedly improved cytotoxicity of P8-D6 against solid and leukemia cell lines compared with other single and dual topoisomerase inhibitors, for example, irinotecan, doxorubicin, or pyrazoloacridine. In this study, we investigated the capacity of P8-D6 to inhibit myeloma cell growth in vitro and in vivo Growth inhibition assays demonstrated significant anti-myeloma effects against different myeloma cell lines with IC50 values in the low nanomolar range. Freshly isolated plasma cells of patients with multiple myeloma were killed by P8-D6 with similar doses. P8-D6 activated caspase 3/7 and induced significant apoptosis of myeloma cells. Supportive effects of bone marrow stromal cells on IL6-dependent INA-6 myeloma cells were abrogated by P8-D6 and apoptosis occurred in a time- and dose-dependent manner. Of note, healthy donor peripheral blood mononuclear cells and human umbilical vein endothelial cells were not affected at concentrations toxic for malignant plasma cells. Treatment of myeloma xenografts in immunodeficient SCID/beige mice by intravenous and, notably, also oral application of P8-D6 markedly inhibited tumor growths, and significantly prolonged survival of tumor-bearing mice.

Dickkopf-1 Inhibition Reactivates Wnt/ß-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo.

The Wnt/ß-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/ß-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to ß-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.

Pharmacological preconditioning by TERT inhibitor BIBR1532 confers neuronal ischemic tolerance through TERT-mediated transcriptional reprogramming.

After a sublethal ischemic preconditioning (IPC) stimulus, the brain has a remarkable capability of acquiring tolerance to subsequent ischemic insult by establishing precautionary self-protective mechanism. Understanding this endogenous mechanism would reveal novel and effective neuroprotective targets for ischemic brain injury. Our previous study has implied that telomerase reverse transcriptase (TERT) is associated with IPC-induced tolerance. Here, we investigated the mechanism of TERT-mediated ischemic tolerance. Preconditioning was modeled by oxygen-glucose deprivation (OGD) and by TERT inhibitor BIBR1532 in primary neurons. We found that ischemic tolerance was conferred by BIBR1532 preconditioning. We used the Cleavage-Under-Targets-And-Tagmentation approach, a recently developed method with superior signal-to-noise ratio, to comprehensively map the genomic binding sites of TERT in primary neurons, and showed that more than 50% of TERT-binding sites were located at the promoter regions. Mechanistically, we demonstrated that under normal conditions TERT physically bound to many previously unknown genomic loci in neurons, whereas BIBR1532 preconditioning significantly altered TERT-chromatin-binding profile. Intriguingly, we found that BIBR1532-preconditioned neurons showed significant up-regulation of promoter binding of TERT to the mitochondrial anti-oxidant genes, which were correlated with their elevated expression. Functional analysis further indicated that BIBR1532-preconditioning significantly reduced ROS levels and enhanced tolerance to severe ischemia-induced mitochondrial oxidative stress in neurons in a TERT-dependent manner. Together, these results demonstrate that BIBR1532 confers neuronal ischemic tolerance through TERT-mediated transcriptional reprogramming for up-regulation of mitochondrial anti-oxidation gene expression, suggesting the translational potential of BIBR1532 as a therapeutic agent for the treatment of cerebral ischemic injury and oxidative stress-induced neurological disorders.