Thiazoles

Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-b 42 (Ab 42 ) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau 181 (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Ab 42 but not for plasma Ab species. Some individuals have low CSF Ab 42 but no cortical PIB binding. Together, these data suggest that changes in brain Ab 42 metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Ab 42 initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.

Objectives: High failure rates of randomized controlled trials (RCTs) are well recognized but poorly understood. We report exploratory analyses from an adjunctive ziprasidone double-blind RCT in adults with bipolar I disorder (reported in part 1 of this article). Data collected by computer interviews and by site-based raters were analyzed to examine the impact of eligibility criteria on signal detection. Method: Clinical assessments and a remote monitoring system, including a computeradministered Young Mania Rating Scale (YMRS Comp) were used to categorize subjects as eligible or ineligible on 3 key protocol-specified eligibility criteria. Data analyses compared treatment efficacy for eligible versus ineligible subgroups. All statistical analyses reported here are exploratory. Criteria were considered "impactful" if the difference between eligible and ineligible subjects on the YMRS change scores was ≥ 1 point. Results: 504 subjects had baseline and ≥ 1 post-randomization computer-administered assessments but only 180 (35.7%) met all 3 eligibility criteria based on computer assessments. There were no statistically significant differences between treatment groups in change from baseline YMRS score on the basis of site-based rater or computer assessments. All criteria tested improved signal detection except the entry criteria excluding subjects with ≥ 25% improvement from screen to baseline. Conclusions: On the basis of computer assessments, nearly two-thirds of randomized subjects did not meet at least 1 protocolspecified eligibility criterion. These results suggest enrollment of ineligible subjects is likely to contribute to failure of acute efficacy studies.

Tacrolimus (FK506) is widely used as an immunosuppres-sor in clinical practice; nonetheless a great part of its mecha-nisms of action and the processes triggering side effects remain unknown.1) A wide spectrum of adverse effects including neurotoxic, nephrotoxic, ...

Aims/hypothesis We evaluated the insulinotropic and antihyperglycaemic actions of glucokinase activators (GKAs), especially through acute and subchronic studies in rodent diabetes models with (2R)-2-(4-cyclopropanesulphonylphenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a novel and potent GKA. Materials and methods The action of PSN-GK1 on or in the following were investigated: (1) on human liver glucokinase, insulin secretion from MIN6 cells and 2-deoxy-d-[3H]glucose (2-DG) uptake into rat hepatocytes; and (2) in Zucker diabetic fatty rats and in non-diabetic C57Bl/6, diabetic db/db and ob/ob mice. Results At 5 mmol/l glucose, PSN-GK1 activated glucokinase (4.3-fold, median effective concentration [EC50] 130 nmol/l), increased MIN6 insulin secretion (26-fold, EC50 267 nmol/l) and 2-DG hepatocytic uptake (threefold, EC50 1 μmol/l); at higher glucose concentrations, EC50s and fold-effectiveness were both lower. In C57Bl/6 mice, PSN-GK1 reduced blood glucose at 1 and 10 mg/kg (by mouth), but insulin was increased significantly at only the higher dose. In hyperinsulinaemic 10-mmol/l glucose clamps, PSN-GK1 increased 2-DG incorporation into liver glycogen sixfold, directly demonstrating liver effects. PSN-GK1 improved glycaemic profiles in db/db mice and Zucker diabetic fatty rats, diabetic animal models in which GKA efficacy has not previously been described, without causing hypoglycaemia. In ob/ob mice, it dose-dependently reduced excursions in OGTTs. Moreover, after subchronic administration, no tachyphylaxis was evident and glycaemia was improved without alterations to lipid levels, liver weight, glycogen content or body weight. Conclusions/interpretation PSN-GK1 was potently antihyperglycaemic through its effects on insulin release and hepatic glucose metabolism. It is one of the most potent GKAs described in the literature and is active in diabetic animal models where GKAs have not been reported to show efficacy to date. Ongoing human trials are investigating the potential of this novel therapeutic approach.

Brain-pancreas relative protein (BPRP) is a novel protein that mainly expresses in brain and pancreas. In our previous study, we found that various stressors significantly decreased the expression of BPRP in pancreas in vivo, accompanied by changes in insulin and glucose levels, and that expression of BPRP in pancreas also decreased significantly in diabetic rats induced by Streptozocin (STZ). All these findings suggest that BPRP may be a glucose or insulinsensitive protein. However, how the changes in insulin or glucose levels influence the expression of BPRP in hippocampus requires further study. Here, we investigated the effects of insulin or glucose on the expression of BPRP in primary cultured hippocampal neurons. We supplied hippocampal neurons with glucose, insulin, or supernatant from pancreatic b-cells, which secrete insulin into the supernatant. Our data showed that insulin had beneficial effect on the viability while no significant effect on the expression of BPRP in hippocampal neurons. On the contrary, 40 mM glucose or free glucose culture significantly decreased the expression of BPRP, while had no significant effect on the viability and apoptosis of hippocampal neurons. Further study showed that levels of insulin in the supernatant collected from pancreatic b-cells medium changed over days, and that supernatant increased the viability of hippocampal neurons, while it had no obvious effect on the expression of BPRP in hippocampal neurons. These results suggest that BPRP may be a glucose-sensitive protein.

Under laboratory conditions, the effects of thiamethoxam were investigated in larvae, pupae and emerging honey bees after exposure at larval stages with different concentrations in the food (0.00001 ng/μL, 0.001 ng/μL and 1.44 ng/μL). Thiamethoxam reduced the survival of larvae and pupae and consequently decreased the percentage of emerging honey bees. Thiamethoxam induced important physiological disturbances. It increased acetylcholinesterase (AChE) activity at all developmental stages and increased glutathione-S-transferase (GST) and carboxylesterase para (CaEp) activities at the pupal stages. For midgut alkaline phosphatase (ALP), no activity was detected in pupae stages, and no effect was observed in larvae and emerging bees. We assume that the effects of thiamethoxam on the survival, emergence and physiology of honey bees may affect the development of the colony. These results showed that attention should be paid to the exposure to pesticides during the developmental stages of ...

INTRODUCTION Epilepsy is the fourth most common neurological problem affecting human population after migrane, stroke and Alzheimer's disease (Epilepsy foundation). Epilepsy belongs to a group of neurological disorders showing neuronal hyperexcitability characterized by recurrent seizures in different parts of the brain [1]. According to WHO, it is estimated that the condition affects approximately 50 million people worldwide, 80 % of which resides in developing countries. Enormous AEDs belonging to different classes are used nowadays to treat epilepsy including phenytoin, carbamazepine, valproic acid, topiramate, gabapentin, felbamate, levetiracetam, etc. [2]. However, the current therapy using the presently available antiepileptic drugs shows limitations viz. insufficient, seizure control, unpredictability of effect and its loss, poor efficacy, inadequate information about the receptors involved, etc. Moreover AEDs do not prevent epilepsy in persons at risk of drug-resistance. Further, long term therapy with these drugs pose an array of side effects which includes but is not limited to drowsiness, ataxia, gastrointestinal disturbances, megaloblasticanaemia and hirsutism [3,4]. Hence there exists the continuous need for the discovery and development of new antiepileptic agents with higher activity, minimal or negligible toxicity and side effects. A number of heterocyclic derivatives possessing nitrogen has been reported to play an important role in pharmaceutical Design, Synthesis and Anticonvulsant Evaluation of N-[(Substituted 1H-pyrazol-3-yl)amino]-2-(4-methylphenyl)quinazolin-4(3H)-one Derivatives

Three haloderivatives of noscapine 2-4 were synthesized chemoselectively and their in vitro cytotoxicity was assessed by MTT assay on U-87 human glioblastoma cell lines. At 50 lM concentration after 72 h, 9-chloronoscapine 2, 9-bromonoscapine 3 (EM011), and 9-iodonoscapine 4 killed 87.8%, 51.2%, and 56.8% cells, respectively, however noscapine kills only 40% of the cells; revealing 9-chloronoscapine as a potential cytotoxic agent than noscapine and 9-bromonoscapine (EM011). At low concentration (1 lM) 9-bromonoscapine (46.7%) and 9-chloronoscapine (45.7%) did not show any significant difference.

Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.

Field-collected Reticulitermes flavipes (Kollar) termites were placed in bioassay tubes containing soil treated with one of three termiticides: thiamethoxam, acetamiprid, or a combination of acetamiprid ϩ bifenthrin. In the bioassay tubes, treated soil was placed in a layer centered within untreated sand between two 1.5-cm agar plugs. All termiticides were tested at concentrations of 0.1, 1, 10, and 100 ppm with narrow (1 mm), medium (5 mm), and broad (50 mm) thicknesses of treated soil. Soil penetration and termite mortality were measured after 7 d, and repellency was assessed. Thiamethoxam treatments allowed the greatest soil penetration, whereas acetamiprid ϩ bifenthrin treatments were the most inhibitory to soil penetration. Thiamethoxam treatments also caused consistently greater termite mortality than acetamiprid treatments. These data indicated that acetamiprid prevented soil penetration by termites more than thiamethoxam, although both were less repellent compared with bifenthrin alone, which causes little termite mortality at the tested doses. When there was direct contact of treated soil with the agar plugs in broad treatments, the combination of acetamiprid ϩ bifenthrin was more toxic to R. flavipes termites than either acetamiprid or thiamethoxam alone. The combination acetamiprid ϩ bifenthrin termiticide may be effective in keeping termites away from the treated soil, because of the combined effects of acetamiprid and bifenthrin.

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, stroke, blindness, and end-stage renal failure, which could account for disabilities and high mortality rates in patients with diabetes. Recent clinical studies have substantiated the concept of "hyperglycemic memory" in the pathogenesis of cardiovascular disease (CVD) in diabetes. Indeed, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that intensive therapy during the DCCT reduces the risk of cardiovascular events by about 50% in type 1 diabetic patients 11 years after the end of the trial. Among various biochemical pathways activated under diabetic conditions, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory "hyperglycemic memory." Further, there is a growing body of evidence that AGEs play an important role in CVD in diabetes. These observations suggest that the inhibition of AGEs formation may be a promising target for therapeutic intervention in diabetic vascular complications. Therefore, in this article, we review several agents with inhibitory effects on AGEs formation and their therapeutic implications in CVD in diabetes.

Although the development of tyrosine kinase inhibitors (TKIs) to control the unregulated activity of BCR-ABL revolutionized the therapy of chronic myeloid leukemia, resistance to TKIs is a clinical reality. Among the postulated mechanisms of resistance is the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), which mediate reduced intracellular drug accumulation. We compared the interactions of the TKIs imatinib, nilotinib, and dasatinib with ABCB1 and ABCG2 in ex vivo and in vitro systems. The TKIs inhibited rhodamine 123 and Hoechst 33342 efflux mediated by endogenous expression of the transporters in murine and human hematopoietic stem cells with potency order nilotinib Ͼ Ͼ imatinib Ͼ Ͼ dasatinib. Studies with ABCB1-, ABCG2-, and ABCC1-transfected human embryonic kidney 293 cells verified that nilotinib was the most potent inhibitor of ABCB1 and ABCG2. Cytotoxicity assays in stably transduced K562-ABCG2 and K562-ABCB1 cells confirmed that the TKIs were also substrates for the two transporters. Like imatinib, both nilotinib and dasatinib decreased ABCG2 surface expression in K562-ABCG2 cells. Finally, we found that all TKIs were able to compete labeling of ABCB1 and ABCG2 by the photo-cross-linkable prazosin analog [ 125 I]iodoarylazidoprazosin, suggesting interaction at the prazosin-binding site of both proteins. Our experiments support the hypothesis that all three TKIs are substrates of ABC transporters and that, at higher concentrations, TKIs overcome transporter function. Taken together, the results suggest that therapeutic doses of imatinib and nilotinib may diminish the potential of ABCB1 and ABCG2 to limit oral absorption or confer resistance. Clinical data are required to definitively answer the latter question.

Previous studies suggest membrane binding is a key determinant of amyloid β (Aβ) neurotoxicity. However, it is unclear whether this interaction is receptor driven. To address this issue, a D-handed enantiomer of Aβ42 (D-Aβ42) was synthesized and its biophysical and neurotoxic properties were compared to the wild-type Aβ42 (L-Aβ42). The results showed D- and L-Aβ42 are chemically equivalent with respect to copper binding, generation of reactive oxygen species and aggregation profiles. Cell binding studies show both peptides bound to cultured cortical neurons. However, only L-Aβ42 was neurotoxic and inhibited long term potentiation indicating L-Aβ42 requires a stereospecific target to mediate toxicity. We identified the lipid phosphatidylserine, as a potential target. Annexin V, which has very high affinity for externalized phosphatidylserine, significantly inhibited L-Aβ42 but not D-Aβ42 binding to the cultured cortical neurons and significantly rescued L-Aβ42 neurotoxicity. This suggests that Aβ mediated toxicity in Alzheimer disease is dependent upon Aβ binding to phosphatidylserine on neuronal cells.

The present 16-week double-blind, randomized, placebocontrolled trial was aimed to explore the efficacy of ziprasidone addon pharmacotherapy on clinical symptoms and cognitive functioning in 40 schizophrenic patients (active group, n = 20; placebo group, n = 20) with residual symptoms Brief Psychiatric Rating Scale mean [SD] baseline total score in active group vs placebo, 40.4 [5.9] vs 37.9 [6.8]) despite receiving clozapine monotherapy at the highest tolerated dosage. The results obtained evidenced that ziprasidone augmentation of clozapine significantly reduced Positive and Negative Syndrome Scale ''Negative'' (P = 0.006, mean change [SD] in active group vs placebo, j2.7 [2.3] vs 1.1 [2.1], Cohen d = 1.7) and ''General Psychopathology'' (P = 0.009, mean change [SD] in active group vs placebo, j5.3 [3.8] vs j0.7 [2.0], Cohen d = 1.5). Regarding cognitive domains, ziprasidone was more effective than placebo in improving semantic fluency (P G 0.0001, mean change [SD] in active group vs placebo, 4.4 [3.5] vs j0.1 [4.1], Cohen d = 1.2). Ziprasidone had only a small effect on prolongation of heart-rate corrected QT interval (QTc) of the electrocardiogram, not significantly different from placebo (QTc milliseconds, mean [SD], week 16 in active group vs placebo, 408.17 [20.85] vs 405.45 [17.11], P = 0.321); within-group comparison revealed that QTc prolongation induced by ziprasidone was statistically significant (baseline vs week 16, P = 0.002).

A reversed-phase ion-pair high-performance liquid chromatographic method was developed for the determination of difethialone residues in laboratory rats (Rattus norvegicus). Difethialone was extracted from rat tissue with chloroform/acetone/formic acid. The extracts were cleaned up by a solid-phase extraction (SPE) procedure using both silica and aminopropyl SPE sorbents, concentrated, and analyzed by reversed-phase ion-pair high-performance liquid chromatography. Difethialone was quantitated via ultraviolet absorbance at 262 nm. A surrogate compound, brodifacoum, was used to correct for method performance. The mean surrogate-corrected recoveries for whole ground rodent fortified at 0.2, 1.0, and 20 µg/g difethialone were 92.3 ( 7.7, 84.8 ( 6.6, and 90.2 ( 3.1%, respectively. The method limit of detection was 0.054 µg/g.

Auricular reconstruction remains a major challenge facing reconstructive surgeons owing to the complexity of autogenous transplants. In this study, the development of a three-dimensional custom-made polyurethane (PU) auricular implant with hydroxyapatite (HA) coating is described. The PU implant was produced by computerized tomography (CT) scanning and indirect rapid prototyping. To improve the physiological response of the implant, the PU prototype was coated with a microrough, homogenous layer of HA by a novel solvent-compression coating method. Bioactivity of the HA coated PU substrates was confirmed by apatite formation on the HA coating after 9 days in revised simulated body fluid (pH 7.4). Adhesion strength of the HA coating to the PU surface using the tensile pull-off test revealed partial failure of the coating with an average tensile strength of 1.6 MPa. As an initial stage indication of cytocompatibility for a soft tissue application, in vitro cell culturing on the HA-coated PU substrates using Graham 293 fibroblast cells was performed. After 24 and 72 h, the HA coated surfaces displayed significantly higher cell numbers and metabolically active cells compared with the virgin uncoated PU surfaces. This indicates that HA coated PU surfaces are cytocompatible towards fibroblasts and could potentially be applied to auricular cartilage tissue replacement.

Gallic acid-based indanone derivatives have been synthesised. Some of the indanones showed very good anticancer activity in MTT assay. Compounds 10, 11, 12 and 14 possessed potent anticancer activity against various human cancer cell lines. The most potent indanone (10, IC 50 = 2.2 lM), against MCF-7, that is, hormone-dependent breast cancer cell line, showed no toxicity to human erythrocytes even at higher concentrations (100 lg/ml, 258 lM). While, indanones 11, 12 and 14 showed toxicities to erythrocytes at higher concentrations.

We report the occurrence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with monosomy 7 transformation in two patients with chronic myeloid leukemia (CML) after imatinib and dasatinib treatment without previous exposure to chemotherapeutic agents.

a b s t r a c t 4,5-Dichloro-1,2,3-dithiazolium chloride 2 (Appel salt) reacts with either DMSO, diphenylsulfoxide 11 or methylphenylsulfoxide 12 to give 4-chloro-5H-1,2,3-dithiazol-5-one 1 in excellent yields. The use of catalytic amounts of DMSO (1 mol %) in MeCN in the presence of water (1 equiv) transforms Appel salt 2 into dithiazolone 1 in near quantitative yields (92%). Rational mechanisms are proposed to explain the catalytic nature of these reactions.

Malaria remains one of the most important infectious diseases. Treatment options for severe malaria are limited and the choline analogue SAR97276A is a novel chemical entity that was developed primarily as treatment for severe malaria. Before starting clinical investigations in severely ill malaria patients, safety and efficacy of SAR97276A was studied in patients with uncomplicated malaria. Here, we summarize two open-label, multi-center phase 2 trials assessing safety and efficacy of parenterally administered SAR97276A in African adults and children with falciparum malaria. Study 1 was conducted in Burkina Faso, Gabon, Benin and Tanzania between August 2008 and July 2009 in malaria patients in an age de-escalating design (adults, children). A total of 113 malaria patients received SAR97276A. Adults were randomized to receive a single dose SAR97296A given either intramuscularly (IM) (0.18 mg/kg) or intravenously (IV) (0.14 mg/kg). If a single dose was not efficacious a second adult...

Preparation of drug-loaded freeze-dried (FD) liposomes, designed for delivery to lungs after rehydration/nebulization was investigated. Rifampicin (RIF) incorporating multilamelar (MLV) and dried rehydrated vesicles (DRV); composed of phosphatidylcholine (PC), dipalmitoyloglycero-PC (DPPC) or distearoyloglycero-PC (DSPC), containing or not Cholesterol (Chol), were prepared. Vesicles were characterized for encapsulation efficiency (EE%), size distribution, zeta-potential, stability during freeze drying (FD) and nebulization (nebulization efficiency (NE%) and retention of RIF after nebulization (NER%)). Mucoadhesion and toxicity in A549 cells was measured. RIF EE% was not affected by liposome type but lipid composition was important; Synthetic lipid vesicles (DPPC and DSPC) had higher EE% compared to PC. As Chol increased EE% decreased. Freeze drying (FD) had no effect on EE%, however trehalose decreased EE% possibly due to RIF displacement. NER% was highly affected by lipid composition. Results of NE% and NER% for RIF-loaded liposomes show that DSPC/Chol (2:1) is the best composition for RIF delivery in vesicular form to lungs, by nebulization. Mucoadhesion and A549 cell toxicity studies were in line with this conclusion, however if mucoadhesion is required, improvement may be needed.

Purpose To evaluate the eYcacy and safety of masitinib combined with gemcitabine in patients with advanced pancreatic cancer. Patients and methods Twenty-two non-randomised patients with unresectable, locally advanced (n = 9) or metastatic pancreatic cancer (n = 13) received oral masitinib (9 mg/ kg/day) combined with standard gemcitabine. All patients were naÂve to systemic chemotherapy or radiotherapy. The primary endpoint was time-to-progression (TTP) with eYcacy and safety analyses performed on the intent-to-treat population. Secondary endpoints included overall survival (OS), as well as, subgroup analyses according to baseline disease, and performance status. Results Overall median TTP was 6.4 months (95% CI [2.7-11.7]); 8.3 and 2.7 months, respectively, for locally advanced and metastatic patients; 6.4 and 0.8 months, respectively, for patients with KPS [80-100] or KPS [70]. Median OS was 7.1 months (95% CI [4.8-17.0]); 8.4 and 6.8 months for locally advanced or metastatic patients, respectively; 8.0 and 4.4 months in patients with KPS [80-100] or KPS [70]

A series of structurally novel benzothiazole based small molecule inhibitors of p56 lck were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in the T-cell proliferation assay. BMS-243117 (compound 2) is identified as a potent, and selective Lck inhibitor with good cellular activity (IC 50 =1.1 mM) against T-cell proliferation. #

BackgroundChemoresponse is a significant outcome predictor in patients with head and neck cancer, regardless of the treatment modality used. The histoculture drug response assay (HDRA) has been shown to be a reliable method for in vitro chemoresponse assessment. In this study, we have correlated the HDRA assessment with survival in patients with head and neck squamous cell carcinoma (HNSCC).Chemoresponse is a significant outcome predictor in patients with head and neck cancer, regardless of the treatment modality used. The histoculture drug response assay (HDRA) has been shown to be a reliable method for in vitro chemoresponse assessment. In this study, we have correlated the HDRA assessment with survival in patients with head and neck squamous cell carcinoma (HNSCC).MethodTumor specimens from 41 of 42 patients undergoing treatment for HNSCC were successfully evaluated by the HDRA. Tumor tissue was histocultured on Gelfoam sponges gel in 24-well plates, followed by treatment with cisplatin (15 μg/mL) or 5-fluorouracil (40 μg/mL) in triplicate. A control group received no drug treatment. After completion of drug treatment, the relative cell survival in the tumors was determined using the MTT assay. The inhibition rate (IR) for each drug was calculated relative to the control for each case, and sensitivity was defined as a tumor IR of greater than 30%. Treatment was based on established protocols for the location and stage of the tumor and included surgery, radiation, and/or chemotherapy. Survival comparisons were performed using the generalized Wilcoxon test for the comparison of Kaplan-Meier survival curves.Tumor specimens from 41 of 42 patients undergoing treatment for HNSCC were successfully evaluated by the HDRA. Tumor tissue was histocultured on Gelfoam sponges gel in 24-well plates, followed by treatment with cisplatin (15 μg/mL) or 5-fluorouracil (40 μg/mL) in triplicate. A control group received no drug treatment. After completion of drug treatment, the relative cell survival in the tumors was determined using the MTT assay. The inhibition rate (IR) for each drug was calculated relative to the control for each case, and sensitivity was defined as a tumor IR of greater than 30%. Treatment was based on established protocols for the location and stage of the tumor and included surgery, radiation, and/or chemotherapy. Survival comparisons were performed using the generalized Wilcoxon test for the comparison of Kaplan-Meier survival curves.ResultsResistance to 5-fluorouracil was present in 13 cases (32%), to cisplatinum in 13 cases (32%), and to both agents in 11 cases (27%). The 2-year cause-specific survival was significantly greater for patients sensitive to 5-fluorouracil (85% vs 64%; p = .04), cisplatinum (86% vs 64%; p = .05), or both agents (85% vs 63%; p = .01). The association between HDRA assessment of chemoresponse and clinical outcome remained significant even after controlling for the effects of TNM stage and the presence of recurrent cancer at presentation by multivariate analysis.Resistance to 5-fluorouracil was present in 13 cases (32%), to cisplatinum in 13 cases (32%), and to both agents in 11 cases (27%). The 2-year cause-specific survival was significantly greater for patients sensitive to 5-fluorouracil (85% vs 64%; p = .04), cisplatinum (86% vs 64%; p = .05), or both agents (85% vs 63%; p = .01). The association between HDRA assessment of chemoresponse and clinical outcome remained significant even after controlling for the effects of TNM stage and the presence of recurrent cancer at presentation by multivariate analysis.ConclusionsChemosensitivity determined by the HDRA seems to be a strong predictor of survival in patients with advanced HNSCC and should be considered further. © 2002 Wiley Periodicals, Inc.Chemosensitivity determined by the HDRA seems to be a strong predictor of survival in patients with advanced HNSCC and should be considered further. © 2002 Wiley Periodicals, Inc.

Background Ponesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P 1 ) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P 1 receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis).

Although health-related quality of life (HRQOL) has been included in multiple Parkinson's disease (PD) clinical trials, little is known about how HRQOL responds to treatments over time. Here we assess the effect of therapy on HRQOL and explore factors that influence the HRQOL profiles and subdomains. A total of 301 subjects with early PD were randomized to either initial pramipexole or initial levodopa and followed every 3 months over a 4-year period. To estimate health outcomes, we used EQ-5D and PDQUALIF. We calculated the incremental effectiveness as the accumulated difference in the total HRQOL over time between treatments. The subgroup analyses (by sex, race, age, baseline patient characteristics, and occurrence of adverse events) were conducted using the same approach. Sensitivity analysis was performed to test the effect of missing data imputation on the results. All three HRQOL measures resulted in similar profiles over time characterized by initial improvement over the ...

Many persons are exposed to preservatives/biocides based on methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), since toiletries and cosmetics, as well as products/water-based systems used occupationally, may all contain MCI/MI. In toiletries and cosmetics, the MCI/MI concentration is often below 15 ppm (0.0015%). In some industries, workers handle high concentrations of MCI/MI, which can cause chemical burns and induce sensitization if skin is exposed. Contact allergy to MCI/MI is common and reports on chemical burns have been published. Thus, there is a need for prevention of skin diseases caused by MCI/MI. The inactivation of MCI/MI by glutathione (GSH) in emollients, containing different amounts of lipids, was studied by HPLC. Various amounts of GSH were added to Fenuril A , Essex A , and Locobase A , giving 3 preparations of each emollient containing 0.10%, 0.50% and 2.0% GSH, respectively. The inactivation of 15 ppm MCI/ MI and the total inactivating capacity of GSH in these preparations, kept at room temperature and refrigerated, was studied over a period of 6 months. The inactivating capacity of GSH in the emollients was almost equivalent, regardless of the lipid contents of the emollients, type of storage and age. On the other hand, the GSH concentration in the emollients had a crucial importance on the inactivation of MCI/MI. Emollients containing 2% GSH were capable of inactivating up to 2400 ppm MCI/MI.

It is no longer necessary to use dialkylzinc reagents to obtain enantioselectivities >95% in the copper-catalyzed asymmetric conjugate addition of organometallic compounds to cyclic enones. We now report how this can be accomplished by using inexpensive and readily available Grignard reagents. Screening of bidentate ligands provided outstanding results with copper complexes of commercially available chiral ferrocenyl-based diphosphines, in particular TaniaPhos and JosiPhos derivatives. These catalysts tolerate a range of Grignard reagents and different cyclic enones as substrates, leading to high regioselectivities and unprecedented enantioselectivities. Moreover, the reactions are successful with moderate catalyst loading (5 mol %) under mild conditions and in the absence of additives.

Background. Glioblastoma (GBM) is poorly responsive to current chemotherapy. The nuclear transporter exportin 1 (XPO1, CRM1) is often highly expressed in GBM, which may portend a poor prognosis. Here, we determine the efficacy of novel selective inhibitors of nuclear export (SINE) specific to XPO1 in preclinical models of GBM. Methods. Seven patient-derived GBM lines were treated with 3 SINE compounds (KPT-251, KPT-276, and Selinexor) in neurosphere culture conditions. KPT-276 and Selinexor were also evaluated in a murine orthotopic patient-derived xenograft (PDX) model of GBM. Cell cycle effects were assayed by flow cytometry in vitro and immunohistochemistry in vivo. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase 3/7 activity assays. Results. Treatment of GBM neurosphere cultures with KPT-276, Selinexor, and KPT-251 revealed dose-responsive growth inhibition in all 7 GBM lines [range of half-maximal inhibitory concentration (IC 50), 6-354 nM]. In an orthotopic PDX model, treatment with KPT-276 and Selinexor demonstrated pharmacodynamic efficacy, significantly suppressed tumor growth, and prolonged animal survival. Cellular proliferation was not altered with SINE treatment. Instead, induction of apoptosis was apparent both in vitro and in vivo with SINE treatment, without overt evidence of neurotoxicity. Conclusions. SINE compounds show preclinical efficacy utilizing in vitro and in vivo models of GBM, with induction of apoptosis as the mechanism of action. Selinexor is now in early clinical trials in solid and hematological malignancies. Based on these preclinical data and excellent brain penetration, we have initiated clinical trials of Selinexor in patients with relapsed GBM.

Disponible sur Internet le 8 avril 2008 2. En termes d'application thérapeutique chez l'homme, c'est dans le cadre des stéatopathies que les études animales sont les plus nombreuses et que les essais thérapeutiques sont les plus avancés. Néanmoins une attention particulière devra être apportée aux effets indésirables spécifiques des glitazones, notamment sur le plan cardiaque.

The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented.