Triazoles

The aim of this study was to investigate the influence of the long-term treatment of rats with letrozole on the testis morphology. The pharmacologically induced estrogen deficiency caused statistically significant decreases of both intratesticular and serum levels of estradiol, and morphological changes in the seminiferous epithelium and in the interstitial tissue of the testes. Six months of treatment resulted in the sloughing of premature germ cells of the seminiferous epithelium into the tubular lumen and in intraepithelial vacuolization. Multinucleated giant cells composed of premature germ cells, conglomerates of various cell nuclei and cell debris as well as irregularities and infoldings of the tubular basement membrane were also seen. Moreover, deep invaginations of the lamina propria with myoid cells were observed. Cells in the interstitial tissue showed changes similar to that observed in aging processes. The cytoplasm of LH-R-positive Leydig cells was loaded with lipofuscin granules. The number of lipofuscin-loaded cells was significantly increased in the interstitial tissue of testis in letrozole-treated rats. The results indicate the direct influence of estrogens on seminiferous tubules and the interstitial tissue morphology.

Clinical trials conducted over the last two decades have demonstrated that 5 years of treatment with tamoxifen (TAM) after local treatment in postmenopausal patients with positive hormone receptor early breast cancer improves disease-free survival and overall survival. More recently, aromatase inhibitors (AI) have been tested in several randomized clinical trials in this setting. The studies have tested either AI versus TAM or different sequential approaches combining the two agents. While the most effective strategy remains to be determined, overall, incorporation of AI resulted in better diseasefree survival, particularly in the worstprognosis subgroup of patients. In addition, long-term treatment with AI was, in general, well tolerated. However, mature results are needed in order to be able to assess the effect in overall survival. The authors of this supplement paper include the key points of roundtable presentations and discussions of hormonal therapy in breast cancer by topic.

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and other filamentous fungi from the SECURE trial. Two hundred and thirty one patients who received the clinical dosing regimen and had exposure parameters were included in this analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included: all-cause mortality through Day 42 in the intent-to-treat (ITT) and modified ITT population, data-review committee (DRC)-adjudicated overall respons...

Triadimefon is a triazole fungicide that produces hyperactivity in both mice and rats similar to that seen following administration of compounds with catecholaminergic activity (e.g., d-amphetamine). To determine whether the triadimefon-induced hyperactivity is due to an action on CNS catecholaminergic systems, we evaluated the effects of combined treatment of triadimefon with either the tyrosine hydroxlase inhibitor d,l-a-methyl-p-tyrosine methyl ester HCl

Deferasirox is the first oral iron chelator and, as such, is widely used for the treatment of chronic iron overload. However, recent data from large studies confirmed the renal toxicity of deferasirox. We report a case of Fanconi syndrome associated with acute renal failure in a patient receiving deferasirox. In particular, new insights regarding the pathophysiology of the renal disease due to this treatment are discussed. This case highlights the importance of a careful monitoring of kidney function, markers of proximal tubulopathy and ferritinaemia in patients receiving deferasirox.

Objective: To compare the effectiveness of letrozole and clomiphene citrate (CC) in ovulatory patients with borderline male factor infertility, early stage endometriosis, and unexplained infertility. Design: Prospective quasi-randomized trial. Setting: University infertility clinic. Patient(s): Forty-six consecutive patients with ovulatory infertility were recruited. Twenty-five patients (67 cycles) were given CC and 21 patients (52 cycles) were given letrozole. Both drugs were given orally on days 3-7 of menses. Intervention(s): Letrozole, CC, ovulation induction, IUI, timed intercourse. Main Outcome Measure(s): Number of follicles, endometrial thickness, and pregnancy rates. Result(s): The median serum E 2 concentration on the day of hCG administration in the letrozole and CC groups were 191.5 pmol/L and 476.0 pmol/L, respectively. The median endometrial thickness on the day of hCG were 8 mm in both groups. Ovulation occurred in 81% (42/52) of the letrozole-treated and 85% (57/67) of the CC-treated patients. Pregnancy rate (PR) per cycle was 9% (5/52) in the letrozole group and 12% (8/67) in the CC group. Conclusion(s): Letrozole and CC have comparable effectiveness in ovulatory patients with borderline male factor infertility, early stage endometriosis, and unexplained infertility. (Fertil Steril 2006;85:1045-8.

Akathisia is a subset of the larger antipsychotic side effect profile known as extrapyramidal syndrome (EPS). It is associated with antipsychotic treatment and is characterized as a feeling of inner restlessness that results in a compulsion to move. There are currently no primate models available to assess drug-induced akathisia; the present research was designed to address this shortcoming. We developed a novel rating scale based on both the Barnes Akathisia Rating Scale (BARS) and the Hillside Akathisia Scale (HAS) to measure the objective, observable incidence of antipsychotic-induced akathisia-like behavior in Cebus apella non-human primates (NHPs). To induce akathisia, we administered the atypical antipsychotic aripiprazole (1 mg/kg) or the selective phosphodiesterase 10A (PDE10A) inhibitor MP-10 (1-3 mg/kg). Treatment with both compounds produced significantly greater akathisia scores on the rating scale than vehicle treatment. Characteristic behaviors observed included vocalizations, stereotypies, teeth grinding, restless limb movements, and hyperlocomotion. Adenosine A 2A receptor antagonists have previously been shown to be effective in blocking antipsychotic-induced EPS in primates. The selective A 2A receptor antagonist, SCH 412348 (10-30 mg/kg), effectively reduced or reversed akathisialike behavior induced by both aripiprazole and MP-10. This work represents the first NHP measurement scale of akathisia and demonstrates that NHPs are responsive to akathisia-inducing agents. As such, it provides a useful tool for the preclinical assessment of putative antipsychotics. In addition, these results provide further evidence of the utility of A 2A receptor antagonists for the treatment of antipsychotic-induced movement disorders.

Background The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the effi cacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months.

Information provided to patients is thought to influence placebo and drug effects. In a prospective, withinsubjects, repeated-measures study of 66 subjects with episodic migraine, we investigated how variations in medication labeling modified placebo and drug effects. An initial attack with no treatment served as a control. In six subsequent migraine attacks, each participant received either placebo or Maxalt (10-mg rizatriptan) administered under three information conditions ranging from negative to neutral to positive (told placebo, told Maxalt or placebo, told Maxalt) (N = 459 documented attacks). Treatment order was randomized. Maxalt was superior to placebo for pain relief. When participants were given placebo labeled as (i) placebo, (ii) Maxalt or placebo, and (iii) Maxalt, the placebo effect increased progressively. Maxalt had a similar progressive boost when labeled with these three labels. The efficacies of Maxalt labeled as placebo and placebo labeled as Maxalt were similar. The efficacy of open-label placebo was superior to that of no treatment. Relative to no treatment, the placebo, under each information condition, accounted for more than 50% of the drug effect. Increasing "positive" information incrementally boosted the efficacy of both placebo and medication during migraine attacks. The benefits of placebo persisted even if placebo was honestly described. Whether treatment involves medication or placebo, the information provided to patients and the ritual of pill taking are important components of care.

Background A randomized, double-blind, multicenter study was conducted to compare the anti-tumor activity of letrozole vs. tamoxifen in postmenopausal women with ER and/or PgR positive primary untreated breast cancer Patients and methods Three hundred thirty-seven postmenopausal women with ER and/or PgR positive primary untreated breast cancer were randomly assigned once daily treatment with either letrozole 2 5 mg or tamoxifen 20 mg for four months At baseline none of the patients were considered to be candidates for breast-conserving surgery (BCS) and 14% of the patients were considered inoperable The primary endpoint was to compare overall objective response (CR + PR) determined by clinical palpation Secondary endpoints included overall objective response on ultrasound and mam-mography and the number of patients who qualified for BCS Results Overall objective response rate (clinical palpation) was statistically significantly superior in the letrozole group, 55% compared to tamoxifen, 36% (P < 0 001) Secondary endpoints of ultrasound response, 35% vs 25% (P = 0.042). mammographic response, 34% vs 16% (P < 0 001), and BCS. 45% vs. 35% (P = 0 022) between the letrozole and tamoxifen groups, respectively, showed letrozole to be significantly superior Both treatments were well tolerated Conclusions This study shows that letrozole is more effective than tamoxifen as preoperative therapy in postmenopausal patients with ER and/or PgR positive primary untreated breast cancer and is at least as well tolerated

Background: An increasing number of publications point to the importance of voriconazole plasma monitoring. Our aim was to develop a fast and simple LC-MS/MS method for the quantification of plasma voriconazole. Methods: 20 μL of plasma was extracted by adding a precipitation reagent containing the internal standard (d 3 -voriconazole). Analysis was performed on a Quattro Micro tandem mass spectrometer equipped with an Alliance HPLC 2795 separations module. MRM transitions were m/z 350.0→281.4 for voriconazole and m/z 353.0→284.4 for d 3 -voriconazole. Quantification was done by both linear calibration curves and multiplication of the response ratio by a predefined factor. Results: A method using protein precipitation as only pretreatment with an analysis time of 2 min was developed. Within-and between-run precision, expressed as coefficient of variation, at 6 concentrations ranged from 2.8% to 11.7%. Accuracy, expressed as a percentage of the theoretically added concentration, ranged from 89.0% to 109.0%. Linearity was demonstrated from 0.06 mg/L (0.17 μM) to 20.0 mg/L (57.3 μM). Conclusions: The described method offers a simple and rapid analysis of voriconazole in human plasma for clinical routine. Quantification with a predefined factor permits omitting calibration to each run and thereby reduces workload, costs and turn-around time.

A new sample pre-treatment technique termed cone-shaped membrane liquid phase microextraction (CSM-LPME) was developed and combined with micro-liquid chromatography (micro-LC) for the determination of selected pesticides in water samples. Four pesticides (hexaconazole, procymidone, quinalphos and vinclozolin) were considered as target analytes. Several important extraction parameters such as types of extraction solvent, agitation rate, pH value, total exposure time and effect of salt and humic acids were optimized. Enrichment factors of >50 folds were easily achieved within 20 min of extraction. The analytical data demonstrated relative standard deviations for the reproducibility of the optimized CSM-LPME method ranging from 6.3 to 7.5%. The correlation coefficients of the calibration curves were at least 0.9995 across a concentration range of 2–100 μg/L. The detection limits for all the analytes were found to be in the range of 1.1–1.9 μg/L.

We describe a unique case of a 67-year-old patient with primary uterine rhabdomyosarcoma with a history of breast cancer and gastrointestinal stromal tumor of the stomach. Uterine rhabdomyosarcoma was diagnosed in our patient during adjuvant treatment of breast cancer with anastrozole. To the best of our knowledge, the development of primary uterine rhabdomyosarcoma has never been described in patients treated with anastrozole. Due to the suggested causative role of tamoxifen in the development of uterine sarcomas, it is interesting to analyze whether the new drug, anastrozole, exerts any pathogenic effect on the development of uterine sarocomas.

In this study, we describe a green and simple procedure for the synthesis of steroidal 2Hpyrans 4-6 using chitosan as an eco-friendly heterogeneous catalyst. The synthesized compounds were characterized by IR, 1 H NMR, 13 C NMR, MS and analytical data. These compounds were tested in vitro against two cancer cell lines [HeLa (cervical) and Jurkat (leukemia)] and one normal cell line (PBMC). The compounds exhibited moderate to good activity against the two human cancer cell lines and were less toxic against the non-cancer cell line. In addition, the synthesized compounds were tested for their in vitro antioxidant activity by 1,1-diphenylpicrylhydrazyl method in which compounds 4 and 6 exhibited good antioxidant activity. This study provided a new molecular scaffold for the further development of anticancer as well as antioxidant agents.

Reaction of 1-adamantanecarbonyl chloride with certain carboxylic acid hydrazides in pyridine yielded the corresponding N-acyl adamantane-1-carbohydrazide derivatives 3a–j, which were cyclized to the corresponding 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles 4a–jvia heating with phosphorus oxychloride. Treatment of 1-adamantylisothiocyanate with some carboxylic acid hydrazides in ethanol yielded the corresponding 1-acyl-4-(1-adamantyl)-3-thiosemicarbazides 7a–g, which were cyclized to the corresponding 2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazole derivatives 8a–g. Compounds 4a–j, 7a–g, and 8a–g were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives produced good or moderate activities particularly against the tested Gram-positive bacteria Bacillus subtilis. Meanwhile, compounds 4i and 8g displayed marked antifungal activity against C. albicans. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using the carrageenin-induced paw oedema method in rats. The oxadiazole derivatives 4c, 4g, 4i and 4j produced good dose-dependent anti-inflammatory activity.New compounds with the above structures were synthesized and tested for antimicrobial and anti-inflammatory activity.

The indolinonic and quinolinic aromatic nitroxides synthesized by us are a novel class of biological antioxidants, which afford a good degree of protection against free radical-induced oxidation in different lipid and protein systems. To further our understanding of their antioxidant behavior, we thought it essential to have more information on their effects on DNA exposed to free radicals. Here, we report on the results obtained after exposure of plasmid DNA and calf thymus DNA to peroxyl radicals generated by the water-soluble radical initiator, 2,2Ј-azobis(2amidinopropane)dihydrochloride (AAPH), and the protective effects of the aromatic nitroxides and their hydroxylamines, using a simple in vitro assay for DNA damage. In addition, we also tested for the potential of these nitroxides to inhibit hydroxyl radical-mediated DNA damage inflicted by Fenton-type reactions using copper and iron ions. The commercial aliphatic nitroxides 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), and bis(2,2,6,6-tetramethyl-1-oxyl-piperidin-4-yl)sebacate (TINUVIN 770) were included for comparison. The results show that the majority of compounds tested protect: (i) both plasmid DNA and calf thymus DNA against AAPH-mediated oxidative damage in a concentration-dependent fashion (1-0.1 mM), (ii) both Fe(II) and Cu(I) induced DNA oxidative damage. However, all compounds failed to protect DNA against damage inflicted by the presence of the transition metals in combination with H 2 O 2 . The differences in protection between the compounds are discussed in relation to their molecular structure and chemical reactivity.

Purpose: In this study, the antiproliferative effects of the aromatase inhibitor anastrozole (arimidex®) was evaluated on estrogen receptor (ER) positive FM3A cell line originated from C3H mouse mammary carcinoma. Methods: For this purpose cell kinetic parameters including viability analysis, mitotic index and labelling index were used. Three different doses of anostrozole (D1= 0.01 μM, D2= 0.1μM, D3= 1μM) were applied to cells for 24 h to determine the most effective dose. A dose of 1μM dose was determined as the most effective and this was used in all subsequent applications for 0-72 h. Results: The results showed that there was a significant decrease in viability, mitotic index and labelling index for all experimental groups. The differences between control and all experimental groups were statistically significant (p&lt;0.01) for all applications. Conclusions: Anastrozole offers a promising treatment modality in estrogen sensitive breast cancer.

1 In the present study we investigated the role of A 2A adenosine receptors in hippocampal synaptic transmission under in vitro ischaemia-like conditions. 2 The eects of adenosine, of the selective A 2A receptor agonist, CGS 21680 (2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine), and of selective A 2A receptor antagonists, ZM 241385 (4-(2-[7-amino-2-(2-furyl)-{1,2,4}-triazolo{2,3-a}{1,3,5}triazin-5-ylamino]ethyl)phenol) and SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine), have been evaluated on the depression of ®eld e.p.s.ps induced by an in vitro ischaemic episode. 3 The application of 2 min of in vitro ischaemia brought about a rapid and reversible depression of ®eld e.p.s.ps, which was completely prevented in the presence of the A 1 receptor antagonist DPCPX (1,3-dipropyl-8-cyclopentylxanthine) (100 nM). On the other hand both A 2A receptor antagonists, ZM 241385 and SCH 58261, by themselves did not modify the ®eld e.p.s.ps depression induced by in vitro ischaemia. 4 A prolonged application of either adenosine (100 mM) or CGS 21680 (30, 100 nM) before the in vitro ischaemic episode, signi®cantly reduced the synaptic depression. These eects were antagonized in the presence of ZM 241385 (100 nM). 5 SCH 58261 (1 and 50 nM) did not antagonize the eect of 30 nM CGS 21680 on the ischaemiainduced depression. 6 These results indicate that in the CA1 area of the hippocampus the stimulation of A 2A adenosine receptors attenuates the A 1 -mediated depression of synaptic transmission induced by in vitro ischaemia.

It is no longer necessary to use dialkylzinc reagents to obtain enantioselectivities &gt;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.

Iron overload in b-thalassemia major (TM) typically results in iron-induced cardiomyopathy, liver disease, and endocrine complications. We examined the incidence and progression of endocrine disorders (hypothyroidism, diabetes, hypoparathyroidism, hypogonadism), growth and pubertal delay, and bone metabolism disease during long-term deferasirox chelation therapy in a real clinical practice setting. We report a multicenter retrospective cohort study of 86 transfusion-dependent patients with TM treated with once daily deferasirox for a median duration of 6.5 years, up to 10 years. No deaths or new cases of hypothyroidism or diabetes occurred. The incidence of new endocrine complications was 7% (P 5 0.338, for change of prevalence from baseline to end of study) and included hypogonadism (n 5 5) and hypoparathyroidism (n 5 1). Among patients with hypothyroidism or diabetes at baseline, no significant change in thyroid parameters or insulin requirements were observed, respectively. Mean lumbar spine bone mineral density increased significantly (P < 0.001) and the number of patients with lumbar spine osteoporosis significantly decreased (P 5 0.022) irrespective of bisphosphonate therapy, hormonal replacement therapy, and calcium or vitamin D supplementation. There were no significant differences in the number of pediatric patients below the 5th centile for height between baseline and study completion. Six pregnancies occurred successfully, and four of them were spontaneous without ovarian stimulation. This is the first study evaluating endocrine function during the newest oral chelation therapy with deferasirox. A low rate of new endocrine disorders and a stabilization of those pre-exisisting was observed in a real clinical practice setting.

Chagas disease, a chronic systemic parasitosis caused by the Kinetoplastid protozoon Trypanosoma cruzi, is the first cause of cardiac morbidity and mortality in poor rural and suburban areas of Latin America and the largest parasitic disease burden in the continent, now spreading worldwide due to international migrations. A recent change in the scientific paradigm on the pathogenesis of chronic Chagas disease has led to a consensus that all T. cruzi-seropositive patients should receive etiological treatment. This important scientific advance has spurred the rigorous evaluation of the safety and efficacy of currently available drugs (benznidazole and nifurtimox) as well as novel anti-T. cruzi drug candidates in chronic patients, who were previously excluded from such treatment. The first results indicate that benznidazole is effective in inducing a marked and sustained reduction in the circulating parasites' level in the majority of these patients, but adverse effects can lead to treatment discontinuation in 10-20% of cases. Ergosterol biosynthesis inhibitors, such as posaconazole and ravuconazole, are better tolerated but their efficacy at the doses and treatment duration used in the initial studies was significantly lower; such results are probably related to suboptimal exposure and/or treatment duration. Combination therapies are a promising perspective but the lack of validated biomarkers of response to etiological treatment and eventual parasitological cures in chronic patients remains a serious challenge.

Regular blood transfusions from an early age are an essential therapy for patients with b-thalassaemia major in order to achieve optimal growth and adequate organ function, as well as to improve survival. As the human body cannot excrete excess iron, regularly transfused patients with b-thalassaemia will accumulate toxic, and eventually lethal levels of iron in the body. For more than 40 yr, deferoxamine (Desferal Ò ; Novartis Pharma AG, Basel, Switzerland) has been the established chelation therapy for iron-overloaded patients, however the demanding infusion regimen often results in poor patient compliance.(1-3) Deferiprone (Ferriprox Ò ; Apotex Inc., Toronto, ON, Canada) is a three-times daily, oral iron chelator that is available as a second-line therapy for b-thalassaemia

An expeditious method for the determination of triclosan (TCS) and methyl triclosan (MTCS) in sludge and sediment samples is presented. Extraction and cleanup steps were integrated in the same process using matrix solid-phase dispersion as sample preparation technique. Effects of different variables on the efficiency and the selectivity of the sample preparation process are discussed. Under final working conditions, samples (0.5 g) were dispersed with diatomaceous earth (1 g) and transferred to a polypropylene syringe containing 2 g of silica impregnated with sulphuric acid (15%, w:w). Analytes were recovered with 10 mL of dichloromethane. After solvent exchange to ethyl acetate, TCS was converted into the tert-butyldimethylsilyl derivative, and the extract was analysed by gas chromatography-mass spectrometry, without any additional cleanup. Obtained recoveries, for sludge and sediment samples spiked at different concentration levels, ranged from 86% to 113%, with associated standard deviations between 2 and 13%. Limits of quantification of the global method were 6 and 7 ng g−1 for MTCS and TCS, respectively. Both compounds were detected in all the processed sludge samples with maximum concentrations of 191 ng g−1 (MTCS) and 2,640 ng g−1 (TCS). The parent bactericide was also found in some sediment samples at concentrations up to 200 ng g−1.

The new mononuclear neutral metal complexes of the type [M(L) 2 (H 2 O) n X n ] (where n= 0,1,2…; X= Cl; ½ SO 4 ; CH 3 COO; Br) by using the metal(II/III) salts {M = Cu(II), Co(II), Ni(II), Pd(II) and Ru(III)} with the Clomiphene citrate (L) were synthesized. The ligand and its complexes were characterized by elemental analysis, infrared, ESR, 1 H-NMR, electronic spectral studies and magnetic susceptibility measurement, which reveals that L acts as a monodentate ligand. They simultaneously give Thermogravimetric and Differential Thermal Analysis patterns of the complexes recorded at heating rate of 10 °C min -1 . The antimicrobial activity of ligand and its metal complexes were evaluated against Gram positive and Gram negative bacteria.

In oil palm plantations, the fungicide hexaconazole is used to control Ganoderma infection that threatens to destroy or compromisethe palm. The application of hexaconazole is usually through soil drenching, trunk injection, or a combination of these two methods. It is therefore important to have a method to determine the residual amount of hexaconazole in the field such as in samples of water, soil, and leaf to monitor the use and fate of the fungicide in oil palm plantations. This study on the behaviour of hexaconazole in oil palm agro-environment was carried out at the UKM-MPOB Research Station, Bangi Lama, Selangor. Three experimental plots in this estate with 7-year-old Dura x Pisifera (DxP) palms were selected for the field trial. One plot was sprayed with hexaconazole at the manufacturer's recommended dosage, one at double the recommended dosage, and the third plot was untreated control. Hexaconazole residues in the soil, leaf, and water were determined before and after fungicide treatment. Soil samples were randomly collected from three locations at different depths (0-50 cm) and soil collected fromthe same depth were bulked together. Soil, water, and palm leaf were collected at À1 (day before treatment), 0 (day of treatment), 1, 3, 7, 14, 21, 70, 90, and 120 days after treatment. Hexaconazole was detected in soil and oil palm leaf, but was not detected in water from the nearby stream.

Optisol-GS, the most common corneal storage medium in the United States, contains antibacterial but no antifungal supplementation. Most postkeratoplasty endophthalmitis and keratitis cases are now of a fungal origin. To assess the efficacy and safety of voriconazole and amphotericin B in reducing Candida species contamination of Optisol-GS under normal storage conditions. In vitro laboratory study using 15 pairs of research-grade donor corneas and 20-mL vials of Optisol-GS. Twenty vials of Optisol-GS were supplemented with either voriconazole at 1×, 10×, 25×, or 50× minimum inhibitory concentration (MIC) or amphotericin B at 0.25×, 0.5×, 1×, or 10× MIC. Known concentrations of Candida albicans and Candida glabrata were each added to a set of vials. Safety studies were performed by separating 15 pairs of donor corneas into unsupplemented Optisol-GS or Optisol-GS plus an antifungal. Efficacy outcomes were viable fungal colony counts determined from samples taken on days 2, 7, and 14 immediately after removal from refrigeration and after warming to room temperature for 2 hours. Safety outcomes included percentage of intact epithelium and endothelial cell density on days 0, 7, and 14, as well as percentage of nonviable endothelial cells by vital dye staining on day 14. Growth of C albicans and C glabrata was observed in all voriconazole-supplemented vials. In contrast, there was no growth of either organism in amphotericin B-supplemented vials, except at 0.25× and 0.5× MIC on day 2, when viable counts of C glabrata were reduced by 99% and 96%, respectively. Compared with paired controls, with the exception of Optisol-GS plus amphotericin B at 10× MIC, donor corneas in supplemented Optisol-GS appeared to have no difference in endothelial cell density reduction, percentage of intact epithelium, or percentage of nonviable endothelial cells. The addition of amphotericin B to Optisol-GS may significantly improve activity against contamination with Candida species, the primary cause of fungal infection after corneal transplantation. This study found significant endothelial toxic effects at the maximal concentration of amphotericin B.

Chitosan is functionalized with poly(ethylene glycol) methyl ether (mPEG) at the amino and hydroxyl groups via a single step reaction in a homogeneous aqueous system. A chitosan aqueous solution obtained from the mixture of chitosan and hydroxybenzotriazole (HOBt) in water is a key factor in providing mild conditions to conjugate mPEG by using a carbodiimide conjugating agent. The reaction at ambient temperature for 24 h gives chitosan-g-mPEG with water solubility with mPEG content as high as 42%. This work demonstrates that a water-soluble chitosan-HOBt complex is an effective system for the preparation of chitosan derivatives via the aqueous system without the use of acids or organic solvents. #

The major cytotoxic metabolites of Lisroclinum patella from Pohnpei have been isolated and identified. Most of the cytotoxicity is attributed to a new cyclic peptide, ulithiacyclamide B { 4 ] , which is closely related to ulithiacyclamide 11). The proposed structure of 4 is based on spectroscopic analysis and chemical degradation. Compound 4 exhibits an ICso of 17 ng/ml against the KB cell line but does not show selective cytotoxicity against solid tumor cells in the Corbett assay. Extracts of the ascidian Lissoclinum patella Gottschaldt are generally strongly cytotoxic (IC5,'s against KB, a human nasopharyngeal carcinoma cell line, 1. 0. 0 0 1 p,g/ml). The thiazole-containing cyclic peptide ulithiacyclamide 111 (1,2) is responsible for most of the cytotoxicity (3) of L. patella from Palau. Several other thiazole-containing cyclic peptides which are much less cytotoxic, e.g., patellamides A, B 121, and C 131 (2 4 , are also present in the Palauan tunicate. Ulithiacyclamide also accounts for most of the cytotoxicity of L. patella from Tudu Island in the Torres Straits, north of Queensland, Australia. (The Tudu Island tunicate also contained patellamides A X .) Recently thiazole-containing macrolides, the patellazoles, have been shown to be responsible for the potent cytotoxicity of L. patella from Fiji (5) and Guam (6). W e report here the isolation and structure determination of the potent cytotoxin associated with L. patella from Pohnpei. Fractionation of the crude extract (KB IC,, = 1 p,g/ml) by flash Si gel chromatography yielded several fractions which were further purified by hplc to give patellamides A, B 121, and C 131 (2-4) and a new cyclic peptide ulithiacyclamide B 141. Ulithiacyclamide 111 was not present in this variety of L. patella.

A novel, quick, simple and highly sensitive spectrofluorimetric method was developed and validated for the determination of sitagliptin (SG) in its pharmaceutical formulations. The proposed method is based on investigation of the fluorescence spectral behavior of sitagliptin in an SDS micellar system. In an aqueous solution of phosphate buffer pH 4.0, the fluorescence intensity of SG in the presence of SDS was greatly enhanced, by 200%, i.e. twofold enhancement. The fluorescence intensity of SG was measured at 300 nm after excitation at 270 nm. The method showed good linearity in the range 0.03-10.0 mg/mL with a good correlation coefficient (r = 0.9998). The limits of detection and quantitation values were 5.31 and 16.1 ng/mL, respectively. The proposed method was successfully applied to the analysis of SG in its single and co-formulated commercial tablets; the results were in good agreement with those obtained using a reference method. Application of the proposed method was extended to stability studies of SG after exposure to different forced degradation conditions according to the ICH guidelines, such as acidic, alkaline, thermal, photo-and oxidative stress. The chemical structure of certain potential degradation products (DPs) were investigated using LC-MS. a The average of three separate determinations. M. M. Salim et al.

New measures of iron accumulation in liver and heart (superconducting quantum inference device and magnetic resonance imaging), and oral iron chelators (deferiprone and deferasirox) are available for managing iron overload in thalassemia major. To assure appropriate use of these new health technologies, the Italian Society of Hematology appointed a panel of experts to produce clinical practiceguidelines for the management of iron overload in thalassemia major and related disorders. The analytical hierarchy process, a technique for multicriteria decision analysis, was applied to relevant key questions in order to identify the alternative strategies, generate explicit criteria for their evaluation, and check how well the alternatives fulfilled the criteria. The result of a comprehensive systematic review of articles released from 1990 to 2007 was used as a source of scientific evidence to compare the decisional options pairwise, and select the final recommendation. Every step in the model was developed from questionnaires and group discussion. The resulting recommendations advise about which examination to carry out in order to plan iron chelation therapy, when to start iron chelation, which iron chelator to choose in regularly transfused patients, how to monitor iron chelation therapy, and when and how to switch standard therapy.