Search

Purpose: To determine the effectiveness, risk factors for surgical failure, and adverse events in a large cohort of patients receiving stand-alone ab externo poly(styrene-block-isobutylene-block-styrene) (SIBS) microshunt implantation with mitomycin C (MMC) over 3 years of follow-up., Design: Retrospective, interventional case series., Participants: Glaucomatous eyes on maximally tolerated medical therapy with no previous subconjunctival glaucoma surgery., Methods: Records of eyes that underwent ab externo SIBS microshunt with MMC between July 2015 and November 2017 were reviewed. Data from all follow-up visits were utilized and included intraocular pressure (IOP), medication use, postoperative interventions, complications, and reoperations., Main Outcome Measures: The primary outcome was proportion of eyes at 3 years with (1) no 2 consecutive IOPs > 17 mmHg (or < 6 mmHg with > 2 lines of vision loss from baseline); (2) ≥ 20% reduction from baseline IOP; and (3) using no glaucoma medications (complete success). Secondary outcomes included 14 and 21 mmHg upper IOP thresholds with and without ≥ 20% IOP reduction from baseline, qualified success (with glaucoma medications), risk factors for failure, median IOP/medications, postoperative interventions, complications, and reoperations., Results: One hundred fifty-two eyes from 135 patients were included. Complete and qualified success was achieved in 55.6% and 74.8% of eyes, respectively. Time to first glaucoma medication use was a median of 16.9 (interquartile range [IQR], 12.1-34.1) months; however, 59.4% of eyes remained medication free at 3 years. Significant risk factors for failure included receiving < 0.4 mg/ml of MMC (adjusted hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.44-4.05) and baseline IOP < 21 mmHg (adjusted HR, 1.79; 95% CI, 1.03-3.13). The most common complications were choroidal detachment, hyphema, and anterior chamber shallowing, occurring in 7%, 5%, and 5% of eyes, respectively. The needling rate was 15.1%, with significantly higher frequency for baseline IOP > 21 mmHg (HR, 3.21; 95% CI, 1.38-7.48). Revisions occurred in 7% of eyes and reoperations in 2.6%. Eyes receiving < 0.4 mg/ml of MMC underwent more revisions (odds ratio, 4.9; 95% CI, 1.3-18.3)., Conclusions: Three-year follow-up data from this large cohort continues to support promising rates of qualified and complete success, with decreased medication burden postoperatively and few postoperative complications and interventions. Comparisons to other filtering surgeries will further facilitate integration of the SIBS microshunt into the surgical treatment paradigm., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Arthritis, a primary autoimmune disorder having a global incidence of 2.03% person/year, is presently being treated by many commercially available drugs that treat symptomatically or improve the disease's clinical state; however, all the therapies pose varying amount of side effects. Therefore, it has become a fundamental need to search for therapeutics that offer better efficacy and safety profile, and the natural or nature-derived products are known for their outstanding performance in this arena. OA-DHZ, known to possess anti-inflammatory and analgesic properties, when explored for its efficacy against arthritis in adjuvant-induced arthritis (AIA) model, was found to inhibit paw edema by 34% and TNF-α, IL-6, and IL-1β by 67%, 39%, and 45% respectively when compared to diseased control. It was also able to reduce the inflamed spleen size by 45% and successfully normalized biochemical and hematological changes that followed arthritis. In vitro studies revealed that the underlying mechanism for inhibiting arthritis progression might be due to NF-κB /MAPK pathway modulation. OA-DHZ also showed selective inhibition of COX-2 in vitro while showing gastroprotective effects when evaluated for ulcerogenic and antiulcer potential in vivo. In contrast to the results obtained from in vivo experimentation, there is a disparity in the pharmacokinetic profile of OA-DHZ, where it showed low oral exposure and high clearance rate. OA-DHZ being antiarthritic acting via NF-κB /MAPK/ COX inhibition while showing gastroprotective effects, can be a suitable candidate to be in the drug pipeline and further exploration., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite various advances in the arena of the current system of medicine, there are numerous side effects associated with the therapeutics which essentially demand research on the development of safer therapeutics. One way is to explore the bioactive plant secondary metabolites and their semisynthetic derivatives. In context to this, we analyzed OA-DHZ, a dehydrozingerone derivative as the later has been reported to show anti-inflammatory and analgesic properties. OA-DHZ was found to be having promising anti-inflammatory and analgesic potential. OA-DHZ was found to inhibit the carrageenan-induced edema and leukocyte migration, acetic acid-induced increase in vascular permeability and lipopolysaccharide-induced pro-inflammatory cytokines like TNF-α, IL-6, and IL-1β. Meanwhile, it was also found to potentially inhibit thermally as well as chemically induced pain signifying its analgesic/nociceptive potential. Further, safety pharmacology studies using in vivo animal models for the central nervous system, gastrointestinal tract, the cardio-respiratory system suggest that optimum functioning of vital organ systems does not get altered after single oral administration. Also, the acute toxicity study revealed its nontoxic nature up to 2000 mg/kg. This study paves the way for future exploration and development of OA-DHZ based on its potent activity and nontoxic nature., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans -1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis / trans isomers that can discriminate between structurally related enzyme isoforms.

The present study investigated a possible antidepressant-like effect of ((4-tert-butylcyclohexylidene)methyl) (4-methoxystyryl) sulfide (BMMS) by using the forced swimming test (FST) and the tail suspension test (TST) in Swiss mice. The contribution of serotoninergic, glutamatergic and nitrergic systems in the antidepressant-like activity of BMMS was evaluated. We also examined the involvement of monoamine oxidase (MAO)-A, MAO-B and Na + , K + -ATPase activities in prefrontal cortex of mice. BMMS, (0.1-10 mg/kg, intragastrically (i.g.)) and fluoxetine (32 mg/kg, i.g.) decreased the immobility time in the FST and TST. The anti-immobility effect of BMMS (10 mg/kg, i.g.) in the TST was prevented by the pretreatment of mice with WAY100635 (0.1 mg/kg, subcutaneously (s.c.), a 5-HT 1A receptor antagonist), ketanserin (5 mg/kg, intraperitoneal (i.p.), a 5-HT 2A/2C receptor antagonist), and partially blocked by ondansetron (1 mg/kg, i.p., a 5-HT 3 receptor antagonist). The anti-immobility effect of BMMS (10 mg / kg, i.g.) was not avoided by pretreatment with MK-801 (0.01 mg/kg, s.c. a non-competitive N-methyl D-Aspartate (NMDA) receptor) in the TST. Pretreatment with L-arginine (500 mg/kg, i.p., a nitric oxide precursor) reversed partially the reduction in the immobility time elicited by BMMS (10 mg/kg, i.g.) in TST. BMMS altered Na + ,K + -ATPase and MAO-A activities in prefrontal cortex of mice, but was not able to change the MAO-B activity. In conclusion, BMMS exerted an antidepressant-like effect in mice and serotonergic and nitrergic systems are involved in the antidepressant-like action of compound. BMMS modulated MAO-A and Na + , K + - ATPase activities in prefrontal cortex of mice.

Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG‑3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro‑apoptotic effects of the compounds were found to be reactive oxygen species and caspase‑dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3‑kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co‑cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.

Drugs against malaria are losing their effectiveness because of emerging drug resistance. This underscores the need for novel therapeutic options for malaria with mechanism of actions distinct from current antimalarials. To identify novel pharmacophores against malaria we have screened compounds containing structural features of natural products that are pharmacologically relevant. This screening has identified a 4-nitro styrylquinoline (SQ) compound with submicromolar antiplasmodial activity and excellent selectivity. SQ exhibits a cellular action distinct from current antimalarials, acting early on malaria parasite's intraerythrocytic life cycle including merozoite invasion. The compound is a fast-acting parasitocidal agent and also exhibits curative property in the rodent malaria model when administered orally. In this report, we describe the synthesis, preliminary structure-function analysis, and the parasite developmental stage specific action of the SQ scaffold., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Acne is a prominent skin condition affecting >80% of teenagers and young adults and ~650 million people globally. Isotretinoin, a vitamin A derivative, is currently the standard of care for treatment. However, it has a well-established teratogenic activity, a reason for the development of novel and low-risk treatment options for acne., Objective: To investigate the effectiveness of Zolav(®), (a p-carboethoxy-tristyrylbenzene derivative) [corrected] a novel antibiotic as a treatment for acne vulgaris., Materials and Methods: Minimum inhibitory concentration of Zolav(®) (a p-carboethoxy-tristyrylbenzene derivative) against Propionibacterium acnes was determined by following a standard protocol using Mueller-Hinton broth and serial dilutions in a 96-well plate. Cytotoxicity effects on human umbilical vein endothelial cells and lung cells in the presence of Zolav(®) (a p-carboethoxy-tristyrylbenzene derivative) were investigated by determining the growth inhibition (GI50) concentration, total growth inhibition concentration, and the lethal concentration of 50% (LC50). The tryptophan auxotrophic mutant of Escherichia coli strain, WP2 uvrA (ATCC 49979), was used for the AMES assay with the addition of Zolav(®) (a p-carboethoxy-tristyrylbenzene derivative) tested for its ability to reverse the mutation and induce bacterial growth. The in vivo effectiveness of Zolav(®) (a p-carboethoxy-tristyrylbenzene derivative) was tested in a P. acnes mouse intradermal model where the skin at the infection site was removed, homogenized, and subjected to colony-forming unit (CFU) counts., Results: Susceptibility testing of Zolav(®) (a p-carboethoxy-tristyrylbenzene derivative) against P. acnes showed a minimum inhibitory concentration of 2 µg/mL against three strains with no cytotoxicity and no mutagenicity observed at the highest concentrations tested, 30 µM and 1,500 µg/plate, respectively. The use of Zolav(®) (a p-carboethoxy-tristyrylbenzene derivative) at a concentration of 50 µg/mL (q8h) elicited a two-log difference in CFU/g between the treatment group and the control., Conclusion: This study demonstrates the potential of Zolav(®) (a p-carboethoxy-tristyrylbenzene derivative) as a novel treatment for acne vulgaris.

Atherosclerosis is characterized by endothelial dysfunction, mainly induced by inflammation and oxidative stress. Increased reactive oxygen species (ROS) production together with increased adhesion molecules and thrombogenic tissue factor (TF) expression on endothelial cells has a key role in proatherogenic mechanisms. Therefore downmodulation of these molecules could be useful for reducing the severity of inflammation and atherosclerosis progression. Dehydrozingerone (DHZ) is a nutraceutical compound with anti-inflammatory and antioxidant activities. In this study we evaluated the ability of DHZ and its symmetric dimer to modulate hydrogen peroxide- (H 2 O 2 -) induced ROS production in human umbilical vein endothelial cells (HUVEC). We also evaluated intercellular adhesion molecule- (ICAM-) 1, vascular cell adhesion molecule- (VCAM-) 1, and TF expression in HUVEC activated by tumor necrosis factor- (TNF-) α . HUVEC pretreatment with DHZ and DHZ dimer reduced H 2 O 2 -induced ROS production and inhibited adhesion molecule expression and secretion. Of note, only DHZ dimer was able to reduce TF expression. DHZ effects were in part mediated by the inhibition of the nuclear factor- (NF-) κ B activation. Overall, our findings demonstrate that the DHZ dimer exerts a potent anti-inflammatory, antioxidant, and antithrombotic activity on endothelial cells and suggest potential usefulness of this compound to contrast the pathogenic mechanisms involved in atherosclerosis progression., Competing Interests: The authors declare that there are no competing interests in this study.

Aims: The interactions between cancer cells and platelets have been recognized to play an important role in cancer progress as well as metastasis, and interference with cancer-platelet interactions is an attractive strategy for cancer therapy. In the present study, two β-nitrostyrene derivatives: 3, 4-methylene-dioxy-β-nitrostyrene (MNS) and 4-O-benzoyl-3-methoxyl-β-nitrostyrene (BMNS) have been tested for their inhibitory effect on platelet activation caused by metastatic human breast cancer MDA-MB-231 and Hs578T cells., Main Methods: Washed human platelets were co-incubated with breast cancer cells, and platelet aggregation was determined turbidimetrically. Platelet adhesion to cancer cells and P-selectin expression were measured by flow cytometry. Platelet-derived growth factor (PDGF) released from cancer cell-stimulated platelets was determined by enzyme-linked immunosorbent assay (ELISA)., Key Findings: MNS and BMNS prevented cancer cell-induced platelet aggregation, P-selectin expression, and PDGF secretion. Moreover, the β-nitrostyrenes reduced platelet adhesion to cancer cells, suggesting the initial cancer-platelet interactions are inhibited. In contrast to current antiplatelet strategies, the glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist RGDS peptide only prevented cancer cells-induced platelet aggregation, but not platelet adhesion and secretion; whereas the cyclooxygenase inhibitor aspirin and the adenosine diphosphate (ADP) scavenger apyrase affected neither platelet aggregation nor platelet secretion., Significance: The inhibitory effects of the β-nitrostyrene derivatives on cancer-platelet interactions may offer a potential approach for repressing cancer metastasis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Fifty two compounds based on 5-nitropyrimidine-2,4-dione moiety have been synthesized and evaluated for their inhibitory potency on the production of nitric oxide. Among them, compound 36 inhibited the production of nitric oxide (IC50 : 8.6 μm) on lipopolysaccharide-induced RAW 264.7 cells and inducible nitric oxide synthase activity (IC50 : 6.2 μm), as well as exerted no potential cytotoxicity (IC50 > 80.0 μm). Docking study confirmed that compound 36 was an inducible nitric oxide synthase inhibitor with perfect binding to the active site of inducible nitric oxide synthase. At a dose of 10 mg/kg, oral administration of 36 possessed protective properties in carrageenan-induced paw edema of male ICR mice., (© 2014 John Wiley & Sons A/S.)

Dehydrozingerone (DHZ) is a phenolic compound isolated from ginger rhizomes (Zingiber officinale). It is known for its diverse spectrum of biological activities as an antioxidant, anti-inflammatory and antitumor compound. The present study was designed to assess the antidepressant effect of DHZ and the involvement of the monoaminergic system and to evaluate its in vitro antioxidant activity in the hippocampus, cortex and cerebellum of mice. For this study, the tail suspension test (TST), forced swim test (FST) and yohimbine lethality test were performed. DHZ administered orally 30min prior to testing reduced the immobility time in the TST (1-40mg/kg) and the FST (10-40mg/kg), with no change in locomotor activity in the open field test. The antidepressant-like effect of DHZ (1mg/kg) was prevented by ketanserin (1mg/kg, i.p.; a 5-HT2A/2C receptor antagonist), ondansetron (1mg/kg, i.p.; a 5-HT3 receptor antagonist), prazosin (1mg/kg, i.p., an α1-adrenoceptor antagonist) and yohimbine (1mg/kg, i.p., an α2-adrenoceptor antagonist) pretreatments. Furthermore, DHZ administered at doses of 10 and 20mg/kg increased the lethality of yohimbine (35mg/kg, i.p.). DHZ had antioxidant activity on in vitro lipid peroxidation induced by sodium nitroprusside in all brain regions tested. The results revealed that DHZ has a potent antidepressant effect, which seems to involve the serotonergic and noradrenergic systems., (Copyright © 2014. Published by Elsevier Inc.)

Hydrophobic thermoplastic elastomers, e.g., poly(styrene-b-isobutylene-b-styrene) (SIBS), have found various in vivo biomedical applications. It has long been recognized that biomaterials can be adversely affected by bacterial contamination and clinical infection. However, inhibiting bacterial colonization while simultaneously preserving or enhancing tissue-cell/material interactions is a great challenge. Herein, SIBS substrates were functionalized with nucleases under mild conditions, through polycarboxylate grafts as intermediate. It was demonstrated that the nuclease-modified SIBS could effectively prevent bacterial adhesion and biofilm formation. Cell adhesion assays confirmed that nuclease coatings generally had no negative effects on L929 cell adhesion, compared with the virgin SIBS reference. Therefore, the as-reported nuclease coating may present a promising approach to inhibit bacterial infection, while preserving tissue-cell integration on polymeric biomaterials.

Alzheimer's disease (AD) is the most common age related human neurodegenerative disorder. The major histopathological characteristics of the AD brain are extracellular amyloid-beta (Aβ) peptide loaded plaques and intraneuronal neurofibrillary tangles made of phosphorylated tau proteins. Amyloid plaques consist primarily of aggregated Aβ1-42 and Aβ1-40 peptides. The aim of our current study was to test novel ligands/agents with the potential to disrupt or inhibit the aggregation of Aβ peptide, specifically K114, (trans,trans)-1-bromo-2,5-bis(4-hydroxystyryl)benzene, which was initially developed as a potential positron emission tomography (PET) ligand for the in vivo detection of amyloid plaques. Systemic administration of K114 has been shown in the AD/transgenic (Tg) mouse model to be capable of crossing the blood-brain barrier (BBB) and be colocalized with amyloid plaques. In this study we determined whether K114 has the potential to inhibit Aβ aggregation in vitro in AD/Tg mice and also tested, in vivo, whether chronic daily orally administered K114 has any therapeutic potential as evidenced by inhibition or reduction of the deposits of amyloid aggregates in the brains of AD/Tg mice. Our results demonstrated that K114 strongly blocked, in vitro, the aggregation of Aβ peptide in the amyloid plaques of AD/Tg mouse brain. Systemic treatment with K114 was also effective in significantly reducing the deposits of amyloid plaques in the brains of living transgenic AD mice. Additionally, K114 significantly inhibited the typically observed plaque associated astrocytic activation, as revealed by GFAP immunohistochemistry, suggesting possible anti-inflammatory properties.

Background & Aims: Copolymers of hydroxyethyl methacrylate and styrene sulfonate complex with isolated gliadin (the toxic fraction of gluten) and prevent damage to the intestinal barrier in HLA-HCD4/DQ8 mice. We studied the activity toward gluten and hordein digestion and biologic effects of poly(hydroxyethyl methacrylate-co-styrene sulfonate (P(HEMA-co-SS)). We also investigated the effect of gliadin complex formation in intestinal biopsy specimens from patients with celiac disease., Methods: We studied the ability of P(HEMA-co-SS) to reduce digestion of wheat gluten and barley hordein into immunotoxic peptides using liquid chromatography-mass spectrometry. The biodistribution and pharmacokinetic profile of orally administered P(HEMA-co-SS) was established in rodents using tritium-labeled polymer. We assessed the capacity of P(HEMA-co-SS) to prevent the immunologic and intestinal effects induced by a gluten-food mixture in gluten-sensitized HLA-HCD4/DQ8 mice after short-term and long-term administration. We measured the effects of gliadin complex formation on cytokine release ex vivo using intestinal biopsy specimens from patients with celiac disease., Results: P(HEMA-co-SS) reduced digestion of wheat gluten and barley hordein in vitro, thereby decreasing formation of toxic peptides associated with celiac disease. After oral administration to rodents, P(HEMA-co-SS) was predominantly excreted in feces, even in the presence of low-grade mucosal inflammation and increased intestinal permeability. In gluten-sensitized mice, P(HEMA-co-SS) reduced paracellular permeability, normalized anti-gliadin immunoglobulin A in intestinal washes, and modulated the systemic immune response to gluten in a food mixture. Furthermore, incubation of P(HEMA-co-SS) with mucosal biopsy specimens from patients with celiac disease showed that secretion of tumor necrosis factor-α was reduced in the presence of partially digested gliadin., Conclusions: The copolymer P(HEMA-co-SS) reduced digestion of wheat gluten and barley hordein and attenuated the immune response to gluten in a food mixture in rodents. It might be developed to prevent or reduce gluten-induced disorders in humans., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented., (2010 Elsevier Ltd. All rights reserved.)

The search for small molecules that preferentially target the functionally important surfaces of estrogen receptor and disrupt the transcriptional activity in the cell has emerged as a promising area towards rationale based drug design. Herein, we report substituted styryl chromones as a new class of compounds that exhibit selectivity for ERbeta binding at the second binding site of HT and antiproliferative activity in human breast cancer cell line., (2010 Elsevier Ltd. All rights reserved.)

Human noroviruses (NoV) are now recognized as the most frequent cause of outbreaks and sporadic cases of acute gastroenteritis. Despite the significant economic impact and considerable morbidity of norovirus disease, no drug or vaccine is currently available to treat or prevent this disease, therefore the discovery of anti-norovirus drugs is urgent. In the present work, a total of 12 structure related chromone and (E)-2-styrylchromones were evaluated for their potential anti-norovirus activity using the murine norovirus (MNV) as a surrogate model for human NoV. From the 12 compounds studied, six (E)-2-styrylchromones were found to have with interesting anti-norovirus activity. The best compounds of the series were (E)-5-hydroxy-2-styrylchromone and (E)-4'-methoxy-2-styrylchromone with an IC(50) approximately 7muM. A first insight into the mechanism of action of these compounds was possible. An interesting relationship between the anti-norovirus activity and the chemical structure was observed. The present study points out that the (E)-2-styrylchromones skeleton is an important one which deserves to be developed and further explored as new antiviral drugs against NoV., (Copyright 2010 Elsevier Ltd. All rights reserved.)

We synthesized new chemical compounds to detect amyloid fibrils named (trans, trans) -1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy) styrylbenzene (BSB) and 1-fluoro-2,5-bis (3-carboxy-4-hydroxystyryl) benzene (FSB). We used these compounds to detect amyloid fibrils in autopsy and biopsy samples from patients with systemic amyloidosis, such as familial amyloidotic polyneuropathy, amyloid A (AA) amyloidosis, light chain (AL) amyloidosis, and dialysis-related amyloidosis, and localized amyloidosis, such as familial prion disease (Gerstmann-Straussler-Scheimker syndrome: GSS). BSB showed reactions in all Congo red positive and immunoreactive regions of the samples examined in the study, and some amyloid fibrils in the tissues could be detected more precisely with BSB and FSB than with the other methods. In the mouse model of AA amyloidosis, injected BSB reacted with amyloid in all regions in the serial sections in which Congo red staining was positive. A highly sensitive 27-MHz quartz crystal microbalance analysis revealed that BSB showed a significant affinity for amyloid fibrils purified from familial amyloidotic polyneuropathy and dialysis-related amyloidosis samples and suppressed formation of transthyretin amyloid in vitro. These results suggest that BSB and FSB may become valuable tools for detection of amyloid deposits in amyloidosis and of the mechanism of amyloid formation.

Disalicylic acid derivatives with stilbene and bis-styrylbenzene skeleton were synthesized as PTP1B inhibitors. The most potent in this series exhibited a submicromolar IC(50) value. One of the compounds 7b was tested in an animal model for its efficacy as an anti-diabetic or an anti-obesity agent. In feeding compound 7b to diet-induced obese mice, no significant differences in weight gain and food consumption were observed between the drug-treated and the obese control mice. However, 7b significantly lowered the fasting glucose level and improved the glucose tolerance in the obesity-induced diabetic mice.

As the world's population continues to soar, contraception has become increasingly important. Recently, men have expressed willingness to share the burden of family planning. Thus, safe, effective and reversible male contraceptives would satisfy an urgent need among couples. Currently, there are several promising non-hormonal contraceptives at various stages of research and development. In addition, major advances in genomic and proteomic research have been instrumental in identifying and characterizing genes and proteins expressed uniquely in the testis or other male reproductive organs, which might become 'druggable' targets for non-hormonal male contraceptive development in the future. Through committed research, advocacy and support, male contraceptives are likely to become a valuable addition to the current choices of family planning.

Liver transplantation has been considered as a promising therapy to halt the progression of clinical symptoms in familial amyloidotic polyneuropathy (FAP) because most transthyretin (TTR) is produced by the liver. In addition, domino liver transplantation using an FAP patient's liver has been performed because of a shortage of donor livers. However, because the use of liver transplantation as therapy for FAP has given rise to several problems, an alternative treatment is needed. We have tried several other approaches. Recent studies suggested that certain metal ions affect amyloidogenesis. Among metal ions tested in an in vitro amyloid formation study, Cr3+ increased stability of both normal and mutant TTR tetramers and suppressed TTR amyloidogenesis induced by low pH. Our findings indicate that Cr3+ acts to suppress TTR amyloidogenesis. BSB, a Congo red derivative that binds to amyloid fibrils in FAP as well as to those in senile plaques in Alzheimer's disease, effectively suppressed TTR amyloid formation in vitro. BSB may thus be useful for preventing amyloid formation. Free radical scavenger therapy was also tried in FAP patients but yielded no conclusive results. Immunization for transgenic mice having the ATTR V30M gene using ATTR Y78P resulted in suppression of amyloid deposits. Finally, an RNA/DNA chimera and single-stranded oligonucleotides (SSOs) were tested in vitro and in vivo in an attempt to repair the amyloidogenic TTR gene in the liver and retina. On the basis of results achieved so far, SSO is a promising tool for gene therapy.

Extracellular senile plaques (SPs) are hallmark brain lesions of sporadic Alzheimer's disease (AD) and the likely consequence of genetic mutations that cause familial AD by increasing production of amyloidogenic amyloid-beta (Abeta). Although Abeta vaccines and inhibitors of amyloidogenic secretases are potential AD therapies, multifaceted strategies may be needed to effectively interrupt Abeta amyloidosis and prevent/arrest AD. One such strategy is the inhibition of Abeta fibrillization as a potential therapy for AD. Certain amyloid-binding molecules, such as Congo red (CR) and chrysamine G (CG) and Thioflavin S (TS) have been shown to bind SPs with high affinity and they can also arrest the formation of Abeta fibrils; however, CR, CG and TS are unsuitable for AD therapy because they do not cross the blood brain barrier (BBB). Therefore, we have generated novel CG and TS derivatives that specifically recognize fibrillar Abeta in vitro, arrest the formation of Abeta fibrils, and cross the BBB of transgenic (TG) mice that model AD amyloidosis. As proof of their ability to cross the BBB and of their high specificity for Abeta fibrils in vivo, we show that following intravenous injection in TG mice these compounds specifically label AD-like brain deposits of fibrillar Abeta. Furthermore, we demonstrate that CG derivative IMSB binds to SPs comprised of Abeta40 with much higher affinity than Abeta42 whereas TS derivative TDZM shows the opposite affinity. Moreover, IMSB but not TDZM binds selectively to neurofibrillary tangles. Significantly both IMSB and TDZM inhibit Abeta fibrillization in test tubes and in cultured cells. Thus, small amyloid binding molecules such as IMSB and TDZM which cross the BBB are potential therapeutic agents for the treatment of AD.

The activities of artemisinin (QHS) and a number of its semi-synthetic analogues, as well as Fenozan B07 (B07), a synthetic 1,2,4-trioxane, and arteflene (ATF), a synthetic surrogate of yingzhaosu, were compared in mice infected with drug-sensitive Plasmodium berghei or chloroquine-resistant P. yoelii ssp. NS. The studies were stimulated by the observation that B07, in certain aqueous preparations, appears to be equipotent by the subcutaneous (sc) or oral (po) routes in the rodent model but not in a simian model. In the rodent model, B07 was found to undergo rapid alteration (with a half-life of <24h) in an aqueous stock solution prepared using dimethyl sulphoxide (DMSO) to pre-dissolve the drug. Therefore, for all later experiments with aqueous preparations, the test material was newly formulated each day. In a carboxymethylcellulose formulation used as a 'standard suspending vehicle' (SSV), B07 and dihydroartemisinin (DIHYD) were found to be, respectively, one sixth and one 10th as active po as when the drugs were pre-dissolved in DMSO and then diluted with water. ATF in DMSO given po was less than one 20th as active as when used sc in the rodent model, and this drug in SSV was almost inactive po. The relatively low oral activity of these three compounds (especially DIHYD and ATF) may be attributable to extensive first-pass metabolism in the mouse. Oral beta-artemether (AM) and beta-arteether (AE) were highly active when used in SSV. ATF has been found to have low activity in simian models and clinical trials because of its poor absolute bio-availability. In in-vivo studies of the blood schizontocidal action of anti-malarials, in rodent malaria models, the data collected on the structure-activity relationships (SAR) of the drugs must be viewed critically when selecting specific compounds from a chemical series for further development. A study of the influence of drug formulation on the activity of other, novel antimalarials is crucial to the evaluation of the drugs, and merits high priority.

STI571 selectively inhibits the ABL-tyrosine kinase, the activity of which is activated by the formation of chimeric BCR/ABL. A phase I study in the USA showed STI571 to be remarkably effective in cases of interferon-refractory chronic myeloid leukemia, with almost no adverse effects. STI571 may become the first choice drug prior to stem cell transplantation and interferon treatment.

We have investigated the effect of phenolic antioxidants on cisplatin-induced cytotoxicity in vero (African Green Monkey Kidney) cells and in rat renal cortical slices in vitro, and on cisplatin-induced nephrotoxicity in rats in vivo. Incubation of cisplatin with vero cells resulted in time- and concentration-dependent cytotoxicity, as characterized by decreased tryphan blue exclusion (TBE) and increased release of lactate dehydrogenase (LDH) into the medium. Cisplatin also caused reduction of glutathione (GSH) in a concentration-dependent manner. In the rat renal cortical slices model, incubation of cisplatin for 120 min caused an increase in malondialdehyde (MDA), a decrease in GSH and inhibited p-aminohippurate (PAH) uptake in a concentration-dependent manner. Among phenolic antioxidants, isoeugenol (IG) was found to be more active against cisplatin-induced cytotoxicity in vero cells as well as in rat renal cortical slices than eugenol (EG) and dehydrozingerone (DZ). However none of the test compounds were able to arrest the reduction of the GSH content induced by cisplatin in either the vero cells or the renal cortical slice model. Administration of cisplatin (3 mg/kg) i.p. to rats resulted in significant reduction of body weight, and elevation of blood urea nitrogen (BUN) and serum creatinine. Treatment with IG 10 mg/kg i.p. 1 h before cisplatin resulted in partial but significant protection against the cisplatin-induced reduction of body weight, and elevation of BUN and serum creatinine, the protection being 34, 46, and 62%, respectively. EG and DZ (10 mg/kg, i.p.) were found to be inactive in vivo. Because IG is a potent free radical scavenger and protects against cisplatin-induced toxicitiy, the present results have many clinical implications in chemotherapy and thus warrants further investigation.

The reversing action of anthelminthic praziquantel (P) on the effect of chloroquine (C) and compound R-70-Zh (styrylquinazoline) was revealed on a Plasmodium berghei model (white inbred mice), using a LNK65 isolate with naturally reduced sensitivity to chloroquine and its polyresistant line LNK65CHLFR with acquired resistance to chloroquine/fansidar (selected in our laboratory). P (125 mg/kg) in combination with C showed a potentiating effect not only on the LNK65 isolate, but also on the LNK65CHLFR line, while investigated separately on this line, both drugs were not effective in tested doses. Moreover, the similar effect of C on the LNK65CHLFR line was achieved in the dose that was 4 times higher than that of P/C combination. P in a standard dose on the LNK65 isolate showed a more marked activation of compound R-70-Zh that on C. The potentiating effect was manifested in combination with R-70-Zh in the dose half as high as that of C; this phenomenon was also reflected by the efficiency index (5.0 against the 4.0) accepted in our laboratory and may be associated with the higher sensitivity of the LNK65 isolate to R-70-Zh. P showed some antimalarial action which manifested itself only by morphological changes on P. berghei parasites similar to those observed under the action of some dihydropholate reductase inhibitors, such as pyrimethamine.

Arteflene is a synthetic peroxide recently developed from an indication of antimalarial activity found in the Chinese plant Artabotrys uncinatus. The new antimalarial was compared against mefloquine in a phase 3, open-labeled, randomized trial in children with uncomplicated Plasmodium falciparum malaria in Gabon. Patients received single oral doses of either 25 mg/kg of arteflene suspension or 15 mg/kg of mefloquine tablets. High-grade (RII and RIII) resistance was observed in eight (40%) of the 20 patients receiving the single dose of arteflene, but in none of the 21 mefloquine-treated patients (P < 0.005). At day 28, only one patient in the arteflene group, compared with all 21 patients in the mefloquine group, was cured (P < 0.001). Arteflene cleared fever slightly but not significantly faster than mefloquine and the 50% and 90% parasite clearance times were comparable in both treatment groups. In vitro results in the arteflene group suggest an increase of arteflene resistance when comparing sensitivity of paired parasite isolates before treatment and at recrudescence. Both treatment regimens were well-tolerated. In conclusion, single dose monotherapy with arteflene was not effective in curing children suffering from uncomplicated P. falciparum malaria in Gabon, while mefloquine proved to be highly effective for this purpose.

The novel antimalarial Ro 42-1611 (arteflene) was evaluated for safety and efficacy in an open, non-comparative study of patients with mild malaria in the south of Cameroon. Thirty male patients aged 12 to 42 years, with an initial Plasmodium falciparum count of > 5000 (mean: 21,406) parasites/microliters and a body temperature of 37.7% to 39.8 degrees C, were selected to receive a single dose of arteflene, corresponding to 25 +/- 2.5 mg/kg bodyweight. Efficacy was assessed at 6, 9, 12, 24, 36, 48 and 72 hours, and at seven days by: reduction in parasitaemia and time to parasite clearance; resolution of fever and clinical cure (defined as the absence of signs and symptoms of malaria). Adverse events were reported at baseline and at each assessment point, and laboratory tests were carried out at 2 and 7 days. The mean number of parasites/microliter fell from 21,406 at baseline to 157 after 48 hours, at which point 80% of patients were completely free of parasites. Mean body temperature was reduced from 38.9 degrees C at baseline to 37.3 degrees C 12 hours after arteflene administration, and by this time 80% of patients had a normal temperature. Clinical cure rates were also high, with 70% of patients free of all signs and symptoms after 24 hours. However, by day 7, 6/30 (20%) presented with smears positive for P. falciparum. There were no adverse events considered to be related to treatment. A single dose of 25 mg/kg arteflene was found to be an effective and well-tolerated treatment for mild P. falciparum malaria.

The sesquiterpene peroxide Ro 42-1611 (arteflene), a synthetic derivative of yingzhaosu, was evaluated extensively against various drug-sensitive and drug-resistant lines of Plasmodium falciparum in vitro and P. berghei in vivo in mice. The potential therapeutic and prophylactic activities were studied comparatively with the standard antimalarials chloroquine, mefloquine and quinine, as well as qinghaosu and the derivatives artemether and artesunic acid. Experimentally arteflene proved to be a highly effective antimalarial drug. In vivo it is active at low doses against blood stages of P. berghei in mice after oral or parenteral administration. It has a rapid onset of drug action and a long lasting suppressive effect when given after infection, as well as a good potential for prophylactic activity when given before infection. The suppressive and prophylactic properties are comparable to chloroquine and superior to qinghaosu, artemether and artesunic acid. In vitro the compound showed no signs of cross-resistance with existing antimalarials. It was consistently rather more active against drug-resistant than against drug-sensitive strains of P. falciparum. Drug interaction studies in vitro and in vivo with chloroquine, mefloquine and quinine revealed an additive to synergistic effect with arteflene. Antagonism with these drugs was not observed. Compared with standard antimalarials the activity of arteflene in vitro is lower than would be expected from the in vivo results. This may be due to pharmacokinetic properties of the compound and the formation of an active metabolite which sustains the activity of arteflene in vivo.

An open, non-comparative clinical trial was carried out in Nigeria and Burkina Faso to investigate the safety and efficacy of the novel antimalarial arteflene in patients with mild malaria. Patients were males aged 12 to 16 years, with a Plasmodium falciparum count of 10(4) to 10(5) parasites/microliters and a body temperature of 37.5 to 38.5 degrees C. Twenty-three patients received a single dose of Ro 42-1611 (arteflene), corresponding to 25 +/- 2.5 mg/kg bodyweight. Nineteen patients were evaluable for standard efficacy. Efficacy was assessed at 6, 9, 12, 24, 36, 48 and 72 hours, and at seven days, by: reduction in parasitaemia and time to parasite clearance; resolution of fever; and clinical cure (defined as the absence of signs and symptoms of malaria). Adverse events were reported at each assessment point, and laboratory tests were carried out at baseline and at 2 and 7 days. The parasite count was reduced by 50% or more in 89.5% of patients after 48 hours, and 52.6% were completely free of parasites at the same time. Normal temperature was achieved in 89.5% of patients and clinical cure in 75%, after 48 hours. One patient reported mild vertigo and mild pruritus. The lower than expected effect was thought to be due to inadequate storage of the arteflene suspension. There were no withdrawals due to adverse events and no deaths. A single dose of 25 mg/kg arteflene was found to be an effective and well-tolerated treatment for mild P. falciparum malaria.

New 2-benzylideneimino- and 2-styryl-1,3-benzimidazole and benzothiazole derivatives have been prepared and tested in vitro against Caenorhabditis elegans, and Heligmosomoides polygyrus, showing some of them, interesting properties as inhibitors, which were not observed in the complementary in vivo tests. In order to rationalize the activity, log P was measured for all compounds, and QSAR models were developed, allowing the optimisation of the in vitro activity.

A comparative trial was carried out in 4 orphanges in Seoul, to compare the anthelminthic efficacy of oxantel-pyrantel suspension and mebendazole tablets against mixed infections of Ascaris lumbricoides and Trichuris trichiura. 40 patients were divided into 4 groups and received oxantel-pyrantel suspension at 15 or 20mg/kg once only or on 2 consecutive days. Another group of 20 patients was treated with 100mg of mebendazole twice a day for 3 days. Both drugs achieved a 100% cure rate for Ascaris infections. Against Trichuris infections, the average cure rate and egg reduction rate of oxantel-pyrantel treated groups was 87.5% and 92.3% respectively, and that for mebendazole was 65% and 89.1%. There were no side-effects. The results of the present study suggest that oxantel-pyrantel is more effective in the treatment of mixed infections of Ascaris and Trichuris, and was more acceptable to the patients, than mebendazole.

The efficacy of oxantel pamoate (1, 4, 5, 6-tetrahydro-2-[trans-3-hydroxystyryl]-1-methyl pyrimidine pamoate) was evaluated in 25 children with severe Trichuris infection. The presence of chronic dysentery and sigmoidoscopic demonstration of whipworms in the intestinal mucosa were the criteria for inclusion in the trial. Most of these patients had severe anemia, rectal prolapse, digital clubbing, hypoproteinemia, and growth retardation. There were a high incidence of concomitant parasitism with other intestinal helminths and with Entamoeba histolytica and Giardia lamblia. Sigmoidoscopic grading of Trichuris load and egg count in the feces were carried out prior to treatment and 2 days after each course of oxantel therapy. Oxantel was administered at a dose of 10 mg/kg body weight twice daily for a 3-day course. Satisfactory response, as judged by relief of dysentery and absence of whipworms from the mucosa at sigmoidoscopy, was achieved in 17 patients after the first course and in the remaining 8 patients after a second course of oxantel. The drug was well tolerated and no side effects were noted during or after treatment. It is concluded that oxantel is a safe and effective anthelmintic for severe clinical trichuriasis.

Single doses of oxantel given to 24 children and 37 adults with light to moderate infections of Trichuris trichiura effected cures in 20 of 26 (77%) trials with 10 mg/kg body weight, in 23 of 25 (92%) with 15 mg/kg, and in 10 of 10 trials with 20 mg/kg. In cases not cured, the egg-counts were reduced 50% to 91%. Side effects were not observed, and no drug-associated changes were detected by biochemical, hematologic, and urine examinations before and after treatment.

In a pilot study in 17 children, oxantel-pyrantel as one single dose of 10 to 20mg/kg of each, gave good results in ascariasis but poor cure rates in both trichuriasis and necatoriasis. However in the latter groups the infection was extremely heavy. In a controlled trial in 51 children, using oxantel-pyrantel at the same dose, but given daily for 3 consecutive days, or mebendazole 100mg twice daily for 3 days, the drugs gave similar response rates. Both gave 100% cure rates, as assessed by the absence of ova by both Beaver and brine-flotation techniques, in Ascaris lumbricoides infection. The percentage cures and egg reduction rates were 66.7 and 94.5 in trichuriasis and 53 and 93.6 in necatoriasis respectively. Those for mebendazole were 52 and 91.2 in trichuriasis and 37.5 and 89.7 in necatoriasis. Oxante-pyrantel treatment was associated with more cures, and a marginally greater reduction in ovum excretion than mebendazole but the differences were not statistically significant. No side-effects were seen with either treatment.

A number of nuclear-substituted styryl ketones, the related Mannich bases, and allyl alcohols were synthesized and evaluated for antitumor activity, principally in the L-1210 lymphoid leukemia and P-388 lymphocytic leukemia screening tests. The cytotoxicity of some of these compounds assessed in Eagle's 9KB carcinoma cell culture system was also recorded. Two of the Mannich bases showed promising levels of activity in the P-388 screening; of the results obtained to date, over one-third of the derivatives showed cytotoxicity at dose levels of 1-3 ppm. Other pharmacological results of these compounds are briefly reported.

A Mannich base namely 4-dimethylaminomethyl-1-phenyl-1-penten-3-one hydrochloride was shown to have far greater activity than 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) towards P388 leukemia cells in vitro. However, the compound was inactive in an in vivo P388 murine screen, and the object of this study was to discern molecular features which conferred in vivo activity. Mannich bases containing electron-attracting substituents in the aryl ring had in vivo potency in contrast to the analogs which had electron-donating groups in the ring. A number of hydrazones of the Mannich bases were prepared as potential prodrugs and did not enhance bioactivity. This observation was probably due to a lack of facile hydrolysis of the hydrazones to the corresponding Mannich bases in vivo since high resolution 1H NMR spectroscopy revealed that representative hydrazones either did not regenerate the ketones or produced them only in minute quantities at pH values normally encountered in living tissues.

A series of 33 thioacetals and hydrazones of 2-(4-formylstyryl)-5-nitro-1-vinylimidazole was prepared and examined for antitrypanosomal properties. The thioacetals were inactive as antitrypanosomal agents but three hydrazones derived from N-aminoguanidine, pyridylacethohydrazide chloride (Girard reagent P), and dimethylaminoacetohydrazide (Girard reagent D) displayed good activity against Trypanosoma rhodesiense.

A series of 2-styryl-5-nitro-1-vinylimidazoles carrying alkylaminomethyl or amidino functions in the 4 position of the styryl ring was prepared and evaluated for antitrypanosomal activity in mice infected with Trypanosoma rhodesiense. The alkylaminomethyl compounds were found inactive against Trypanosoma cruzi infections in mice. One compound, 2-(4-methylamidinostyryl)-5-nitro-1-vinylimidazole hydrochloride, showed antitrypanosomal activity comparable to the standard drugs suramin, pentamidine, diminazene, and melarsoprol when tested ip against T. rhodesiense infected mice and also showed some activity when tested ip against T. cruzi infected mice.

32 elementary school children were treated for multiple intestinal helminthiasis (ascariasis, trichuriasis and hookworm infections) with a combination of the pamoate salts of oxantel and pyrantel in a dose of 15 to 20mg/kg body weight of each in 1 daily dose for 3 consecutive days. The cure rate for ascariasis was 96.7%, and 84.4% for both trichuriasis and hookworm infections. 68.7% were completely cured of all 3 helminths. However, among those not completely cured, only 1 species of the previous 3 infecting helminths was present after treatment and then with a very marked reduction in egg count.

204 individuals from a rural community were given a single dose of oxantel-pyrantel at 15mg/kg bodyweight and if still infected, 20mg/kg bodyweight, with cure rates of 100%, 53% and 71% for ascariasis, trichuriasis and hookworm infection, respectively. From an urban community, 124 patients were given the same drug either as 15mg/kg bodyweight given twice in one day, with an interval of about 12 hours, or 20mg/kg bodyweight given daily for 2 days. Cure rates obtained were 100% in both groups for ascariasis; 89.2% of those given the first regimen were cured of trichuriasis compared with 71.2% of those on the second. For trichuriasis, oxantel-pyrantel given twice, 12 hours apart, appears to be the best treatment schedule and further clinical trials using this regimen are suggested.

A novel series of bis-Mannich bases have been synthesized and evaluated against P388 lymphocytic leukemia in mice. Two compounds showed a perceptible beneficial response in this screen and all the compounds displayed marked murine toxicity. A representative compound inhibited respiration in mitochondria isolated from rat and mouse liver cells by 90% approximately at a dose of 2.5 mumol and it caused a small elevation in mouse liver glutathione equivalent concentrations at 5 mg/kg.

704 patients with intestinal nematode infestation were treated with oxantel and oxantel-pyrantel in either liquid or tablet form, at doses from 10 to 25mg/kg. All were given the drug or drugs as a single dose. In 699 patients with trichuriasis cure rates between 64 and 93% were obtained and there were egg reduction rates of between 90 and 100%. The best results were obtained using oxantel, either alone or in combination with pyrantel, at 15 to 20mg/kg. Only 2 of 152 patients with ascariasis were not cured after a single dose of pyrantel (given as oxantel-pyrantel) of 10, 15 or 20mg/kg, and both these patients were from the group given the lowest dose. Only mild side-effects were noted. The combination, oxantel-pyrantel is a safe and effective treatment for multiple intestinal nematode infection.