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.

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.

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.

α-Cyperone (CYP) down-regulates NF-κB and MAPKs signaling, attenuating inflammation and extracellular matrix degradation in chondrocytes, to ameliorate osteoarthritis in mice.

Inflammation and extracellular matrix (ECM) degradation have been implicated in the pathological process of osteoarthritis (OA). α-Cyperone is the main active component of the traditional Chinese medicine Cyperus rotundus L. In this study, we found that α-Cyperone abolished the IL-1ß-induced production of inflammatory cytokines in isolated rat chondrocytes, such as cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS), in a dose-dependent manner (0.75, 1.5 or 3 µM). Also, the results showed that α-Cyperone downregulated the expression of metalloproteinases (MMPs) and thrombospondin motifs 5 (ADAMTS5), and upregulated the expression of type-2 collagen. Mechanistically, molecular docking tests revealed that α-Cyperone stably and effectively binds to p65, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). α-Cyperone inhibited NF-κB activation by blocking its nuclear transfer, and decreasing the phosphorylation of mitogen-activated protein kinase (MAPKs). In addition, in vivo studies based on a mouse model of arthritis showed that α-Cyperone prevented the development of osteoarthritis. Therefore, α-Cyperone may be a potential anti-OA drug.

Lipoxygenase inhibitor ML351 dysregulated an innate inflammatory response leading to impaired cardiac repair in acute heart failure.

The presistent increase of 12/15 lipoxygenase enzyme activity is correlated with uncontrolled inflammation, leading to organ dysfunction. ML351, a potent 12/15 lipoxygenase (12/15LOX) inhibitor, was reported to reduce infarct size and inflammation in a murine ischemic stroke model. In the presented work, we have applied three complementary experimental approaches, in-vitro, ex-vivo, and in-vivo, to determine whether pharmacological inhibition of 12/15LOX could dampen the inflammatory response in adult mice after Kdo2-Lipid A (KLA) as an endotoxin stimulator or post myocardial infarction (MI). Male C57BL/6 (8-12 weeks) mice were subjected to permanent coronary ligation thereby inducing acute heart failure (MI-d1 and MI-d5) for in-vivo studies. 12/15LOX antagonist ML351 (50 mg/kg) was subcutaneously injected 2 h post-MI, while MI-controls received saline. For ex-vivo experiments, ML351 (25 mg/kg) was injected as bolus after 5 min of inflammatory stimulus (KLA 1 µg/g) injection. Peritoneal macrophages (PMɸ) were harvested after 4 h post KLA. For in-vitro studies, PMɸ were treated with KLA (100 ng/mL), ML351 (10 µM), or KLA + ML351 for 4 h, and inflammatory response was evaluated. In-vivo, 5LOX expression was reduced after ML351 administration, inducing a compensatory increase of 12LOX that sensitized PMɸ toward a proinflammatory state. This was marked by higher inflammatory cytokines and dysregulation of the splenocardiac axis post-MI. ML351 treatment increased CD11b+ and Ly6Chigh populations in spleen and Ly6G+ population in heart, with a decrease in F4/80+ macrophage population at MI-d1. In-vitro results indicated that ML351 suppressed initiation of inflammation while ex-vivo results suggested ML351 overactivated inflammation consequently delaying the resolution process. Collectively, in-vitro, ex-vivo, and in-vivo results indicated that pharmacological blockade of lipoxygenases using ML351 impaired initiation of inflammation thereby dysregulated acute immune response in cardiac repair.

Albicanol Alleviates D-Galactose-Induced Aging and Improves Behavioral Ability Via by Alleviating Oxidative Stress-Induced Damage.

Albicanol is a natural terpenoid derived from Dryopteris fragrans. Herein, we assessed the ability of Albicanol to protect against oxidative stress-induced senescence. Using a murine model of D-galactose (D-gal)-induced aging, we determined that Albicanol treatment can reverse D-gal-mediated learning impairments and behavioral changes, while also remediating brain tissue damage in treated mice. We found that serum SOD, CAT, GSH-Px, and T-AOC levels were significantly decreased in aging mice, and that Albicanol treatment significantly increased the serum levels of these antioxidant enzymes. We additionally evaluated the impact of Albicanol treatment on the Keap1/Nrf2/ARE signaling pathway, and found that it was able to decrease Keap1 expression while increasing the expression of Nrf2, thereby activating this signaling pathway, suppressing oxidative damage, and enhancing the expression of downstream target genes including SOD, GSH, GST, HO-1, and NQO1 in this murine aging model system. Albicanol treatment also inhibited the secretion of inflammatory TNF-a and IL-1b. Together, these data indicated that Albicanol can activate Nrf2 pathway-related genes, thereby inhibition of delayed aging by alleviating oxidative stress-induced damage.

α-Cyperone inhibitory effects on tumor-derived DNA trigger microglia by STING pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Cyperus rotundus L. (Cyperaceae) is a widespread herbal in China and widely used in Traditional Chinese Medicine for multiple effects such as anti-arthritic, anti-genotoxic, anti-mutagenic, anti-bacterial effects, and analgesic. α-Cyperone is an active compound in Cyperus rotundus and has analgesic effects, but the exact molecular mechanisms require further investigations. MATERIALS AND METHODS: Tumor-derived DNA isolated from Lewis cell lines was transfected into microglia, and analyzed for stimulator of interferon genes (STING) effects. The downstream protein, such as interferon regulatory factor 3 (IRF3) and p65 nuclear factor-κB (NF-κB) were treated with STING siRNA and 5,6-dimethyllxanthenone-4-acetic acid (DMXAA) in microglia. The α-Cyperone effect on microglia was also investigated. RESULTS: Tumor-derived DNA activate microglia by upregulation of STING and downstream proteins. STING siRNA was reduced to its downstream expression and neuroinflammation inhibition was caused by tumor-derived DNA. However, DMXAA reversed the STING siRNA effect and increased neuroinflammation. α-Cyperone takes inhibitory effects on tumor-derived DNA that trigger microglia by STING pathway. CONCLUSIONS: α-Cyperone inhibition by tumor-derived DNA activated microglial to neuroinflammation in STING signaling pathway.

Topical clotrimazole cream for the treatment of tinea cruris: A retrospective study.

This retrospective study assessed the efficacy and safety of 1% topical clotrimazole cream for the treatment of patients with tinea cruris (TC).We included 86 patients with confirmed TC for the presence of fungal hyphae. Of those, 43 patients received 1% topical clotrimazole cream for a total of 4 consecutive weeks, and were assigned to an experimental group. The other 43 patients underwent 1% topical butenafine cream for a total of 2 consecutive weeks, and were allocated to a control group. The efficacy and safety were measured and analyzed after 4 weeks treatment.After treatment, patients in both groups achieved better improvements in erythema (P < .01), scaling (P < .01), itching (P < .01), and KOH-negative results (P < .01), compared with those in patients before the treatment. However, there were not significant differences in erythema (P = .61), scaling (P = .57), itching (P = .47), and KOH-negative results (P = .67) between 2 groups. In addition, no treatment-related adverse events were recorded in both groups.Both 1% topical clotrimazole and butenafine cream are found to be effective and safe for patients with TC. However, there is not significant difference in efficacy and safety between two groups.

Cannabinoids and Prostate Cancer: A Systematic Review of Animal Studies.

Prostate cancer is a major cause of death among men worldwide. Recent preclinical evidence implicates cannabinoids as powerful regulators of cell growth and differentiation, as well as potential anti-cancer agents. The aim of this review was to evaluate the effect of cannabinoids on in vivo prostate cancer models. The databases searched included PubMed, Embase, Scopus, and Web of Science from inception to August 2020. Articles reporting on the effect of cannabinoids on prostate cancer were deemed eligible. We identified six studies that were all found to be based on in vivo/xenograft animal models. Results: In PC3 and DU145 xenografts, WIN55,212-2 reduced cell proliferation in a dose-dependent manner. Furthermore, in LNCaP xenografts, WIN55,212-2 reduced cell proliferation by 66-69%. PM49, which is a synthetic cannabinoid quinone, was also found to result in a significant inhibition of tumor growth of up to 90% in xenograft models of LNCaP and 40% in xenograft models of PC3 cells, respectively. All studies have reported that the treatment of prostate cancers in in vivo/xenograft models with various cannabinoids decreased the size of the tumor, the outcomes of which depended on the dose and length of treatment. Within the limitation of these identified studies, cannabinoids were shown to reduce the size of prostate cancer tumors in animal models. However, further well-designed and controlled animal studies are warranted to confirm these findings.

Development of evocalcet for unmet needs among calcimimetic agents.

INTRODUCTION: The calcium-sensing receptor is an important treatment target for secondary hyperparathyroidism (SHPT) in patients undergoing dialysis. In addition to vitamin D receptor activator, cinacalcet has recently been widely used for SHPT management, and the significant suppression of parathyroid hormone (PTH) with better control of serum calcium and phosphorus has been reported. However, low adherence and insufficient dose escalation mainly due to frequent gastrointestinal adverse events, still remain as major issues. To overcome these unmet needs, we have developed a new oral calcimimetic agent evocalcet, which has recently been approved by the Pharmaceutical Affairs Act in Japan. AREAS COVERED: PubMed was searched from inception until April 2020 with the word evocalcet to summarize the development of this new calcimimetic agent, its pharmacokinetics, and the results of clinical trials, along with an overview of the differences among calcimimetic agents. This review also includes the management of SHPT with a focus on calcimimetics. EXPERT OPINION: Evocalcet evoked fewer gastrointestinal-related adverse events while suppressing PTH at a lower dose than cinacalcet. These data suggest evocalcet may contribute to better adherence and sufficient dose escalation in patients with SHPT. Whether or not evocalcet improves clinical outcomes remains to be elucidated.

The Efficacy of the Comprehensive Use of Naphthalan and Non-Selective Chromotherapy in the Treatment of Patients with Gonarthrosis.

In the last decade, a new direction of phototherapy - the non-selective chromotherapy (NSC) with Bioptron - has become widespread in clinical physiotherapy. The aim of the study was the scientific justification of the comprehensive treatment of patients with osteoarthritis of knee joints, including the combined use of refined naphthalan applications and irradiation with incoherent polarized Bioptron light. The article presents the results of the study which investigated the efficacy of the comprehensive treatment of osteoarthritis of knee joints in patients using the combined exposure to naphthalan applications with irradiation using the non-selective Bioptron chromotherapy in the sanatorium. 64 patients aged 40-69 years with stage 1-3 knee osteoarthritis were examined and treated. It was shown that the combined use of naphthalan and non-selective chromotherapy in patients with gonarthrosis reduces pain, improves the functional state of the affected knee joints and improves the quality of life of patients in the absence of adverse effects. A comparative analysis of the study results showed that the efficacy of the combined use of naphthalan and non-selective chromotherapy is superior to the isolated effect of naphthalan.

Naphthalene-triazolopyrimidine hybrid compounds as potential multifunctional anti-Alzheimer's agents.

In an attempt to construct potential anti-Alzheimer's agents Naphthalene-triazolopyrimidine hybrids were synthesized and screened in vitro against the two cholinesterases (ChE)s, amyloid ß aggregation and for antioxidation activity. Single-crystal X-ray crystallography was utilized for crystal structure determination of one of the compounds. In vitro study of compounds revealed that most of the compounds are capable of inhibiting acetylcholinesterase and Butyrylcholinesterase activity. Particularly, the compounds 4e and 4d exhibited IC50 values ranging from 8.6 to 14 nM against AChE lower than the standard drug Donepezil (IC50 49 nM). Best result was found for compound 4e with IC50 of 8.6 nM (for AChE) and 150 nM (for BuChE). Selectivity upto that of Donepezil and even more was observed for 4a, 4c and 4h. Investigation by electron microscopy, transmission electron microscopy and ThT fluorescence assay unveils the fact that synthesized hybrids exhibit amyloid ß self-aggregation inhibition. The compounds 4i and 4j revealed highest inhibitory potential, 85.46% and 72.77% at 50 µM respectively; above the standard Aß disaggregating agent, Curcumin. Their antioxidation profile was also analyzed. Studies from DPPH free radical scavenging assay and ORAC assay depicts molecules to possess low antioxidation profile. Results suggest that triazolopyrimidines are potential candidate for Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), and amyloid ß aggregation inhibition. In silico ADMET profiling indicates drug-like properties with a very low toxic influence. Such synthesized compounds provide a strong vision for further development of potential anti-Alzheimer's agents.

Behavioral effects of chronic WIN 55,212-2 administration during adolescence and adulthood in mice.

Marijuana, a psychoactive drug that activates cannabinoid-1 (CB1) receptors in the brain, is the most prevalently abused illicit drug among American adolescents and young adults. However, the long-term consequences of adolescent exposure to cannabinoids on the brain and behavior remain poorly understood. In both humans and nonhumans, adolescence is characterized by the maturation of the endocannabinoid neurotransmitter system in the prefrontal cortex and striatum-brain regions that underlie choice and decision making and are densely packed with CB1 receptors. In the current study, the effects of chronic WIN 55,212-2 (a CB1 agonist) exposure during adolescence on reversal learning and delay discounting were compared with those of adult-onset exposure using mice. Mice were administered 3.0 mg/kg/day WIN 55,212-2 or vehicle for 21 days beginning in adolescence (postnatal days 28-49) or adulthood (postnatal days 90-111). For the reversal-learning task, there was no difference in errors or omissions to criterion following a reversal in adolescent-exposed mice but adult-exposed mice showed a delay in beginning the reversal, suggesting that adolescents, but not adults, are resilient to this drug. Adult mice given WIN 55,212-2 in adolescence displayed greater impulsivity in the form of preference for smaller-sooner reinforcers over larger-delayed ones in the delay-discounting procedure, but this was seen to a lesser extent with adult-onset exposure. These data underscore the importance of variables related to the timing and duration of exposure as well as the specific and persistent behavioral endpoints affected by chronic cannabinoid administration. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Sigma-2 receptor/TMEM97 agonist PB221 as an alternative drug for brain tumor.

BACKGROUND: There are limited effective drugs that can reach the brain to target brain tumors, in particular glioblastoma, which is one of the most difficult cancers to be cured from. Because the overexpression of the sigma-2 receptor is frequently reported in glioma clinical samples and associated with poor prognosis and malignancy, we herein studied the anti-tumor effect of the sigma-2 receptor agonist PB221 (4-cyclohexyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperidine) on an anaplastic astrocytoma tumor model based on previous encouraging results in pancreatic cancer and neuroblastoma SK-N-SH cells. METHODS: The expression of the sigma-2 receptor, transmembrane protein 97 (TMEM97), in ALTS1C1 and UN-KC6141 cell lines was measured by RT-PCR and quantitative RT-PCR. The binding of sigma-2 receptor fluorescent ligands PB385 (6-[5-[3-(4-cyclohexylpiperazin-1-yl)propyl]-5,6,7,8-tetrahydronaphthalen-5-yloxy]-N-(7-nitro-2,1,3-benzoxadiazol-4-yl)hexanamine) and NO1 (2-{6-[2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one-5-yloxy]hexyl}-5-(dimethylamino)isoindoline-1,3-dione) was examined by flow cytometry and the fluorescent plate reader. The antitumor activity of PB221 was initially examined in the murine brain tumor cell line ALTS1C1 and then in the murine pancreatic cell line UN-KC6141. The potential therapeutic efficacy of PB221 for murine brain tumors was examined by in vitro migration and invasion assays and in vivo ectopic and orthotopic ALTS1C1 tumor models. RESULTS: The IC50 of PB221 for ALTS1C1 and UN-KC6141 cell lines was 10.61 ± 0.96 and 13.13 ± 1.15 µM, respectively. A low dose of PB221 (1 µM) significantly repressed the migration and invasion of ALTS1C1 cells, and a high dose of PB221 (20 µM) resulted in the apoptotic cell death of ALTS1C1 cells. These effects were reduced by the lipid antioxidant α-tocopherol, but not by the hydrophilic N-acetylcysteine, suggesting mitochondrial oxidative stress is involved. The in vivo study revealed that PB221 effectively retarded tumor growth to 36% of the control tumor volume in the ectopic intramuscular tumor model and increased the overall survival time by 20% (from 26 to 31 days) in the orthotopic intracerebral tumor model. CONCLUSIONS: This study demonstrates that the sigma-2 receptor agonist PB221 has the potential to be an alternative chemotherapeutic drug for brain tumors with comparable side effects as the current standard-of-care drug, temozolomide.

Design, synthesis, and antibacterial evaluation of novel derivatives of NPS-2143 for the treatment of methicillin-resistant S. aureus (MRSA) infection.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a significant global health challenge due to the emergence of strains exhibiting resistance to nearly all classes of antibiotics. This necessitates the rapid development of novel antimicrobials to circumvent this critical problem. Screening of compounds based on phenotypes is one of the major strategies for finding new antibiotics at present. Hence, we here performed a phenotypic screening against MRSA and identified NPS-2143 exhibiting activity against MRSA with an MIC value of 16 µg ml-1. In order to discover more potent anti-MRSA agents, a series of derivatives of NPS-2143 were designed and synthesized. The most promising compounds 48 and 49 exhibited favorable antimicrobial activity with an MIC value of 2 µg ml-1.

Inhibition of lipid droplet formation by Ser/Thr protein phosphatase PPM1D inhibitor, SL-176.

Obesity is a worldwide public health problem, which is associated with various severe diseases including diabetes, hypertension, atherosclerosis, and cancer. Recent studies have revealed that combination treatment of several different compounds using low doses is effective to reduce side effects. Thus, there is a need to develop an efficient inhibitor for reducing lipid droplets with a divergent target/pathway. Ser/Thr protein phosphatase PPM1D is involved in cellular metabolic processes and is a promising target for anti-obesity treatment. We have previously developed a potent and specific PPM1D inhibitor, SL-176. In this study, we demonstrated that significant reduction of lipid droplet formation in adipocytes by the PPM1D specific inhibitor, SL-176. Using Oil-red O staining and fluorescent imaging of lipid droplet, we found that treatment of SL-176 significantly suppressed lipid droplet formation of 3T3-L1 cells both in amount and in size. SL-176 also repressed mRNA and protein expression of PPARγ and C/EBPα, adipogenic markers, at nontoxic conditions. Thus, SL-176 is a unique and potent inhibitor of lipid droplet formation that acts via PPM1D, a novel target toward inhibiting adipocyte differentiation.

New 4-methoxy-naphthalene derivatives as promisor antifungal agents for paracoccidioidomycosis treatment.

AIM: Novel 4-methoxy-naphthalene derivatives were synthesized based on hits structures in order to evaluate the antifungal activity against Paracoccidioides spp. METHODS: Antifungal activity of compounds was evaluated against P. brasiliensis and most promising compounds 2 and 3 were tested against eight clinically important fungal species. RESULTS: Compound 3 was the more active compound with MIC 8 to 32 µg.ml-1 for Paracoccidioides spp without toxicity monkey kidney and murine macrophagecells. Carbohydrazide 3 showed good synergistic antifungal activity with amphotericin B against P. brasiliensis specie. Titration assay of carbohydrazide 3 with PbHSD enzyme demonstrates the binding ligand-protein. Molecular dynamics simulations show that ligand 3 let the PbHSD protein more stable. CONCLUSION: New carbohydrazide 3 is an attractive lead for drug development to treat paracoccidioidomycoses.

Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common condition in ageing men that may cause lower urinary tract symptoms (LUTS). Treatment aims are to relieve symptoms and prevent disease-related complications. Naftopidil is an alpha-blocker (AB) that has a high affinity for the A1d receptor that may have advantages in treating LUTS in this setting. This is an update of a Cochrane Review first published in 2009. Since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant. OBJECTIVES: To evaluate the effects of naftopidil for the treatment of LUTS associated with BPH. SEARCH METHODS: We performed a comprehensive search using multiple databases (the Cochrane Library, MEDLINE, Embase, Scopus, LILAC, and Web of Science), trials registries, other sources of grey literature, and conference proceedings with no restrictions on the language of publication or publication status up to 31 May 2018 SELECTION CRITERIA: We included all parallel RCTs. We also included cross-over design trials. DATA COLLECTION AND ANALYSIS: Two review authors independently classified and abstracted data from the included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. Primary outcomes were urological symptom scores, quality of life (QoL) and treatment withdrawals for any reason; secondary outcomes were treatment withdrawals due to adverse events, acute urinary retention, surgical intervention for BPH, and cardiovascular and sexual adverse events. We considered outcomes measured up to 12 months after randomisation as short term, and later than 12 months as long term. We rated the certainty of the evidence according to the GRADE approach. MAIN RESULTS: We included 22 RCTs with 2223 randomised participants across four comparisons for short-term follow-up. This abstract focuses on only two of four comparisons for which we found data since two comparators (i.e. propiverine and Eviprostat (phytotherapy)) are rarely used. One study comparing naftopidil to placebo did not report any relevant outcomes and was therefore excluded. There were no trials that compared to combination therapy with naftopidil or any 5-alpha reductase inhibitors (5-ARIs) to combination therapy with other ABs and any 5-ARIs.All included studies were conducted in Asian countries. Study duration ranged from four to 12 weeks. Mean age was 67.8 years, prostate volume was 35.4 mL, and International Prostate Symptom Score was 18.3. We were unable to perform any of the preplanned subgroup analyses based on age and baseline symptom score.Naftopidil versus tamsulosinBased on 12 studies with 965 randomised participants, naftopidil may have resulted in little or no difference in urological symptom score (mean difference (MD) 0.47, 95% confidence interval (CI) -0.09 to 1.04 measured on a scale from 0 to 35 with higher score representing increased symptoms), QoL (MD 0.11, 95% CI -0.09 to 0.30; measured on a scale from 0 to 6 with higher scores representing worse QoL), and treatment withdrawals for any reason (risk ratio (RR) 0.92, 95% CI 0.64 to 1.34; corresponding to 7 fewer per 1000 participants, 95% CI 32 fewer to 31 more). Naftopidil may have resulted in little to no difference in sexual adverse events (RR 0.54, 95% CI 0.24 to 1.22); this would result in 26 fewer sexual adverse events per 1000 participants (95% CI 43 fewer to 13 more). We rated the certainty of evidence as moderate for urological symptom score and low for the other outcomes.Naftopidil versus silodosinBased on five studies with 652 randomised participants, naftopidil may have resulted in little or no difference in the urological symptom scores (MD 1.04, 95% CI -0.78 to 2.85), QoL (MD 0.21, 95% CI -0.23 to 0.66), and treatment withdrawals for any reason (RR 0.80, 95% CI 0.52 to 1.23; corresponding to 26 fewer per 1000 participants, 95% CI 62 fewer to 32 more). We rated the certainty of evidence as low for all these outcomes. Naftopidil likely reduced sexual adverse events (RR 0.15, 95% CI 0.06 to 0.42; corresponding to 126 fewer sexual adverse events per 1000 participants, 95% CI 139 fewer to 86 fewer). We rated the certainty of evidence as moderate for sexual adverse events. AUTHORS' CONCLUSIONS: Naftopidil appears to have similar effects in the urological symptom scores and QoL compared to tamsulosin and silodosin. Naftopidil has similar sexual adverse events compared to tamsulosin but has fewer compared to silodosin.