The Effect of Donepezil Treatment on Cardiovascular Mortality

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Sato, K; Urbano, R; Yu, C; Yamasaki, F; Sato, T; Jordan, J; Robertson, D; Diedrich, A

2010-01-01

The acetylcholinesterase inhibitor donepezil hydrochloride improves cognitive function in patients with Alzheimer’s disease and vascular dementia. Given acetylcholine’s important actions on the heart, we undertook a retrospective cohort investigation to assess whether donepezil usage affects cardiovascular mortality. In patients treated with donepezil, hazard ratios for total and cardiovascular mortality were 0.68 (P = 0.045, 95% confidence interval 0.46–0.99) and 0.54 (P = 0.042, 95% confide...

Neuroprotection against vascular dementia after acupuncture combined with donepezil hydrochloride: P300 event related potential

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Qiang Liu

2016-01-01

Full Text Available Acupuncture can be used to treat various nervous system diseases. Here, 168 vascular dementia patients were orally administered donepezil hydrochloride alone (5 mg/day, once a day for 56 days, or combined with acupuncture at Shenting (DU24, Tianzhu (BL10, Sishencong (Extra, Yintang (Extra, Renzhong (DU26, Neiguan (PC6, Shenmen (HT7, Fengchi (GB20, Wangu (GB12 and Baihui (DU20 (once a day for 56 days. Compared with donepezil hydrochloride alone, P300 event related potential latency was shorter with an increased amplitude in patients treated with donepezil hydrochloride and acupuncture. Mini-Mental State Examination score was also higher. Moreover, these differences in P300 latency were identified within different infarcted regions in patients treated with donepezil hydrochloride and acupuncture. These findings indicate that acupuncture combined with donepezil hydrochloride noticeably improves cognitive function in patients with vascular dementia, and exerts neuroprotective effects against vascular dementia.

Enzymes and Inhibitors in Neonicotinoid Insecticide Metabolism

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Shi, Xueyan; Dick, Ryan A.; Ford, Kevin A.; Casida, John E.

2009-01-01

Neonicotinoid insecticide metabolism involves considerable substrate specificity and regioselectivity of the relevant CYP450, aldehyde oxidase, and phase II enzymes. Human CYP450 recombinant enzymes carry out the following conversions: CYP3A4, 2C19 and 2B6 for thiamethoxam (TMX) to clothianidin (CLO); 3A4, 2C19 and 2A6 for CLO to desmethyl-CLO; 2C19 for TMX to desmethyl-TMX. Human liver aldehyde oxidase reduces the nitro substituent of CLO to nitroso much more rapidly than that of TMX. Imidacloprid (IMI), CLO and several of their metabolites do not give detectable N-glucuronides but 5-hydroxy-IMI, 4,5-diol-IMI and 4-hydroxy-thiacloprid are converted to O-glucuronides in vitro with mouse liver microsomes and UDP-glucuronic acid or in vivo in mice. Mouse liver cytosol with S-adenosylmethionine converts desmethyl-CLO to CLO but not desmethyl-TMX to TMX. Two organophosphorus CYP450 inhibitors partially block IMI, thiacloprid and CLO metabolism in vivo in mice, elevating the brain and liver levels of the parent compounds while reducing amounts of the hydroxylated metabolites. PMID:19391582

Comprehensive quantum chemical and spectroscopic (FTIR, FT-Raman, 1H, 13C NMR) investigations of O-desmethyltramadol hydrochloride an active metabolite in tramadol - An analgesic drug

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Arjunan, V.; Santhanam, R.; Marchewka, M. K.; Mohan, S.

2014-03-01

O-desmethyltramadol is one of the main metabolites of tramadol widely used clinically and has analgesic activity. The FTIR and FT-Raman spectra of O-desmethyl tramadol hydrochloride are recorded in the solid phase in the regions 4000-400 cm-1 and 4000-100 cm-1, respectively. The observed fundamentals are assigned to different normal modes of vibration. Theoretical studies have been performed as its hydrochloride salt. The structure of the compound has been optimised with B3LYP method using 6-31G** and cc-pVDZ basis sets. The optimised bond length and bond angles are correlated with the X-ray data. The experimental wavenumbers were compared with the scaled vibrational frequencies determined by DFT methods. The IR and Raman intensities are determined with B3LYP method using cc-pVDZ and 6-31G(d,p) basic sets. The total electron density and molecular electrostatic potential surfaces of the molecule are constructed by using B3LYP/cc-pVDZ method to display electrostatic potential (electron + nuclei) distribution. The electronic properties HOMO and LUMO energies were measured. Natural bond orbital analysis of O-desmethyltramadol hydrochloride has been performed to indicate the presence of intramolecular charge transfer. The 1H and 13C NMR chemical shifts of the molecule have been anlysed.

The combination of donepezil and procyclidine protects against soman-induced seizures in rats

International Nuclear Information System (INIS)

Haug, Kristin Huse; Myhrer, Trond; Fonnum, Frode

2007-01-01

Current treatment of nerve agent poisoning consists of prophylactic administration of pyridostigmine and therapy using atropine, an oxime and a benzodiazepine. Pyridostigmine does however not readily penetrate the blood-brain barrier giving ineffective protection of Brain against centrally mediated seizure activity. In this study, we have evaluated donepezil hydrochloride, a partial reversible inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer's disease, in combination with procyclidine, used in treatment of Parkinson's disease and schizophrenia, as prophylaxis against intoxication by the nerve agent soman. The results demonstrated significant protective efficacy of donepezil (2.5 mg/kg) combined with procyclidine (3 or 6 mg/kg) when given prophylactically against a lethal dose of soman (1.6x LD 50 ) in Wistar rats. No neuropathological changes were found in rats treated with this combination 48 h after soman intoxication. Six hours after soman exposure cerebral AChE activity and acetylcholine (ACh) concentration was 5% and 188% of control, respectively. The ACh concentration had returned to basal levels 24 h after soman intoxication, while AChE activity had recovered to 20% of control. Loss of functioning muscarinic ACh receptors (17%) but not nicotinic receptors was evident at this time point. The recovery in brain AChE activity seen in our study may be due to the reversible binding of donepezil to the enzyme. Donepezil is well tolerated in humans, and a combination of donepezil and procyclidine may prove useful as an alternative to the currently used prophylaxis against nerve agent intoxication

Donepezil improved memory in multiple sclerosis in a randomized clinical trial.

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Krupp, L B; Christodoulou, C; Melville, P; Scherl, W F; MacAllister, W S; Elkins, L E

2004-11-09

To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS). This single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change. Donepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010). Donepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.

A Rare Case of Acute Renal Failure Secondary to Rhabdomyolysis Probably Induced by Donepezil

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Osman Zikrullah Sahin

2014-01-01

Full Text Available Introduction. Acute renal failure (ARF develops in 33% of the patients with rhabdomyolysis. The main etiologic factors are alcoholism, trauma, exercise overexertion, and drugs. In this report we present a rare case of ARF secondary to probably donepezil-induced rhabdomyolysis. Case Presentation. An 84-year-old male patient was admitted to the emergency department with a complaint of generalized weakness and reduced consciousness for two days. He had a history of Alzheimer’s disease for one year and he had taken donepezil 5 mg daily for two months. The patient’s physical examination revealed apathy, loss of cooperation, and decreased muscle strength. Laboratory studies revealed the following: urea: 128 mg/dL; Creatinine 6.06 mg/dL; creatine kinase: 3613 mg/dL. Donepezil was discontinued and the patient’s renal function tests improved gradually. Conclusion. Rhabdomyolysis-induced acute renal failure may develop secondary to donepezil therapy.

Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial.

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Rapp, Stephen R; Case, L Doug; Peiffer, Ann; Naughton, Michelle M; Chan, Michael D; Stieber, Volker W; Moore, Dennis F; Falchuk, Steven C; Piephoff, James V; Edenfield, William J; Giguere, Jeffrey K; Loghin, Monica E; Shaw, Edward G

2015-05-20

Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function. A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated. Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment. Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments. © 2015 by American Society of Clinical Oncology.

Comprehensive quantum chemical and spectroscopic (FTIR, FT-Raman, 1H, 13C NMR) investigations of O-desmethyltramadol hydrochloride an active metabolite in tramadol--an analgesic drug.

Science.gov (United States)

Arjunan, V; Santhanam, R; Marchewka, M K; Mohan, S

2014-03-25

O-desmethyltramadol is one of the main metabolites of tramadol widely used clinically and has analgesic activity. The FTIR and FT-Raman spectra of O-desmethyl tramadol hydrochloride are recorded in the solid phase in the regions 4000-400 cm(-1) and 4000-100 cm(-1), respectively. The observed fundamentals are assigned to different normal modes of vibration. Theoretical studies have been performed as its hydrochloride salt. The structure of the compound has been optimised with B3LYP method using 6-31G(**) and cc-pVDZ basis sets. The optimised bond length and bond angles are correlated with the X-ray data. The experimental wavenumbers were compared with the scaled vibrational frequencies determined by DFT methods. The IR and Raman intensities are determined with B3LYP method using cc-pVDZ and 6-31G(d,p) basic sets. The total electron density and molecular electrostatic potential surfaces of the molecule are constructed by using B3LYP/cc-pVDZ method to display electrostatic potential (electron+nuclei) distribution. The electronic properties HOMO and LUMO energies were measured. Natural bond orbital analysis of O-desmethyltramadol hydrochloride has been performed to indicate the presence of intramolecular charge transfer. The (1)H and (13)C NMR chemical shifts of the molecule have been anlysed. Copyright © 2013 Elsevier B.V. All rights reserved.

Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats.

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Kosasa, T; Kuriya, Y; Matsui, K; Yamanishi, Y

1999-09-10

The effects of oral administration of the centrally acting acetylcholinesterase (AChE) inhibitors, donepezil hydrochloride (donepezil: E2020: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride), tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and ENA-713 (rivastigmine: (S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate), which have been developed for the treatment of Alzheimer's disease, on the extracellular acetylcholine concentration in the hippocampus of rats were evaluated by using a microdialysis technique without adding cholinesterase inhibitor to the perfusion solution. We also compared the inhibition of brain AChE and the brain concentrations of these drugs. Donepezil at 2.5 mg/kg and tacrine at 5 mg/kg showed significant effects for more than 6 h. At these doses, the maximum increases were observed at about 1.5 h after administration of donepezil, and at about 2 h with tacrine, and were 499% and 422% of the pre-level, respectively. ENA-713 produced significant effects at doses of 0.625, 1.25 and 2.5 mg/kg, which lasted for about 1, 2 and 4 h, respectively. The maximum increases produced by these doses at about 0.5 h after administration were 190, 346 and 458% of the pre-level, respectively. The time courses of brain AChE inhibition with donepezil at 2.5 mg/kg, tacrine at 10 mg/kg and ENA-713 at 2.5 mg/kg were mirror images of the extracellular acetylcholine-increasing action at the same doses. The time courses of the brain concentrations of drugs after oral administration of donepezil at 2.5 mg/kg and tacrine at 10 mg/kg were consistent with those of brain AChE inhibition at the same doses, and there was a linear relation between these parameters. Brain concentration of ENA-713 at 2.5 mg/kg was below the limit of quantification at all time points measured. These results suggest that oral administration of donepezil, tacrine and ENA-713 increases acetylcholine concentration in the

Research progress of donepezil for treating mild to moderate Alzheimer's disease

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Xin-xin LI

2017-02-01

Full Text Available Donepezil is the second generation of cholinesterase inhibitors (ChEIs, which has a good effect on mild to moderate Alzheimer's disease (AD. In recent years, there were a lot of studies on the mechanism of donepezil. This paper mainly introduces the diagnosis and treatment situation of AD in China, and the action mechanism of donepezil in the treatment of mild to moderate AD. DOI: 10.3969/j.issn.1672-6731.2017.02.012

Effects of donepezil on behavioural manifestations of thalamic infarction: a single case observation

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Rodrigo eRiveros

2011-03-01

Full Text Available Objective: To examine the effect of donepezil for the treatment of cognitive and behavioural disorders associated with thalamic lesions in a 45 years old male who suffered an infarct in the left thalamus. Background: Recent studies suggest that donepezil may improve executive functions impairments due to subcortical ischemic lesionsMethod: The crossover effects of donepezil were analyzed in a single case of thalamic infarction with cognitive and behavioural alterations. Results: Significant behavioural modifications related to improved performances in executive functions were observed with the treatment. Conclusions: The results suggest that donepezil may have significant effect on executive functions that can alter behavioural outcomes after thalamic infarctions

Donepezil- and scopolamine-induced rCMRglu changes assessed by PET in conscious rhesus monkeys

International Nuclear Information System (INIS)

Asai, Makoto; Fujikawa, Akihiko; Noda, Akihiro; Miyoshi, Sosuke; Nishimura, Shintaro; Matsuoka, Nobuya

2009-01-01

[ 18 F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is a useful tool for measuring the regional cerebral metabolic rate of glucose (rCMRglu), which is an index of neuronal activity. Donepezil, an acetylcholine esterase inhibitor (AChEI), has been recommended as a treatment option for patients with Alzheimer's disease (AD). We aimed to characterize the effects of donepezil on rCMRglu using FDG-PET in non-human primates. We investigated the effects of administration of donepezil (500 μg/kg, intramuscularly (i.m.)), the non-selective muscarinic ACh receptor antagonist scopolamine (30 μg/kg, i.m.), and the coadministration of both drugs on the rCMRglu of conscious young rhesus monkeys. Donepezil increased the rCMRglu in all regions of interest except in the thalamus. Scopolamine treatment also increased the rCMRglu in all regions of interest except the cerebellum and thalamus. However, these effects disappeared with coadministration of the drugs. This PET study showed that administration of donepezil or scopolamine alone increased the rCMRglu in conscious rhesus monkeys. We also found that the donepezil-induced increase was abolished by simultaneous administration of scopolamine, suggesting that muscarinic ACh receptor function plays an important role in the effect of donepezil. (author)

Pharmacist-based Donepezil Outpatient Consultation Service to improve medication persistence

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Watanabe N

2012-08-01

Full Text Available Norio Watanabe,1,2 Keiko Yamamura,3 Yusuke Suzuki,4 Hiroyuki Umegaki,4 Katsuro Shigeno,5 Ryo Matsushita,1 Yoshimichi Sai,1 Ken-ichi Miyamoto,1 Kiyofumi Yamada61Department of Clinical Pharmacy, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa, Japan; 2Department of Pharmacy, Hashima Municipal Hospital, Hashima, Gifu, Japan; 3Department of Clinical Pharmacy, School of Pharmacy, Aichi Gakuin University, Nagoya, Aichi, Japan; 4Department of Community Healthcare and Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; 5Department of Pharmacy Practice and Sciences, School of Pharmacy, Aichi Gakuin University, Nagoya, Aichi, Japan; 6Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Aichi, JapanAim: Donepezil is widely used to delay the progression of cognitive dysfunction in patients with Alzheimer's disease (AD, but the efficacy of pharmacotherapy is often reduced by poor adherence to medication. In order to improve adherence by providing information about AD and the significance of pharmacotherapy, the Donepezil Outpatient Consultation Service (DOCS was set up. The influence of this service on medication persistence was assessed in the present study.Methods: Among outpatients starting donepezil therapy, we enrolled 59 patients between April 2008 and September 2010 before establishment of the DOCS (non-DOCS group and 52 patients between October 2010 and March 2012 who attended the DOCS (DOCS group. Each patient's and their caregiver's understanding about the clinical features of AD and pharmacotherapy with donepezil were also assessed. Their understanding was compared before and after the DOCS, and the 1-year medication persistence rate and the reasons for discontinuation were also investigated.Results: The 1-year medication persistence rate was significantly higher in the DOCS group than in the non-DOCS group (73

Efficacy Of Rivastigmine And Donepezil On Cognitive Impairment Of Vascular Dementia - Some Preliminary Observations

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Jha S

2004-01-01

Full Text Available Background: Vascular Dementia (VaD is common, global, disabling and a rather neglected, age related dementia. It is important to identify and treat it since cognitive impairment produces dysfunction in occupational and social life. Moreso, due to increase in geriatric population, incidence and prevalence of VaD is also increasing. Aim: We share our observations on efficacy of Rivastigmine and Donepezil (drugs advocated for improving cognition in dementia in patients of VaD. Material and Method: This was a non-randomized study based on clinical evaluation. We selected 53 patients suffering from VaD (as per clinical and radiological criteria. Their age range was 55-78 years (mean 65.3 + 6.2 yrs. Clinical, biochemical and radiological (Cranial CT and MRI evaluation was done to establish etiology. Cognition was measured using modified Mini Mental State Examination (MMSE which was repeated 2 times, at interval of 3 months. We observed the role of Rivastigmine in 14 and Donepezil in 19 patients of VaD. The change in MMSE score was compared with 20 control patients of VaD. The associated risk factors like hypertension, diabetes, hyperlipidemia etc. were managed. Acetyl Salicylic Acid (ASA in dose of 150mg/day was given as an antiplatelet agent to all 53 patients in this study. Results: At end of study, no statistically significant improvement was observed in MMSE score in any of the 53 patients. Improvement in MMSE score (though statistically insignificant was observed with Rivastigmine in 11 and with Donepezil in 14 patients. Progressive decline in MMSE score was observed in 14 (70% control patients of VaD who did not receive rivastigmine or donepezil. Conclusion - Rivastigmine and Donepezil are beneficial in halting deterioration of dementia in patients suffering from VaD.

Liquid chromatography and liquid chromatography-mass spectrometry analysis of donepezil degradation products

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Mladenović Aleksandar R.

2015-01-01

Full Text Available This study describes the investigation of degradation products of donepezil (DP using stability indicating RP-HPLC method for determination of donepezil, which is a centrally acting reversible acetylcholinesterase inhibitor. In order to investigate the stability of drug and formed degradation products, a forced degradation study of drug sample and finished product under different forced degradation conditions has been conducted. Donepezil hydrochloride and donepezil tablets were subjected to stress degradation conditions recommended by International Conference on Harmonization (ICH. Donepezil hydrochloride solutions were subjected to acid and alkali hydrolysis, chemical oxidation and thermal degradation. Significant degradation was observed under alkali hydrolysis and oxidative degradation conditions. Additional degradation products were observed under the conditions of oxidative degradation. The degradation products observed during forced degradation studies were monitored using the high performance liquid chromatography (HPLC method developed. The parent method was modified in order to obtain LC-MS compatible method which was used to identify the degradation products from forced degradation samples using high resolution mass spectrometry. The mass spectrum provided the precise mass from which derived molecular formula of drug substance and degradation products formed and proved the specificity of the method unambiguously. [Projekat Ministarstva nauke Republike Srbije, br. 172013

Serotonin syndrome following sibutramine poisoning in a child, with sequential quantification of sibutramine and its primary and secondary amine metabolites in plasma.

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Bucaretchi, Fábio; de Capitani, Eduardo Mello; Mello, Sueli Moreira; Lanaro, Rafael; Barros, Roberta F; Fernandes, Luciane C R; da Costa, José Luiz; Hyslop, Stephen

2009-07-01

To report a case of serotonin syndrome (SS) after sibutramine overdose in a child. A 4-year-old girl was admitted 25 h after accidentally ingesting approximately 27 pills of sibutramine (15 mg, approximately 23 mg/kg). The child developed clinical features suggestive of SS, including diaphoresis, tachycardia, hypertension, agitation, insomnia, incoordination, hypertonia (lower limbs > upper limbs), and hallucinations. Serum creatine phosphokinase levels reached a peak on day 3 (2,577 U/L, reference value sibutramine and the active metabolites, M1 (mono-desmethyl sibutramine) and M2 (di-desmethyl sibutramine), by liquid chromatography/electrospray ionization tandem mass spectrometry in six sequential samples collected from 25 to 147 h post-ingestion revealed a nonlinear decrease in the log-scale plasma concentrations. Treatment was only supportive and involved prolonged sedation to control the agitation, sleeplessness, and hypertension; no cyproheptadine was used. The patient was discharged on day 6 and follow-up revealed no sequelae. To our knowledge, this is the first report of SS after sibutramine overdose in a child, with sequential monitoring of the plasma levels of the drug and its two active metabolites. The growing consumption of weight reducing pills may increase the risk of unintentional acute toxic exposures in children.

Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease

DEFF Research Database (Denmark)

Waldemar, Gunhild; Gauthier, Serge; Jones, Roy

2011-01-01

To determine whether donepezil treatment (10 mg/day over 24 weeks) is associated with delayed emergence of apathy in patients with mild to moderate Alzheimer's disease (AD) and to explore relationships between donepezil's effects on apathy and other Neuropsychiatric Inventory (NPI...

Effect of donepezil hydrochloride on brain perfusion in patients with dementia of Alzheimer type, evaluated by I-123-IMP SPECT

International Nuclear Information System (INIS)

Ogura, Y.; Narabayashi, I.; Utsunomiya, K.; Komori, T.; Adachi, I.; Sugino, M.; Sakai, J.

2002-01-01

Aim: To evaluate the effects of donepezil hydrochloride on brain perfusion in patients with dementia of Alzheimer type (DAT). Materials and Methods: I-123-IMP SPECT was performed on 12 controls (5 males and 7 females, mean age 69.7±6.4) and 30 consecutive patients with DAT (9 males and 21 females, mean age 71.0±5.1) to assess regional cerebral blood flow (rCBF) using the I-123-IMP autoradiography method. All 30 patients were diagnosed as having DAT by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. In 23 of the 30 DAT patients, rCBF in the parietal, occipital, temporal cortex, or hippocampus was decreased more than the control rCBF by 1 SD. These 23 patients were enrolled in this study and received 5 mg/day of donepezil hydrochloride after breakfast. Treatment was continued for 3 to 12 months. At 3 to 6 (DAT/3-6M group) and/or 6 to 12 months (DAT/6-12M group) after the start of the treatment, I-123-IMP SPECT was performed again to obtain the rCBF. Regions of interest were set at the same position in a same patient pair of SPECT images before and after the treatment using an automatic registration tool (ART software, Toshiba, Tokyo, Japan). Results: 10 of the 23 patients in the DAT/3-6M group exhibited improved rCBF. 15 of the 23 patients in the DAT/6-12M group exhibited improved rCBF. These findings were not correlated with the neuropsychological score. Statistically, the rCBF showed no significant difference in the DAT/3-6M group. However, in the DAT/6-12M group, donepezil hydrochloride significantly improved rCBF in the frontal, parietal, and occipital cortices from 25.7±8.7 to 29.3±6.9, 20.6±7.9 to 24.9±6.2, and 27.2±6.0 to 35.0±7.6 [ml/100g/min] respectively. No change, either an increase or a decrease in rCBF was observed in any other regions. Conclusion: Some cases were improved and some cases were not recovered without relationship to the neuropsychological score. Statistically, donepezil hydrochloride did increase r

Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease

DEFF Research Database (Denmark)

Waldemar, Gunhild; Gauthier, Serge; Jones, Roy

2011-01-01

To determine whether donepezil treatment (10 mg/day over 24 weeks) is associated with delayed emergence of apathy in patients with mild to moderate Alzheimer's disease (AD) and to explore relationships between donepezil's effects on apathy and other Neuropsychiatric Inventory (NPI)-measured behav...

Detection of metabolites of lysergic acid diethylamide (LSD) in human urine specimens: 2-oxo-3-hydroxy-LSD, a prevalent metabolite of LSD.

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Poch, G K; Klette, K L; Hallare, D A; Manglicmot, M G; Czarny, R J; McWhorter, L K; Anderson, C J

1999-03-05

Seventy-four urine specimens previously found to contain lysergic acid diethylamide (LSD) by gas chromatography-mass spectrometry (GC-MS) were analyzed by a new procedure for the LSD metabolite 2-oxo-3-hydroxy-LSD (O-H-LSD) using a Finnigan LC-MS-MS system. This procedure proved to be less complex, shorter to perform and provides cleaner chromatographic characteristics than the method currently utilized by the Navy Drug Screening Laboratories for the extraction of LSD from urine by GC-MS. All of the specimens used in the study screened positive for LSD by radioimmunoassay (Roche Abuscreen). Analysis by GC-MS revealed detectable amounts of LSD in all of the specimens. In addition, isolysergic diethylamide (iso-LSD), a byproduct of LSD synthesis, was quantitated in 64 of the specimens. Utilizing the new LC-MS-MS method, low levels of N-desmethyl-LSD (nor-LSD), another identified LSD metabolite, were detected in some of the specimens. However, all 74 specimens contained O-H-LSD at significantly higher concentrations than LSD, iso-LSD, or nor-LSD alone. The O-H-LSD concentration ranged from 732 to 112 831 pg/ml (mean, 16340 pg/ml) by quantification with an internal standard. The ratio of O-H-LSD to LSD ranged from 1.1 to 778.1 (mean, 42.9). The presence of O-H-LSD at substantially higher concentrations than LSD suggests that the analysis for O-H-LSD as the target analyte by employing LC-MS-MS will provide a much longer window of detection for the use of LSD than the analysis of the parent compound, LSD.

Inhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients.

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Coller, Janet K; Michalakas, Jennifer R; James, Heather M; Farquharson, Aaron L; Colvill, Joel; White, Jason M; Somogyi, Andrew A

2012-11-01

Management of pain in opioid dependent individuals is problematic due to numerous issues including cross-tolerance to opioids. Hence there is a need to find alternative analgesics to classical opioids and tramadol is potentially one such alternative. Methadone inhibits CYP2D6 in vivo and in vitro. We aimed to investigate the effect of methadone on the pathways of tramadol metabolism: O-demethylation (CYP2D6) to the opioid-active metabolite M1 and N-demethylation (CYP3A4) to M2 in subjects maintained on methadone or buprenorphine as a control. Compared with subjects on buprenorphine, methadone reduced the clearance of tramadol to active O-desmethyl-tramadol (M1) but had no effect on N-desmethyltramadol (M2) formation. Similar to other analgesics whose active metabolites are formed by CYP2D6 such as codeine, reduced formation of O-desmethyltramadol (M1) is likely to result in reduced analgesia for subjects maintained on methadone. Hence alternative analgesics whose metabolism is independent of CYP2D6 should be utilized in this patient population. To compare the O- (CYP2D6 mediated) and N- (CYP3A4 mediated) demethylation metabolism of tramadol between methadone and buprenorphine maintained CYP2D6 extensive metabolizer subjects. METHODS Nine methadone and seven buprenorphine maintained subjects received a single 100 mg dose of tramadol hydrochloride. Blood was collected at 4 h and assayed for tramadol, methadone, buprenorphine and norbuprenorphine (where appropriate) and all urine over 4 h was assayed for tramadol and its M1 and M2 metabolites. The urinary metabolic ratio [median (range)] for O-demethylation (M1) was significantly lower (P= 0.0002, probability score 1.0) in the subjects taking methadone [0.071 (0.012-0.103)] compared with those taking buprenorphine [0.192 (0.108-0.392)], but there was no significant difference (P= 0.21, probability score 0.69) in N-demethylation (M2). The percentage of dose [median (range)] recovered as M1 was significantly lower

A double-blind placebo-controlled cross-over clinical trial of DONepezil In Posterior cortical atrophy due to underlying Alzheimer's Disease: DONIPAD study.

Science.gov (United States)

Ridha, Basil H; Crutch, Sebastian; Cutler, Dawn; Frost, Christopher; Knight, William; Barker, Suzie; Epie, Norah; Warrington, Elizabeth K; Kukkastenvehmas, Riitta; Douglas, Jane; Rossor, Martin N

2018-05-01

The study investigated whether donepezil exerts symptomatic benefit in patients with posterior cortical atrophy (PCA), an atypical variant of Alzheimer's disease. A single-centre, double-blind, placebo-controlled, cross-over clinical trial was performed to assess the efficacy of donepezil in patients with PCA. Each patient received either donepezil (5 mg once daily in the first 6 weeks and 10 mg once daily in the second 6 weeks) or placebo for 12 weeks. After a 2-week washout period, each patient received the other treatment arm during the following 12 weeks followed by another 2-week washout period. The primary outcome was the Mini-Mental State Examination (MMSE) at 12 weeks. Secondary outcome measures were five neuropsychological tests reflecting parieto-occipital function. Intention-to-treat analysis was used. For each outcome measure, carry-over effects were first assessed. If present, then analysis was restricted to the first 12-week period. Otherwise, the standard approach to the analysis of a 2 × 2 cross-over trial was used. Eighteen patients (13 females) were recruited (mean age 61.6 years). There was a protocol violation in one patient, who subsequently withdrew from the study due to gastrointestinal side effects. There was statistically significant (p effect on MMSE. Therefore, the analysis of treatment effect on MMSE was restricted to the first 12-week period. Treatment effect at 6 weeks was statistically significant (difference = 2.5 in favour of donepezil, 95% CI 0.1 to 5.0, p effect at 12 weeks was close, but not statistically significant (difference = 2.0 in favour of donepezil, 95% CI -0.1 to 4.5, p > 0.05). There were no statistically significant treatment effects on any of the five neuropsychological tests, except for digit span at 12 weeks (higher by 0.5 digits in favour of placebo, 95% CI 0.1 to 0.9). Gastrointestinal side effects occurred most frequently, affecting 13/18 subjects (72%), and were the cause of study discontinuation in one

Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit

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MIKI TSUJITA

2007-01-01

Full Text Available Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C0(2. In the other experiment, apneic threshold PaC0(2 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit

Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and Severe Alzheimer's Disease

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Camryn Berk

2012-01-01

Full Text Available Donepezil, a highly selective acetylcholinesterase inhibitor (AChEI, is approved as a symptomatic treatment mild, moderate, and severe Alzheimer's disease (AD. Donepezil exerts its treatment effect through multiple mechanisms of action including nicotinic receptor stimulation, mitigation of excitotoxicity, and influencing APP processing. The use of donepezil at higher doses is justified given the worsening cholinergic deficit as the disease advances. Donepezil has been investigated in several clinical trials of subjects with moderate-to-severe AD. While the side effects are class specific (cholinergically driven, demonstrable benefit has been shown at the 10 mg dose and the 23 mg doses. Here, we review the clinical justification, efficacy, safety, and tolerability of use of donepezil in the treatment of moderate-to-severe AD.

Different effects of clopidogrel and clarithromycin on the enantioselective pharmacokinetics of sibutramine and its active metabolites in healthy subjects.

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Shinde, Dhananjay D; Kim, Ho-Sook; Choi, Jae-Seok; Pan, Wei; Bae, Soo Kyung; Yeo, Chang-Woo; Shon, Ji-Hong; Kim, Dong-Hyun; Shin, Jae Gook

2013-05-01

In this study, we assessed the effects of clopidogrel and clarithromycin, known CYP2B6 and CYP3A inhibitors, respectively, on the enantioselective disposition of racemic sibutramine in conjunction with CYP2B6 polymorphisms in humans. Sibutramine showed enantioselective plasma profiles with consistently higher concentrations of R-enantiomers. Clopidogrel and clarithromycin significantly increased the sibutramine plasma concentration, but their effects differed between enantiomers; a 2.2-fold versus 4.1-fold increase in the AUC in S-enantiomer and 1.8-fold versus 2.0-fold for the R-enantiomer, respectively. The AUCs of S- and R-desmethyl metabolites changed significantly during the clopidogrel phase (P sibutramine was higher in subjects with the CYP2B6*6/*6 genotype, but no statistical difference was observed among the CYP2B6 genotypes. These results suggest that the enantioselective disposition of sibutramine and its active metabolites are influenced by the altered genetic and environmental factors of CYP2B6 and CYP3A activity in vivo. © The Author(s) 2013.

Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase

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Tsuyoshi Sato

2015-09-01

Conclusions: AChE promotes osteoclast differentiation in vitro. Donepezil inhibits osteoclast function in vitro and prevents bone loss by suppressing bone resorption in vivo, suggesting the possibility that donepezil reduces fracture risk in patients with Alzheimer's disease.

3DSRT evaluation responses of Alzheimer type dementia to donepezil hydrochloride therapy

International Nuclear Information System (INIS)

Higashiyama, Shigeaki; Kawabe, Joji; Hashimoto, Hiroshi

2006-01-01

Dementia of Alzheimer type (DAT) has been diagnosed objectively by using single photon emission tomography (SPECT). Donepezil hydrochloride (donepezil) is available for the symptomatic treatment of DAT. In a quantitative evaluation of therapeutic response in DAT, to compare with regional cerebral blood flows (rCBF) of various lesions before and after treatment, uptake in some sorts of cerebral regions of interests (ROIs) were used to be measured. But ROI analysis has problems such as poor reproducibility and lack of objectivity. The aim of this study was to investigate the evaluation of therapeutic response by three-dimensional stereotaxic ROI template (3DSRT), fully automated ROI analysis software, which can objectively estimate rCBF. SPECT studies and Alzheimer's Disease Assessment Scale Japan cognitive Subscale function test ADAS-Jcog, as recognitive function test were performed for 22 patients (16 females, 6 males mean age=73.6 years) who were diagnosed as DAT. On 3DSRT, we compared ratios of the rCBF values of the parietal lobes, temporo-occipital lobes, hippocampus, corpus callosum and the frontal lobes/cerebellar hemispheres before and after medical treatment. To determine a cut-off number of areas exhibiting improved blood flow optimal as an indicator of improvement in cognitive function in response to treatment, receiver operating characteristics (ROC) analysis of number of areas improved blood flow was performed. The number of cases exhibiting changes in cognitive function was greatest when the cut-off number of areas exhibiting improved blood flow was set at 5. The possibility of evaluation of therapeutic response to Donepezil in patients with DAT using 3DSRT was thus demonstrated by our study. (author)

PET Evidence of the Effect of Donepezil on Cognitive Performance in an Animal Model of Chemobrain

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Ilhan Lim

2016-01-01

Full Text Available A considerable number of patients with breast cancer complain of cognitive impairment after chemotherapy. In this study, we showed that donepezil enhanced memory function and increased brain glucose metabolism in a rat model of cognitive impairment after chemotherapy using behavioral analysis and positron emission tomography (PET. We found that chemotherapy affected spatial learning ability, reference memory, and working memory and that donepezil improved these cognitive impairments. According to PET analysis, chemotherapy reduced glucose metabolism in the medial prefrontal cortex and hippocampus, and donepezil increased glucose metabolism in the bilateral frontal lobe, parietal lobe, and hippocampus. Reduced glucose metabolism was more prominent after treatment with doxorubicin than cyclophosphamide. Our results demonstrated the neural mechanisms for cognitive impairment after chemotherapy and show that cognition was improved after donepezil intervention using both behavioral and imaging methods. Our results suggested that donepezil can be employed clinically for the treatment of cognitive deficits after chemotherapy.

Application of diazene-directed fragment assembly to the total synthesis and stereochemical assignment of (+)-desmethyl-meso-chimonanthine and related heterodimeric alkaloids

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Lathrop, Stephen; Movassaghi, Mohammad

2013-01-01

We describe the first application of our methodology for heterodimerization via diazene fragmentation towards the total synthesis of (−)-calycanthidine, meso-chimonanthine, and (+)-desmethyl-meso-chimonanthine. Our syntheses of these alkaloids feature an improved route to C3a-aminocyclotryptamines, an enhanced method for sulfamide synthesis and oxidation, in addition to a late-stage diversification leading to the first enantioselective total synthesis of (+)-desmethyl-meso-chimonanthine and i...

Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: A meta-analysis.

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Chen, Ruey; Chan, Pi-Tuan; Chu, Hsin; Lin, Yu-Cih; Chang, Pi-Chen; Chen, Chien-Yu; Chou, Kuei-Ru

2017-01-01

This is the first meta-analysis to compare the treatment effects and safety of administering donepezil alone versus a combination of memantine and donepezil to treat patients with moderate to severe Alzheimer Disease, particularly regarding cognitive functions, behavioral and psychological symptoms in dementia (BPSD), and global functions. PubMed, Medline, Embase, PsycINFO, and Cochrane databases were used to search for English and non-English articles for inclusion in the meta-analysis to evaluate the effect size and incidence of adverse drug reactions of different treatments. Compared with patients who received donepezil alone, those who received donepezil in combination with memantine exhibited limited improvements in cognitive functions (g = 0.378, p Alzheimer Disease.

Clinical Recommendations for the Use of Donepezil 23 mg in Moderate-to-Severe Alzheimer's Disease in the Asia-Pacific Region

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Sabbagh, Marwan; Han, SeolHeui; Kim, SangYun; Na, Hae-Ri; Lee, Jae-Hong; Kandiah, Nagaendran; Phanthumchinda, Kammant; Suthisisang, Chuthamanee; Senanarong, Vorapun; Pai, Ming-Chyi; Narilastri, Diatri; Sowani, Ajit M.; Ampil, Encarnita; Dash, Amitabh

2016-01-01

Background The ‘Asia-Pacific Expert Panel (APEX) for donepezil 23 mg’ met in November 2015 to review evidence for the recently approved high dose of donepezil and to provide recommendations to help physicians in Asia make informed clinical decisions about using donepezil 23 mg in patients with moderate-to-severe Alzheimer's disease (AD). Summary In a global phase III study (study 326) in patients with moderate-to-severe AD, donepezil 23 mg/day demonstrated significantly greater cognitive benefits versus donepezil 10 mg/day, with a between-treatment difference in mean change in the Severe Impairment Battery score of 2.2 points (p < 0.001) in the overall population and 3.1 points (p < 0.001) in patients with advanced AD. A subanalysis of study 326 demonstrated that the benefits and risks associated with donepezil 23 mg/day versus donepezil 10 mg/day in Asian patients with moderate-to-severe AD were comparable to those in the global study population. Key Message Donepezil 23 mg is a valuable treatment for patients with AD, particularly those with advanced disease. The APEX emphasized the importance of patient selection (AD severity, tolerability of lower doses of donepezil, and absence of contraindications), a stepwise titration strategy for dose escalation, and appropriate monitoring and counseling of patients and caregivers in the management of patients with AD. PMID:27703471

Effect of donepezil hydrochloride (E2020) on extracellular acetylcholine concentration in the cerebral cortex of rats.

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Kosasa, T; Kuriya, Y; Yamanishi, Y

1999-10-01

Donepezil hydrochloride (donepezil), a potent and selective acetylcholinesterase inhibitor, has been developed for the treatment of Alzheimer's disease. We studied the effect of oral administration of this drug on the extracellular acetylcholine (ACh) concentration in the cerebral cortex of rats using microdialysis. We also observed fasciculation, a peripheral cholinergic sign induced by activation of neuromuscular transmission, after oral administration of the drug as an index of peripheral cholinergic activation. Other cholinesterase inhibitors, tacrine, ENA-713 and TAK-147, were used as reference drugs. Donepezil significantly and dose-dependently increased the extracellular ACh concentration in the rat cerebral cortex within the dose range of 2.5-10 mg/kg. Tacrine, ENA-713 and TAK-147 also elevated the extracellular concentration of ACh. The minimum effective doses of donepezil, tacrine, ENA-713 and TAK-147 were (< or = 2.5, 10, 10 and < or = 10 mg/kg, respectively. Donepezil produced fasciculation at doses of 2.5 mg/kg and above, with a dose-dependent increase in incidence and intensity. The reference compounds also induced fasciculation in a dose-dependent manner. The threshold doses of tacrine, ENA-713 and TAK-147 for fasciculation were 5, 2.5 and 2.5 mg/kg, respectively. The values of the ratio of the minimum effective dose for the ACh-increasing action to that for the fasciculation-producing action were: donepezil, < or = 1; tacrine, 2; ENA-713, 4; TAK-147, < or = 4. These results indicate that orally administered donepezil has a potent and selective activity on the central cholinergic system.

Effect of Donepezil on Wernicke Aphasia After Bilateral Middle Cerebral Artery Infarction: Subtraction Analysis of Brain F-18 Fluorodeoxyglucose Positron Emission Tomographic Images.

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Yoon, Seo Yeon; Kim, Je-Kyung; An, Young-Sil; Kim, Yong Wook

2015-01-01

Aphasia is one of the most common neurologic deficits occurring after stroke. Although the speech-language therapy is a mainstream option for poststroke aphasia, pharmacotherapy is recently being tried to modulate different neurotransmitter systems. However, the efficacy of those treatments is still controversial. We present a case of a 53-year-old female patient with Wernicke aphasia, after the old infarction in the territory of left middle cerebral artery for 8 years and the recent infarction in the right middle cerebral artery for 4 months. On the initial evaluation, the Aphasia Quotient in Korean version of the Western Aphasia Battery was 25.6 of 100. Baseline brain F-18 fluorodeoxyglucose positron emission tomographic images demonstrated a decreased cerebral metabolism in the left temporoparietal area and right temporal lobe. Donepezil hydrochloride, a reversible acetylcholinesterase inhibitor, was orally administered 5 mg/d for 6 weeks after the initial evaluation and was increased to 10 mg/d for the following 6 weeks. After the donepezil treatment, the patient showed improvement in language function, scoring 51.0 of 100 on Aphasia Quotient. A subtraction analysis of the brain F-18 fluorodeoxyglucose positron emission tomographic images after donepezil medication demonstrated increased uptake in both middle temporal gyri, extended to the occipital area and the left cerebellum. Thus, we suggest that donepezil can be an effective therapeutic choice for the treatment of Wernicke aphasia.

Acetylcholinesterase inhibitors for the treatment of Wernicke-Korsakoff syndrome--three further cases show response to donepezil.

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Cochrane, Murray; Cochrane, Ashley; Jauhar, Pramod; Ashton, Elizabeth

2005-01-01

Three patients diagnosed with Wernicke-Korsakoff syndrome were treated with the acetylcholinesterase inhibitor, donepezil, for periods of 6 to 8 months. Cognitive testing [Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), Mini-mental state examination (MMSE), Clock drawing test and six item 2 min recall] and carer questionnaires [Informant Questionnaire (IQ Code), Neuropsychiatric inventory scale (NPI)] were performed at baseline, mid- and endpoint of the treatment period and post-discontinuation. Progressive partial improvement occurred in cognitive measurements through the treatment period, some of which was sustained after discontinuing donepezil. Carer questionnaires also indicated improvement. Confounding factors necessitate caution when attributing improvements to the medication, but these cases suggest that this option merits further investigation.

The Effects of Donepezil on 15-Item Geriatric Depression Scale Structure in Patients with Alzheimer Disease

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Youngsoon Yang

2016-09-01

Full Text Available Background/Aims: In Alzheimer disease (AD, depression is among the most common accompanying neuropsychiatric symptoms and has different clinical manifestations when compared with early-life depression. In patients with drug-naïve AD, we tried to explore the structure of the 15-item Geriatric Depression Scale (GDS15 and the effect of donepezil on these substructures. Methods: GDS15, cognitive function, and activities of daily living function tests were administered to 412 patients with probable AD who had not been medicated before visiting the hospital. Using principal component analysis, three factors were identified. The patients with AD who received only donepezil were retrospectively analyzed and we compared the change of cognition and GDS15 subgroup after donepezil medication. Results: Our study identified three factors and revealed that the GDS15 may be comprised of a heterogeneous scale. The Barthel index was significantly correlated with factor 1 (positively and factor 2 (negatively. The Korean version of the MMSE (K-MMSE was significantly correlated with factor 2 and factor 3. Compared to the baseline state, K-MMSE and GDS15 showed significant improvement after taking donepezil. Among GDS15 subgroups, factor 2 and factor 3 showed significant improvement after donepezil treatment. Conclusions: These results suggest that the GDS15 may be comprised of a heterogeneous scale and donepezil differentially affects the GDS15 subgroup in AD.

Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10-17.

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Kishnani, Priya S; Heller, James H; Spiridigliozzi, Gail A; Lott, Ira; Escobar, Luis; Richardson, Sharon; Zhang, Richard; McRae, Thomas

2010-12-01

The objective of this 10-week, randomized, double-blind, placebo-controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5-10 mg/day) in children (aged 10-17 years) with DS of mild-to-moderate severity. The primary measures were the Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS-II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject-performance-based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double-blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v-scores, improved significantly from baseline in both groups (P < 0.0001), with no significant between-group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated. © 2010 Wiley-Liss, Inc.

Acute effects of donepezil in healthy young adults underline the fractionation of executive functioning.

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Ginani, G E; Tufik, S; Bueno, O F A; Pradella-Hallinan, M; Rusted, J; Pompéia, S

2011-11-01

The cholinergic system is involved in the modulation of both bottom-up and top-down attentional control. Top-down attention engages multiple executive control processes, but few studies have investigated whether all or selective elements of executive functions are modulated by the cholinergic system. To investigate the acute effects of the pro-cholinergic donepezil in young, healthy volunteers on distinct components of executive functions we conducted a double-blind, placebo-controlled, independent-groups design study including 42 young healthy male participants who were randomly assigned to one of three oral treatments: glucose (placebo), donepezil 5 mg or donepezil 7.5 mg. The test battery included measures of different executive components (shifting, updating, inhibition, dual-task performance, planning, access to long-term memory), tasks that evaluated arousal/vigilance/visuomotor performance, as well as functioning of working memory subsidiary systems. Donepezil improved sustained attention, reaction times, dual-task performance and the executive component of digit span. The positive effects in these executive tasks did not correlate with arousal/visuomotor/vigilance measures. Among the various executive domains investigated donepezil selectively increased dual-task performance in a manner that could not be ascribed to improvement in arousal/vigilance/visuomotor performance nor working memory slave systems. Other executive tasks that rely heavily on visuospatial processing may also be modulated by the cholinergic system.

Open-label study of donepezil in traumatic brain injury.

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Masanic, C A; Bayley, M T; VanReekum, R; Simard, M

2001-07-01

To determine preliminarily whether donepezil will improve memory, behavior, and global function after chronic traumatic brain injury (TBI). Sixteen-week open-label study. Outpatient TBI rehabilitation program. Four patients with chronic, severe TBI. Donepezil 5mg daily for 8 weeks followed by 10mg daily for 4 weeks. Memory measures included the Rey Auditory Verbal Learning Test (RAVLT), the Complex Figure Test (CFT), items from the Rivermead Behavioural Memory Test (RBMT), and a semantic fluency task. The Neuropsychiatric Inventory (NPI) evaluated behavior and affect. Function was assessed by using the FIM instrument and a clinical global impression of change. On the RAVLT, the mean scores for learning and short- and long-term recall improved by 0.4, 1.04, and.83 standard deviations (SDs) above baseline, respectively. On the CFT, the mean scores for short-term recall and long-term recall improved by 1.56 and 1.38 SDs above baseline, respectively. A positive trend was observed on the RBMT and on the NPI subscales. Donepezil may improve some aspects of memory and behavior in persons with chronic TBI. Randomized clinical trials are required to support these preliminary findings. Copyright 2001 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation.

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Wirsich, Jonathan; Rey, Marc; Guye, Maxime; Bénar, Christian; Lanteaume, Laura; Ridley, Ben; Confort-Gouny, Sylviane; Cassé-Perrot, Catherine; Soulier, Elisabeth; Viout, Patrick; Rouby, Franck; Lefebvre, Marie-Noëlle; Audebert, Christine; Truillet, Romain; Jouve, Elisabeth; Payoux, Pierre; Bartrés-Faz, David; Bordet, Régis; Richardson, Jill C; Babiloni, Claudio; Rossini, Paolo Maria; Micallef, Joelle; Blin, Olivier; Ranjeva, Jean-Philippe

2018-05-01

Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer's disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative 'PharmaCog'. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.

Cholinergic PET imaging in infections and inflammation using 11C-donepezil and 18F-FEOBV

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Jørgensen, Nis Pedersen; Alstrup, Aage Kristian Olsen; Mortensen, Frank Viborg

2017-01-01

with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. Results In mice, the FDG uptake in abscesses peaked at 24 h...... and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120–144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived...... from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C...

A randomized, 4-week double-blind placebo control study on the efficacy of donepezil augmentation of lithium for treatment of acute mania

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Chen J

2013-06-01

group as compared to the placebo group. The total YMRS difference on the first day approached the conventional significance level (1.97 units, t = 1.84, P = 0.07. Over the course of 4 weeks, we failed to find that donepezil produced any significant difference in the YMRS (6.71 units difference, t = −1.44, P = 0.16 or the BPRS scale (1.29 units difference, t = −0.33, P = 0.75 as compared to placebo. Ten subjects (66.67% in both groups met the criteria for clinical response (Fisher’s exact P = 1.00. Five subjects (33.33% in the donepezil group met the criteria for clinical remission while nine subjects (60.00% in the placebo group met the remission criteria (Fisher’s exact P = 0.27.Conclusion: Use of the oral anticholinergic donepezil had some benefit in the augmentation of lithium treatment on the first day, but did not provide any significant benefits in the long-term.Keywords: acute mania, cholinesterase inhibitors, donepezil, lithium

Cholinergic PET imaging in infections and inflammation using "1"1C-donepezil and "1"8F-FEOBV

International Nuclear Information System (INIS)

Joergensen, Nis Pedersen; Hoegsberg Schleimann, Mariane; Alstrup, Aage K.O.; Knudsen, Karoline; Jakobsen, Steen; Bender, Dirk; Gormsen, Lars C.; Borghammer, Per; Mortensen, Frank V.; Madsen, Line Bille; Breining, Peter; Petersen, Mikkel Steen; Dagnaes-Hansen, Frederik

2017-01-01

Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated. We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen. The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic

Cholinergic PET imaging in infections and inflammation using {sup 11}C-donepezil and {sup 18}F-FEOBV

Energy Technology Data Exchange (ETDEWEB)

Joergensen, Nis Pedersen; Hoegsberg Schleimann, Mariane [Aarhus University Hospital, Department of Infectious Diseases, Aarhus (Denmark); Alstrup, Aage K.O.; Knudsen, Karoline; Jakobsen, Steen; Bender, Dirk; Gormsen, Lars C.; Borghammer, Per [Aarhus University Hospital, Department of Nuclear Medicine and PET Centre, Aarhus C (Denmark); Mortensen, Frank V. [Aarhus University Hospital, Department of Gastroenterology, Aarhus (Denmark); Madsen, Line Bille [Aarhus University Hospital, Department of Histopathology, Aarhus (Denmark); Breining, Peter [Aarhus University Hospital, Department of Endocrinology and Metabolism, Aarhus (Denmark); Petersen, Mikkel Steen [Aarhus University Hospital, Department of Clinical Immunology, Aarhus (Denmark); Dagnaes-Hansen, Frederik [Aarhus University, Department of Biomedicine, Aarhus (Denmark)

2017-03-15

Immune cells utilize acetylcholine as a paracrine-signaling molecule. Many white blood cells express components of the cholinergic signaling pathway, and these are up-regulated when immune cells are activated. However, in vivo molecular imaging of cholinergic signaling in the context of inflammation has not previously been investigated. We performed positron emission tomography (PET) using the glucose analogue 18F-FDG, and 11C-donepezil and 18F-FEOBV, markers of acetylcholinesterase and the vesicular acetylcholine transporter, respectively. Mice were inoculated subcutaneously with Staphylococcus aureus, and PET scanned at 24, 72, 120, and 144 h post-inoculation. Four pigs with post-operative abscesses were also imaged. Finally, we present initial data from human patients with infections, inflammation, and renal and lung cancer. In mice, the FDG uptake in abscesses peaked at 24 h and remained stable. The 11C-donepezil and 18F-FEOBV uptake displayed progressive increase, and at 120-144 h was nearly at the FDG level. Moderate 11C-donepezil and slightly lower 18F-FEOBV uptake were seen in pig abscesses. PCR analyses suggested that the 11C-donepezil signal in inflammatory cells is derived from both acetylcholinesterase and sigma-1 receptors. In humans, very high 11C-donepezil uptake was seen in a lobar pneumonia and in peri-tumoral inflammation surrounding a non-small cell lung carcinoma, markedly superseding the 18F-FDG uptake in the inflammation. In a renal clear cell carcinoma no 11C-donepezil uptake was seen. The time course of cholinergic tracer accumulation in murine abscesses was considerably different from 18F-FDG, demonstrating in the 11C-donepezil and 18F-FEOBV image distinct aspects of immune modulation. Preliminary data in humans strongly suggest that 11C-donepezil can exhibit more intense accumulation than 18F-FDG at sites of chronic inflammation. Cholinergic PET imaging may therefore have potential applications for basic research into cholinergic

Evaluating the cost effectiveness of donepezil in the treatment of Alzheimer's disease in Germany using discrete event simulation

Directory of Open Access Journals (Sweden)

Hartz Susanne

2012-02-01

Full Text Available Abstract Background Previous cost-effectiveness studies of cholinesterase inhibitors have modeled Alzheimer's disease (AD progression and treatment effects through single or global severity measures, or progression to "Full Time Care". This analysis evaluates the cost-effectiveness of donepezil versus memantine or no treatment in Germany by considering correlated changes in cognition, behavior and function. Methods Rates of change were modeled using trial and registry-based patient level data. A discrete event simulation projected outcomes for three identical patient groups: donepezil 10 mg, memantine 20 mg and no therapy. Patient mix, mortality and costs were developed using Germany-specific sources. Results Treatment of patients with mild to moderately severe AD with donepezil compared to no treatment was associated with 0.13 QALYs gained per patient, and 0.01 QALYs gained per caregiver and resulted in average savings of €7,007 and €9,893 per patient from the healthcare system and societal perspectives, respectively. In patients with moderate to moderately-severe AD, donepezil compared to memantine resulted in QALY gains averaging 0.01 per patient, and savings averaging €1,960 and €2,825 from the healthcare system and societal perspective, respectively. In probabilistic sensitivity analyses, donepezil dominated no treatment in most replications and memantine in over 70% of the replications. Donepezil leads to savings in 95% of replications versus memantine. Conclusions Donepezil is highly cost-effective in patients with AD in Germany, leading to improvements in health outcomes and substantial savings compared to no treatment. This holds across a variety of sensitivity analyses.

Adverse Events With Sustained-Release Donepezil in Alzheimer Disease: Relation to Body Mass Index.

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Lee, Chunsoo; Lee, Kyungsang; Yu, Hyewon; Ryu, Seung-Ho; Moon, Seok Woo; Han, Changsu; Lee, Jun-Young; Lee, Young Min; Kim, Shin-Gyeom; Kim, Ki Woong; Lee, Dong Woo; Kim, Seong Yoon; Lee, Sang-Yeol; Bae, Jae Nam; Jung, Young-Eun; Kim, Jeong Lan; Kim, Byung-Soo; Shin, Il-Seon; Kim, Young Hoon; Kim, Bong Jo; Kang, Hyo Shin; Myung, Woojae; Carroll, Bernard J; Kim, Doh Kwan

2017-08-01

Sustained-release, high-dose (23 mg/d) donepezil has been approved for treatment of moderate to severe Alzheimer disease (AD). Based on a previous clinical trial, body weight of less than 55 kg is a risk factor for adverse events with donepezil 23 mg/d treatment in global population. To clarify whether this finding is consistent across ethnic groups that vary in absolute body mass, we recruited Korean patients aged 45 to 90 years with moderate to severe AD who had been receiving standard donepezil immediate release 10 mg/d for at least 3 months. After screening, we analyzed a final cohort of 166 patients who received donepezil 23 mg/d for 24 weeks to compare the occurrence of treatment-emergent adverse events (TEAEs) between patients with high versus low body mass index (BMI) based on the World Health Organization overweight criteria for Asian populations (23 kg/m). Treatment-emergent adverse events were reported by 79.45% of patients in the lower BMI group and 58.06% of patients in the higher BMI group (odds ratio, 2.79; 95% confidence interval, 1.39-5.63; χ = 7.58, P = 0.006). In a multivariable survival analysis, the group with lower BMI showed a higher occurrence of TEAEs (hazard ratio, 1.83; 95% confidence interval, 1.25-2.68; P = 0.002). In Korean patients with moderate to severe AD receiving high-dose donepezil over 24 weeks, TEAEs were significantly more common in those with lower BMI (not clinically overweight), especially nausea. This finding may inform clinical practice for Asian patients.

The effect of funding sources on donepezil randomised controlled trial outcome: a meta-analysis.

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Killin, Lewis O J; Russ, Tom C; Starr, John M; Abrahams, Sharon; Della Sala, Sergio

2014-04-07

To investigate whether there is a difference in the treatment effect of donepezil on cognition in Alzheimer disease between industry-funded and independent randomised controlled trials. Fixed effects meta-analysis of standardised effects of donepezil on cognition as measured by the Mini Mental State Examination and the Alzheimer's Disease Assessment Scale-cognitive subscale. Studies included in the meta-analyses reported in the National Institute for Health and Care Excellence (NICE) technical appraisal 217 updated with new studies through a PubMed search. Inclusion criteria were double-blind, placebo-controlled trials of any length comparing patients diagnosed with probable Alzheimer disease (according to the NINCDS-ADRDA/DSM-III/IV criteria) taking any dosage of donepezil. Studies of combination therapies (eg, donepezil and memantine) were excluded, as were studies that enrolled patients with a diagnosis of Alzheimer disease associated with other disorders (eg, Parkinson's disease and Down's syndrome). Our search strategy identified 14 relevant trials (4 independent) with suitable data. Trials sponsored by pharmaceutical companies reported a larger effect of donepezil on standardised cognitive tests than trials published by independent research groups (standardised mean difference (SMD)=0.46, 95% CI 0.37 to 0.55 vs SMD=0.33, 95% CI 0.18 to 0.48, respectively). This difference remained when only data representing change up to 12 weeks from baseline were analysed (industry SMD=0.44, 95% CI 0.34 to 0.53 vs independent SMD=0.35, 95% CI 0.18 to 0.52). Analysis revealed that the effect of funding as a moderator variable of study heterogeneity was not statistically significant at either time point. The effect size of donepezil on cognition is larger in industry-funded than independent trials and this is not explained by the longer duration of industry-funded trials. The lack of a statistically significant moderator effect may indicate that the differences are due to

Synthesis of novel 11-desmethyl analogues of laulimalide by Nozaki-Kishi coupling.

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Paterson, Ian; Bergmann, Hermann; Menche, Dirk; Berkessel, Albrecht

2004-04-15

As a first entry into structurally simplified analogues of the anticancer agent laulimalide, 11-desmethyl compounds 2 and 3 were selected by molecular modeling. The unfavorable diastereoselectivity in the key synthetic step, a Nozaki-Kishi coupling between macrocyclic aldehyde 4 and vinyl iodide 5, was overcome either by use of catalytic amounts of DIANANE-type ligands or L-Selectride reduction of the derived enone. This methodology should allow modular introduction of other, unnatural, side chains. [reaction: see text

Donepezil improves gait performance in older adults with mild Alzheimer's disease: a phase II clinical trial.

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Montero-Odasso, Manuel; Muir-Hunter, Susan W; Oteng-Amoako, Afua; Gopaul, Karen; Islam, Anam; Borrie, Michael; Wells, Jennie; Speechley, Mark

2015-01-01

Gait deficits are prevalent in people with dementia and increase their fall risk and future disability. Few treatments exist for gait impairment in Alzheimer's disease (AD) but preliminary studies have shown that cognitive enhancers may improve gait in this population. To determine the efficacy of donepezil, a cognitive enhancer that improves cholinergic activity, on gait in older adults newly diagnosed with AD. Phase II clinical trial in 43 seniors with mild AD who received donepezil. Participants had not previously received treatment with cognitive enhancers. Primary outcome variables were gait velocity (GV) and stride time variability (STV) under single and dual-task conditions measured using an electronic walkway. Secondary outcomes included attention and executive function. After four months of treatment, participants with mild AD improved their GV from 108.4 ± 18.6 to 113.3 ± 19.5 cm/s, p = 0.010; dual-task GV from 80.6 ± 23.0 to 85.3 ± 22.3 cm/s, p = 0.028. Changes in STV were in the expected direction although not statistically significant. Participants also showed improvements in Trail Making Tests A (p = 0.030), B (p = 0.001), and B-A (p = 0.042). Donepezil improved gait in participants with mild AD. The enhancement of dual-task gait suggests the positive changes achieved in executive function as a possible causal mechanism. This study yielded a clinically significant estimate of effect size; as well, the findings are relevant to the feasibility and ethics considerations for the design of a Phase III clinical trial.

Low dose of donepezil improves gabapentin analgesia in the rat spared nerve injury model of neuropathic pain

DEFF Research Database (Denmark)

Folkesson, Anna; Honoré, Per Hartvig; Andersen, Lene Munkholm

2010-01-01

the effect of the cholinesterase inhibitor donepezil when administered (1) alone and (2) as low-dose in combination with the first-line recommendation gabapentin. The co-administration studies were performed following single and multiple dosing. Single, parenteral dosing of donepezil (1, 1.5 and 3 mg...

Secondary metabolites from Eremostachys laciniata

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Calis, Ihsan; Güvenc, Aysegül; Armagan, Metin

2008-01-01

), and forsythoside B (18), and five flavone derivatives, luteolin (19), luteolin 7-O-β-D-glucopyranoside (20), luteolin 7-O-(6''-O-β-D-apiofuranosyl)-β-D-glucopyranoside (21), apigenin 7-O-β-D-glucopyranoside (22), and apigenin 7-O-(6''-O-p-coumaroyl)-β-D-glucopyranoside (23). The structures of the metabolites were...... elucidated from spectroscopic (UV, IR, 1D- and 2D-NMR) and ESI-MS evidence, as well as from their specific optical rotation. The presence of these metabolites of three different classes strongly supports the close relationship of the genera Eremostachys and Phlomis....

Combination benefit of cognitive rehabilitation plus donepezil for Alzheimer's disease patients.

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Matsuzono, Kosuke; Hishikawa, Nozomi; Takao, Yoshiki; Wakutani, Yosuke; Yamashita, Toru; Deguchi, Kentaro; Abe, Koji

2016-02-01

Alzheimer's disease (AD) is one of the most important diseases in aging society, and non-drug therapy might be an alternative therapeutic approach. Thus, we evaluated the add-on effect of cognitive rehabilitation on AD patients under donepezil treatment. We retrospectively analyzed 55 AD patients with a Mini-Mental State Examination score of 15-25, dividing them into two groups depending on whether they were receiving ambulatory cognitive rehabilitation (group D + R, n = 32) or not (group D, n = 23) in Kurashiki Heisei Hospital over 1 year. The present cognitive rehabilitation included physical therapy, occupational therapy and speech therapy for 1-2 h once or twice a week. Between group D and group D + R, there was no significant difference in baseline data, such as age, Mini-Mental State Examination score, periventricular hyperintensity on magnetic resonance imaging, deep white matter hyperintensity on magnetic resonance imaging or donepezil dose (4.1 mg/day). At 1 year later, however, the Mini-Mental State Examination score improved only in group D + R from 21.7 to 24.0 (**P cognitive rehabilitation plus a choline esterase inhibitor donepezil showed a better effect for the cognitive function of AD patients than drug only therapy at 1 year. © 2015 Japan Geriatrics Society.

Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers.

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Joshua H Balsters

Full Text Available Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs, by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL and electrophysiological measures (resting EEG power that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta, right frontal-parietal network (Alpha, and default-mode network (Beta. We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify

Determination of levofloxacin in human serum using liquid chromatography tandem mass spectrometry

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Samiksha Ghimire

2018-01-01

Full Text Available A rapid liquid chromatography tandem-mass spectrometry method was developed for the determination of levofloxacin and its metabolite (desmethyl-levofloxacin in human serum. Sample preparation was done using protein precipitation technique. Our method had a run time of 2.5 min and retention times of 1.6 min for all analytes. The standard curves were linear within the concentration range of 0.10 to 5.00 mg/L for levofloxacin and 0.10 to 4.99 mg/L for desmethyl- levofloxacin; a correlation coefficient (R2 of 0.999 and 0.998 respectively. The lower limit of quantification for both analytes was 0.10 mg/L. Within-day precision ranged from 1.4% and 2.4% for levofloxacin, 1.5% to 5% for desmethyl-levofloxacin and between-day precision ranged from 3.6% to 4.1% for levofloxacin and 0.0% to 3.3% for desmethyl-levofloxacin; whereas, accuracy ranged from 0.1% to 12.7% for levofloxacin and 0.2% to 15.6% for desmethyl-levofloxacin. This method could be a useful asset for routine therapeutic drug monitoring of levofloxacin in multi-drug resistant tuberculosis patients.

Therapeutic dosage assessment based on population pharmacokinetics of a novel single-dose transdermal donepezil patch in healthy volunteers.

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Choi, Hee Youn; Kim, Yo Han; Hong, Donghyun; Kim, Seong Su; Bae, Kyun-Seop; Lim, Hyeong-Seok

2015-08-01

We performed population pharmacokinetic (PK) analysis of a novel transdermal donepezil patch in healthy subjects who participated in a phase I trial. We also studied the optimal dosage regimen with repeated patch application for achieving a therapeutic range using a PK simulation model. This study used data from a randomized, single-dose escalation phase I clinical trial conducted in Korea. The population PK analysis was performed using NONMEM software, version 7.3. From the final PK model, we simulated repeat patch application results assuming various transdermal absorption rates. Based on the clinical trial data, novel donepezil patches with doses of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), and 175 mg/50 cm(2) were placed on each subject. A linear one-compartment, first-order elimination with sequential zero- and first-order absorption model best described the donepezil plasma concentrations after patch application. Simulated results on the basis of the PK model showed that repeat application of the patches of 87.5 mg/25 cm(2) and 175 mg/50 cm(2) every 72 h would cover the therapeutic range of donepezil and reach steady-state faster with fewer fluctuations in concentration compared to typical oral administrations. A linear one-compartment with sequential zero- and first-order absorption model was effective for describing the PKs of donepezil after application of patch. Based on this analysis, 87.5 mg/25 cm(2) or 175 mg/50 cm(2) patch application every 72 h is expected to achieve the desired plasma concentration of donepezil.

Efficacy of Memantine, Donepezil, or Their Association in Moderate-Severe Alzheimer’s Disease: A Review of Clinical Trials

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Ivana Molino

2013-01-01

Full Text Available Background. Acetylcholinesterase (AChE/cholinesterase (ChE inhibitors (Is and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer’s disease (AD, respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Method. Double-blind, placebo-controlled randomized trials (RCTs using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012. Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks, and the different cognitive assessment tools used did not allow comparing properly different trials.

A novel LC-MS/MS assay for the simultaneous determination of melatonin and its two major metabolites, 6-hydroxymelatonin and 6-sulfatoxymelatonin in dog plasma: Application to a pharmacokinetic study.

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Zhao, Huimin; Wang, Yifei; Yuan, Bo; Liu, Shu; Man, Shuang; Xu, Haiyan; Lu, Xiumei

2016-01-05

A convenient and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of melatonin (MEL) and its major metabolites, 6-hydroxymelatonin (6-O-MEL) and 6-sulfatoxymelationin (S-O-MEL) in dog plasma. After plasma samples were deproteinized with acetonitrile, the post-treatment samples were analyzed on a Phenomenex Kinetex C18 column (50×2.1 mm, 1.7 μm) interfaced with a triple quadrupole tandem mass spectrometer. Electrospray ionization mode (ESI) and multiple reaction monitoring were used to assay MEL and its metabolites. Acetonitrile and 5 mM ammonium acetate were used as the mobile phase with a gradient elution at a flow rate of 0.2 mL/min. The analytical run time of 6.5 min was divided into two periods according to ionization mode. S-O-MEL was monitored in negative ionization mode (period 1), while MEL and 6-O-MEL were detected in positive ionization mode (period 2). All calibration curves showed good linearity (r>0.991) over the concentration range with a lower limit of quantification (LLOQ) of 0.02 ng/mL for MEL, 0.04 ng/mL for 6-O-MEL and 0.50 ng/mL for S-O-MEL. The intra- and inter-day precision was within 13.5% in terms of relative standard deviation (RSD%) and the accuracy within 13.0% in terms of relative error. This convenient and specific LC-MS/MS method was successfully applied to the pharmacokinetic study of MEL and its metabolites in Beagle dogs after an oral dose of 2.0mg MEL. After ingestion of MEL, S-O-MEL was the predominant component circulating in blood. 6-O-MEL showed similar pharmacokinetic profile to that of MEL. Copyright © 2015 Elsevier B.V. All rights reserved.

Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine.

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Aracava, Yasco; Pereira, Edna F R; Akkerman, Miriam; Adler, Michael; Albuquerque, Edson X

2009-12-01

Galantamine, a centrally acting cholinesterase (ChE) inhibitor and a nicotinic allosteric potentiating ligand used to treat Alzheimer's disease, is an effective and safe antidote against poisoning with nerve agents, including soman. Here, the effectiveness of galantamine was compared with that of the centrally active ChE inhibitors donepezil, rivastigmine, and (+/-)huperzine A as a pre- and/or post-treatment to counteract the acute toxicity of soman. In the first set of experiments, male prepubertal guinea pigs were treated intramuscularly with one of the test drugs and 30 min later challenged with 1.5 x LD(50) soman (42 microg/kg s.c.). All animals that were pretreated with galantamine (6-8 mg/kg), 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A survived the soman challenge, provided that they were also post-treated with atropine (10 mg/kg i.m.). However, only galantamine was well tolerated. In subsequent experiments, the effectiveness of specific treatment regimens using 8 mg/kg galantamine, 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A was compared in guinea pigs challenged with soman. In the absence of atropine, only galantamine worked as an effective and safe pretreatment in animals challenged with 1.0 x LD(50) soman. Galantamine was also the only drug to afford significant protection when given to guinea pigs after 1.0 x LD(50) soman. Finally, all test drugs except galantamine reduced the survival of the animals when administered 1 or 3 h after the challenge with 0.6 or 0.7 x LD(50) soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman.

Does the cholinesterase inhibitor, donepezil, benefit both declarative and non-declarative processes in mild to moderate Alzheimer's disease?

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Winstein, Carolee J; Bentzen, Kirk R; Boyd, Lara; Schneider, Lon S

2007-07-01

Previous research suggests separate neural networks for implicit (non-declarative) and explicit (declarative) memory processes. A core cognitive impairment in mild to moderate Alzheimer's disease (AD) is a pronounced declarative memory and learning deficit with relative preservation of non-declarative memory. Cholinesterase inhibitors has been purported to enhance cognitive function, and previous clinical trials consistently showed that donepezil, a reversible inhibitor of acetylcholinesterase (AChE), led to statistically significant improvements in cognition and patient function. This prospective pilot study is a randomized, double blind, placebo-controlled clinical trial investigating 10 patients with AD. Our purpose was to examine the relationship between declarative and non-declarative capability with particular emphasis on implicit sequence learning. Patients were assessed at baseline and again at 4-weeks. After participants' baseline data were obtained, each was double-blindly randomized to one of two groups: donepezil or placebo. At baseline participants were tested with two outcome measures (Serial Reaction Time Task, Alzheimer's Disease Assessment Scale-Cognitive Subscale). Participants were given either 5 mg donepezil or an identically appearing placebo to be taken nightly for 4 weeks (28 tablets), and then retested. The donepezil group demonstrated a greater likelihood of increases in both non-declarative and declarative processes. The placebo group was mixed without clearly definable trends or patterns. When the data were examined for coincidental changes in the two outcome measures together they are suggestive of a benefit from donepezil treatment for non-declarative and declarative processes.

Determination of olanzapine and N-desmethyl-olanzapine in plasma using a reversed-phase HPLC coupled with coulochemical detection: correlation of olanzapine or N-desmethyl-olanzapine concentration with metabolic parameters.

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Mong-Liang Lu

Full Text Available Olanzapine (OLZ is one of the most prescribed atypical antipsychotic drugs but its use is associated with unfavorable metabolic abnormalities. N-desmethyl-olanzapine (DMO, one of the OLZ metabolites by CYP1A2, has been reported to have a normalizing action on metabolic abnormalities, but this remains unclear. Our aim was to explore the correlation between the concentrations of OLZ or DMO with various metabolic parameters in schizophrenic patients.The chromatographic analysis was carried out with a solvent delivery system coupled to a Coulochem III coulometric detector to determine OLZ and DMO simultaneously in OLZ-treated patients. The correlation between the concentration of OLZ or DMO and the metabolic parameters was analyzed by the Spearman rank order correlation method (r s.The established analytical method met proper standards for accuracy and reliability and the lower limitation of quantification for each injection of DMO or OLZ was 0.02 ng. The method was successfully used for the analysis of samples from nonsmoking patients (n = 48 treated with OLZ in the dosage range of 5-20 mg per day. There was no correlation between OLZ concentrations and tested metabolic parameters. DMO concentrations were negatively correlated with glucose (r s = -0.45 and DMO concentrations normalized by doses were also negatively correlated with insulin levels (r s = -0.39; however, there was a marginally positive correlation between DMO and homocysteine levels (r s = +0.38.The observed negative correlations between levels of DMO and glucose or insulin suggest a metabolic normalization role for DMO regardless of its positive correlation with a known cardiovascular risk factor, homocysteine. Additional studies of the mechanisms underlying DMO's metabolic effects are warranted.

Bivirkninger som årsag til seponering af donepezil ved Alzheimers demens

DEFF Research Database (Denmark)

Carøe, Tanja Korfitsen; Moe, Claus

2009-01-01

INTRODUCTION: The objective was to investigate the frequency of adverse events (AE) as a cause for discontinuation of donepezil treatment for Alzheimer's dementia (DAT) in a geriatric memory unit. MATERIAL AND METHODS: Five-year retrospective study of 123 donepezil-treated patients diagnosed...... mixed dementia. A total of 100 (81%) were female while 23 (19%) were male. The median age was 84 years. In all, 26 (21%) patients discontinued treatment due to AE. The most frequent AE were nausea/vomiting, diarrhoea and loss of appetite. CONCLUSION: In 21% of the cases treatment was discontinued within...... 12 months due to AE. The most frequent AEs were nausea/vomiting, diarrhoea and loss of appetite. For the most part discontinuation took place within the initial three months. However, some treatments were not discontinued until after six months; consequently, treatment should be supervised...

Anti-neuroinflammatory effect of 6,8,1'-tri-O-methylaverantin, a metabolite from a marine-derived fungal strain Aspergillus sp., via upregulation of heme oxygenase-1 in lipopolysaccharide-activated microglia.

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Kim, Kwan-Woo; Kim, Hye Jin; Sohn, Jae Hak; Yim, Joung Han; Kim, Youn-Chul; Oh, Hyuncheol

2018-02-01

In the course of searching for anti-neuroinflammatory metabolites from marine-derived fungi, three fungal metabolites, 6,8,1'-tri-O-methylaverantin, 6,8-di-O-methylaverufin, and 5-methoxysterigmatocystin were isolated from a marine-derived fungal strain Aspergillus sp. SF-6796. Among these, 6,8,1'-tri-O-methylaverantin induced the expression of heme oxygenase (HO)-1 protein in BV2 microglial cells. The induction of HO-1 protein was mediated by the activation of nuclear transcription factor erythroid-2 related factor 2 (Nrf2), and was regulated by the p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B signaling pathways. Furthermore, 6,8,1'-tri-O-methylaverantin suppressed the overproduction of pro-inflammatory mediators, such as nitric oxide, prostaglandin E 2 , inducible nitric oxide synthase, and cyclooxygenase-2 in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. These anti-neuroinflammatory effects were mediated through the negative regulation of the nuclear factor kappa B pathway, repressing the phosphorylation and degradation of inhibitor kappa B-α, translocation into the nucleus of p65/p50 heterodimer, and DNA-binding activity of p65 subunit. The anti-neuroinflammatory effect of 6,8,1'-tri-O-methylaverantin was partially blocked by a selective HO-1 inhibitor, suggesting that its anti-neuroinflammatory effect is at least partly mediated by HO-1 induction. In this study, 6,8,1'-tri-O-methylaverantin also induced HO-1 protein expression in primary microglial cells, and this correlated with anti-neuroinflammatory effects observed in LPS-stimulated primary microglial cells. In conclusion, 6,8,1'-tri-O-methylaverantin represents a potential candidate for use in the development of therapeutic agents for the regulation of neuroinflammation in neurodegenerative diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Isoflurane-induced spatial memory impairment in mice is prevented by the acetylcholinesterase inhibitor donepezil.

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Diansan Su

Full Text Available Although many studies have shown that isoflurane exposure impairs spatial memory in aged animals, there are no clinical treatments available to prevent this memory deficit. The anticholinergic properties of volatile anesthetics are a biologically plausible cause of cognitive dysfunction in elderly subjects. We hypothesized that pretreatment with the acetylcholinesterase inhibitor donepezil, which has been approved by the Food and Drug Administration (FDA for the treatment of Alzheimer's disease, prevents isoflurane-induced spatial memory impairment in aged mice. In present study, eighteen-month-old mice were administered donepezil (5 mg/kg or an equal volume of saline by oral gavage with a feeding needle for four weeks. Then the mice were exposed to isoflurane (1.2% for six hours. Two weeks later, mice were subjected to the Morris water maze to examine the impairment of spatial memory after exposure to isoflurane. After the behavioral test, the mice were sacrificed, and the protein expression level of acetylcholinesterase (AChE, choline acetylase (ChAT and α7 nicotinic receptor (α7-nAChR were measured in the brain. Each group consisted of 12 mice. We found that isoflurane exposure for six hours impaired the spatial memory of the mice. Compared with the control group, isoflurane exposure dramatically decreased the protein level of ChAT, but not AChE or α7-nAChR. Donepezil prevented isoflurane-induced spatial memory impairments and increased ChAT levels, which were downregulated by isoflurane. In conclusions, pretreatment with the AChE inhibitor donepezil prevented isoflurane-induced spatial memory impairment in aged mice. The mechanism was associated with the upregulation of ChAT, which was decreased by isoflurane.

Synthesis procedure for routine production of [carbonyl-{sup 11}C]desmethyl-WAY-100635

Energy Technology Data Exchange (ETDEWEB)

Maiti, Dilip K. [Department of Pediatrics, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States); Chakraborty, Pulak K. [Department of Radiology, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States)]. E-mail: pulak@pet.wayne.edu; Chugani, Diane C. [Department of Pediatrics, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States); Department of Radiology, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States); Muzik, Otto [Department of Pediatrics, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States); Department of Radiology, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States); Mangner, Thomas J. [Department of Radiology, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States); Chugani, Harry T. [Department of Pediatrics, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States); Department of Radiology, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States); Department of Neurology, School of Medicine, PET Center, Children' s Hospital of Michigan, Wayne State University, 3901 Beaubien Blvd., Detroit, MI 48201 (United States)

2005-05-01

An improved one-pot synthesis procedure for routine production of [carbonyl-{sup 11}C]desmethyl-WAY-100635 ([{sup 11}C]DWAY) is described. An efficient purification of the crude product has also been developed and was accomplished by C-18 reversed-phase semi-preparative HPLC using 55/45 EtOH-NaH{sub 2}PO{sub 4} buffer (20mM, pH=6.5) as the eluent. The desired product fraction was collected in a 2.0-2.5mL volume and formulated with 11mL of 0.9% saline. The radioligand was ready for human use in 45min (EOB). The product was obtained with a radiochemical yield of 11.1+/-1.8% (EOB, n=15) with a radiochemical purity of >99%. Specific activity was 133.2-185.0GBq/{mu}mol (3.6-5.0Ci/{mu}mol, EOS, n=2) when ca. 37.0GBq (ca. 1.0Ci) of starting [{sup 11}C]CO{sub 2} was used. Unlabeled mass of [{sup 11}C]DWAY was found to be 0.15-0.24{mu}g/mL and the precursor was present in less than 50ng/mL in final production solution.

In vitro characterization of potential CYP- and UGT-derived metabolites of the psychoactive drug 25B-NBOMe using LC-high resolution MS.

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Boumrah, Yacine; Humbert, Luc; Phanithavong, Melodie; Khimeche, Kamel; Dahmani, Abdallah; Allorge, Delphine

2016-02-01

One of the main challenges posed by the emergence of new psychoactive substances is their identification in human biological samples. Trying to detect the parent drug could lead to false-negative results when the delay between consumption and sampling has been too long. The identification of their metabolites could then improve their detection window in biological matrices. Oxidative metabolism by cytochromes P450 and glucuronidation are two major detoxification pathways in humans. In order to characterize possible CYP- and UGT-dependent metabolites of the 2-(4-bromo-2,5-dimethoxy-phenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25B-NBOMe), a synthetic psychoactive drug, analyses of human liver microsome (HLM) incubates were performed using an ultra-high performance liquid chromatography system coupled with a quadrupole-time of flight mass spectrometry detector (UHPLC-Q-TOF/MS). On-line analyses were performed using a Waters OASIS HLB column (30 x 2.1 mm, 20 µm) for the automatic sample loading and a Waters ACQUITY HSS C18 column (150 x 2 mm, 1.8 µm) for the chromatographic separation. Twenty-one metabolites, consisting of 12 CYP-derived and 9 UGT-derived metabolites, were identified. O-Desmethyl metabolites were the most abundant compounds after the phase I process, which appears to be in accordance with data from previously published NBOMe-intoxication case reports. Although other important metabolic transformations, such as sulfation, acetylation, methylation or glutathione conjugation, were not studied and artefactual metabolites might have been produced during the HLM incubation process, the record of all the metabolite MS spectra in our library should enable us to characterize relevant metabolites of 25B-NBOMe and allow us to detect 25B-MBOMe users. Copyright © 2015 John Wiley & Sons, Ltd.

Regional cerebral blood flow in Alzheimer's disease. Comparison between short and long-term donepezil therapy

International Nuclear Information System (INIS)

Ushijima, Yo; Okuyama, Chio; Kubota, Takao; Nakai, Takako; Nishimura, Tsunehiko; Mori, Satoru

2006-01-01

Treatment with donepezil improves cognitive function of patients with Alzheimer's disease (AD) when compared to a placebo-controlled group. The purpose of this study was to investigate changes in regional cerebral blood flow (rCBF) of AD patients in short-term and long-term treatment with donepezil. rCBF was measured by N-isopropyl-p- 123 I-iodoamphetamine (IMP) autoradiography method. CBF measurements were performed in 17 AD patients before treatment and after 3 months (short-term therapy) and 1 year (long-term therapy). Regions of interest were set at cerebral cortex and cerebellar hemisphere. We used absolute CBF and relative CBF expressed as ratio to cerebellar CBF. Significant increases in relative rCBF were noted in the frontal, parietal and temporal lobes at the end of short-term therapy. rCBF was decreased after the long-term therapy, whereas rCBF was still increased to a slight extent, as compared with the pre-treatment levels. Absolute rCBF showed minimal change and a tendency to decline. Relative rCBF significantly increased in the short-term donepezil therapy, while following the long-term therapy, rCBF decreased to the pre-treatment level. (author)

Effect of donepezil in patients with Alzheimer's disease previously untreated or treated with memantine or nootropic agents in Germany: an observational study.

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Klinger, Tatjana; Ibach, Bernd; Schoenknecht, Peter; Kamleiter, Martin; Silver, Gabrielle; Schroeder, Johannes; Mielke, Ruediger

2005-05-01

This open-label, prospective, observational, Post-Marketing Surveillance (PMS) study assessed the efficacy and safety of donepezil in patients who had been switched from therapies currently used in Germany to treat Alzheimer's disease (AD), such as memantine and nootropics, due to insufficient efficacy or poor tolerability. A treatment-naive population was included as a comparator. Patients with AD were treated with donepezil and observed for a period of approximately 3 months. A cognitive assessment was made using the Mini-Mental State Examination (MMSE). Quality of life (QoL) was assessed by the investigators who answered the question 'How did therapy with donepezil influence the QoL of the patient and/or his family over the observation period?' and was graded using three ratings: improved/unchanged/worsened. Adverse events (AEs) were also monitored. A total of 913 patients entered the study (mean +/- SD MMSE score 18.03 +/- 5.34). Efficacy assessments were analyzed for three groups: an overall group of patients who had received any form of prior AD drug therapy (N+ group; n = 709); a subgroup of patients from the N+ group who had received prior memantine therapy only (M+ group; n = 111) and patients who were drug treatment naive (N- group; n = 204). In the evaluable population donepezil improved MMSE scores by 2.21 +/- 3.47 points on average, with similar improvements observed in all three groups. QoL was judged to be improved in at least 70% of patients, again with similar results obtained for all three groups. Donepezil was well tolerated, with 85 of 913 (9.3%) patients reporting AEs. The most common AEs were those typically seen with cholinergic therapies (i.e., diarrhoea, vomiting and nausea). In this observational PMS study, donepezil was shown to be efficacious and well tolerated in patients who were being insufficiently treated with memantine or nootropic therapy. The magnitude of response was similar to that observed in patients who were previously

Attention Measures of Accuracy, Variability, and Fatigue Detect Early Response to Donepezil in Alzheimer's Disease: A Randomized, Double-blind, Placebo-Controlled Pilot Trial.

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Vila-Castelar, Clara; Ly, Jenny J; Kaplan, Lillian; Van Dyk, Kathleen; Berger, Jeffrey T; Macina, Lucy O; Stewart, Jennifer L; Foldi, Nancy S

2018-04-09

Donepezil is widely used to treat Alzheimer's disease (AD), but detecting early response remains challenging for clinicians. Acetylcholine is known to directly modulate attention, particularly under high cognitive conditions, but no studies to date test whether measures of attention under high load can detect early effects of donepezil. We hypothesized that load-dependent attention tasks are sensitive to short-term treatment effects of donepezil, while global and other domain-specific cognitive measures are not. This longitudinal, randomized, double-blind, placebo-controlled pilot trial (ClinicalTrials.gov Identifier: NCT03073876) evaluated 23 participants newly diagnosed with AD initiating de novo donepezil treatment (5 mg). After baseline assessment, participants were randomized into Drug (n = 12) or Placebo (n = 11) groups, and retested after approximately 6 weeks. Cognitive assessment included: (a) attention tasks (Foreperiod Effect, Attentional Blink, and Covert Orienting tasks) measuring processing speed, top-down accuracy, orienting, intra-individual variability, and fatigue; (b) global measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental Status Examination, Dementia Rating Scale); and (c) domain-specific measures (memory, language, visuospatial, and executive function). The Drug but not the Placebo group showed benefits of treatment at high-load measures by preserving top-down accuracy, improving intra-individual variability, and averting fatigue. In contrast, other global or cognitive domain-specific measures could not detect treatment effects over the same treatment interval. The pilot-study suggests that attention measures targeting accuracy, variability, and fatigue under high-load conditions could be sensitive to short-term cholinergic treatment. Given the central role of acetylcholine in attentional function, load-dependent attentional measures may be valuable cognitive markers of early treatment response.

Major urinary metabolites of 6-keto-prostaglandin F2α in mice[S

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Kuklev, Dmitry V.; Hankin, Joseph A.; Uhlson, Charis L.; Hong, Yu H.; Murphy, Robert C.; Smith, William L.

2013-01-01

Western diets are enriched in omega-6 vs. omega-3 fatty acids, and a shift in this balance toward omega-3 fatty acids may have health benefits. There is limited information about the catabolism of 3-series prostaglandins (PG) formed from eicosapentaenoic acid (EPA), a fish oil omega-3 fatty acid that becomes elevated in tissues following fish oil consumption. Quantification of appropriate urinary 3-series PG metabolites could be used for noninvasive measurement of omega-3 fatty acid tone. Here we describe the preparation of tritium- and deuterium-labeled 6-keto-PGF2α and their use in identifying urinary metabolites in mice using LC-MS/MS. The major 6-keto-PGF2α urinary metabolites included dinor-6-keto-PGF2α (∼10%) and dinor-13,14-dihydro-6,15-diketo-PGF1α (∼10%). These metabolites can arise only from the enzymatic conversion of EPA to the 3-series PGH endoperoxide by cyclooxygenases, then PGI3 by prostacyclin synthase and, finally, nonenzymatic hydrolysis to 6-keto-PGF2α. The 6-keto-PGF derivatives are not formed by free radical mechanisms that generate isoprostanes, and thus, these metabolites provide an unbiased marker for utilization of EPA by cyclooxygenases. PMID:23644380

Impact of CYP2C8*3 polymorphism on in vitro metabolism of imatinib to N-desmethyl imatinib.

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Khan, Muhammad Suleman; Barratt, Daniel T; Somogyi, Andrew A

2016-01-01

1. Imatinib is metabolized to N-desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-desmethyl imatinib formation was unknown. 2. We examined imatinib N-demethylation in human liver microsomes (HLMs) genotyped for CYP2C8*3, in CYP2C8*3/*3 pooled HLMs and in recombinant CYP2C8 and CYP3A4 enzymes. Effects of CYP-selective inhibitors on N-demethylation were also determined. 3. A single-enzyme Michaelis-Menten model with autoinhibition best fitted CYP2C8*1/*1 HLM (n = 5) and recombinant CYP2C8 kinetic data (median ± SD Ki = 139 ± 61 µM and 149 µM, respectively). Recombinant CYP3A4 showed two-site enzyme kinetics with no autoinhibition. Three of four CYP2C8*1/*3 HLMs showed single-enzyme kinetics with no autoinhibition. Binding affinity was higher in CYP2C8*1/*3 than CYP2C8*1/*1 HLM (median ± SD Km = 6 ± 2 versus 11 ± 2 µM, P=0.04). CYP2C8*3/*3 (pooled HLM) also showed high binding affinity (Km = 4 µM) and single-enzyme weak autoinhibition (Ki = 449 µM) kinetics. CYP2C8 inhibitors reduced HLM N-demethylation by 47-75%, compared to 0-30% for CYP3A4 inhibitors. 4. In conclusion, CYP2C8*3 is a gain-of-function polymorphism for imatinib N-demethylation, which appears to be mainly mediated by CYP2C8 and not CYP3A4 in vitro in HLM.

The Gac/Rsm Signaling Pathway of a Biocontrol Bacterium, Pseudomonas chlororaphis O6

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Anne J. Anderson

2017-09-01

Full Text Available Pseudomonas chlororaphis O6, isolated from the roots of dryland, field-grown commercial wheat in the USA, enhances plant health and therefore it is used in agriculture as a biofertilizer and biocontrol agent. The metabolites produced by this pseudomonad stimulate plant growth through direct antagonism of pathogens and by inducing systemic resistance in the plant. Studies upon P. chlororaphis O6 identify the pathways through which defined bacterial metabolites generate protection against pathogenic microbes, insects, and nematodes. P. chlororaphis O6 also triggers plant resistance to drought and salinity stresses. The beneficial determinants are produced from bacterial cells as they form biofilms during root colonization. Molecular control these processes in P. chlororaphis O6 involves the global regulatory Gac/Rsm signaling cascade with cross-talk between other global regulatory pathways. The Gac/Rsm regulon allows for coordinate phasing of expression of the genes that encode these beneficial traits among a community of cells. This review provides insights on the Gac/Rsm regulon in expression of beneficial traits of the P. chlororaphis O6 which can contribute to help yield enhancement and quality in agricultural production.

Plasma lipid levels in Alzheimer's disease patients treated by Donepezil hydrochloride: a cross-sectional study.

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Adunsky, Abraham; Chesnin, Vladimir; Ravona, Ramit; Harats, Dror; Davidson, Michael

2004-01-01

Donepezil hydrochloride is a central acetylcholine esterase inhibitor that is widely used in Alzheimer disease (AD). We have recently observed some differences in lipid profile between occasional cases of Donepezil hydrochloride users (DU) and non-users (DNU). This prompted us to study the levels of plasma lipids in these two groups, cross-sectionally. The medical charts of patients with probable AD were screened for current use of Donepezil hydrochloride and lipids profile, along with other clinical and demographic data. A total number of 105 patients were identified and included in the final analysis. Patients were divided into two groups (DU and DNU). Plasma levels of lipids were recorded. Mann-Whitney or t-test for continuous variables and Fisher exact test for categorical variables were used to test for significant differences between the groups. Regression analysis was applied to identify independently the factors associated with lipid levels. Thirty-three patients were DU and 72 DNU. The two groups differed in terms of age, lipid levels and cognitive level. DU had statistically significant higher levels of triglycerides compared with those not using the drug (P=0.036), higher total cholesterol (Phydrochloride. Alternatively, this may indicate that the effect of the medication may involve lipid metabolism, rather than other proposed mechanisms.

The Efficacy of Licensed-Indication Use of Donepezil and Memantine Monotherapies for Treating Behavioural and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease: Systematic Review and Meta-Analysis

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I.A. Lockhart

2011-07-01

Full Text Available Background/Aims: Behavioural and psychological symptoms of dementia (BPSD in Alzheimer’s disease (AD greatly increase caregiver burden. The abilities of donepezil and memantine to manage BPSD within their licensed indications in AD were compared. Methods: A systematic review, random effects meta-analysis and Bucher indirect comparison were conducted. Results: Six randomised controlled studies (4 donepezil and 2 memantine reported use within the licensed indication and had Neuropsychiatric Inventory (NPI data suitable for meta-analysis. BPSD showed significant improvement with donepezil compared with placebo [weighted mean difference (WMD in NPI –3.51, 95% confidence interval (CI –5.75, –1.27], whereas this was not the case for memantine (WMD –1.65, 95% CI –4.78, 1.49. WMD in NPI for donepezil versus memantine favoured donepezil but was not statistically significant (–1.86, 95% CI –5.71, 1.99; p = 0.34. Conclusion: Within its licensed indication, donepezil is efficacious for the management of BPSD in AD compared with placebo.

2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is Enantioselectively Oxidized to Hydroxylated Metabolites by Rat Liver Microsomes

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Wu, Xianai; Pramanik, Ananya; Duffel, Michael W.; Hrycay, Eugene G.; Bandiera, Stelvio M.; Lehmler, Hans-Joachim; Kania-Korwel, Izabela

2011-01-01

Developmental exposure to multiple-ortho substituted polychlorinated biphenyls (PCBs) causes adverse neurodevelopmental outcomes in laboratory animals and humans by mechanisms involving the sensitization of Ryanodine receptors (RyRs). In the case of PCB 136, the sensitization of RyR is enantiospecific, with only (-)-PCB 136 being active. However, the role of enantioselective metabolism in the developmental neurotoxicity of PCB 136 is poorly understood. The present study employed hepatic microsomes from phenobarbital (PB-), dexamethasone (DEX-) and corn oil (VEH-)treated male Sprague-Dawley rats to investigate the hypothesis that PCB 136 atropisomers are enantioselectively metabolized by P450 enzymes to potentially neurotoxic, hydroxylated PCB 136 metabolites. The results demonstrated the time- and isoform-dependent formation of three metabolites, with 5-OH-PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol) being the major metabolite. The formation of 5-OH-PCB 136 increased with the activity of P450 2B enzymes in the microsomal preparation, which is consistent with PCB 136 metabolism by rat P450 2B1. The minor metabolite 4-OH-PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl-4-ol) was produced by a currently unidentified P450 enzymes. An enantiomeric enrichment of (-)-PCB 136 was observed in microsomal incubations due to the preferential metabolism of (+)-PCB 136 to the corresponding 5-OH-PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol) atropisomer. 4-OH-PCB 136 displayed an enrichment of the atropisomer formed from (-)-PCB 136; however, the enrichment of this metabolite atropisomer didn't affect the enantiomeric enrichment of the parent PCB because 4-OH-PCB 136 is only a minor metabolite. Although the formation of 5- and 4-OH-PCB 136 atropisomers increased with time, the enantioselective formation of the OH-PCB metabolites resulted in constant enantiomeric enrichment, especially at later incubation times. These observations not only demonstrate that the chiral signatures of

Evaluation of the possibility of estimating therapeutic response to Donepezil in patients with dat using ezis

International Nuclear Information System (INIS)

Joji Kawabe; Shigeaki Higashiyama; Terue Okamura; Hiroshi Hashimoto; Hisanori Akiyama; Kouki Inoue; Nobuo Kiriike; Kenji Torii; Hirotaka Ishizu; Etsushi Kawamura; Jin Kotani; Ai Oe; Takehiro Hayashi

2004-01-01

high sensitivity and specificity in detection, but it is difficult to obtain three-dimensional spatial information of abnormalities from surface projection images. eZIS is a new statistical imaging analysis system permitting brain standardization using SPM and statistical analysis of the entire brain using Z-values. In this study, we examined the possibility of estimating therapeutic response to Donepezil in patients with DAT using eZIS. Methods: Eighteen patients (5 men, 13 women, age range, 66-83 years old; mean age, 73.6 years old) who complained of memory impairment were recruited from an outpatient dementia clinic of the Department of Neuro psychiatry of Osaka City University Hospital, between 2001 and 2003. The clinical diagnosis of DAT was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The patients received daily oral doses of Donepezil (5 mg/d). Each patient underwent the Alzheimer's Disease Assessment Scale Japanese edition (ADAS-Jcog) test, a recognition function test, and baseline SPECT examination at the time of initial evaluation and was clinically followed by a second ADAS-Jcog test and SPECT examination 12 weeks later. Informed consent of each patient was obtained after a detailed explanation concerning this study before beginning treatment. Before SPECT scanning was performed, an intravenous line was established in the right cubital vein of all patients while they were supine with their eyes closed. Each patient received a 740-MBq intravenous injection of Tc- 99m -ethyl cysteinate dimer (ECD). Dynamic data were collected (70 x 1-s frame images) simultaneously with the injection using a large field of view encompassing the cranial and thoracic regions. Thirty minutes after injection of Tc- 99m -ECD, brain SPECT imaging was performed with a 128 x 128 pixel matrix in step and shoot mode and with a triple-head SPECT system (GCA 9300 A/HG, Toshiba Medical Systems, Inc., Tokyo, Japan). All subsequent image

Production of urinary selenium metabolites in the rat following 75SeO32- administration

International Nuclear Information System (INIS)

Kiker, K.W.; Burk, R.F.

1974-01-01

Urinary metabolites of 75 Se were studied in male Holtzmann rats fed a Torula yeast diet with either no selenium (basal) or 0.5 ppM selenium (selenium) added as sodium selenite. The animals were anesthetized, a ureter was cannulated, and 20 μCi of 75 SeO 3 2- were injected intraportally. Only a small fraction (1.3 percent) of the injected 75 Se was excreted in 6 h by animals fed the basal diet but 13.3 percent was excreted by animals fed the selenium diet. Paper chromatography showed that both groups excreted mostly inorganic 75 Se in the first 10 min. A decrease in 75 Se excretion followed, and then, 70 min after the collection was started, the selenium diet group had an increase in 75 Se excretion which persisted for the rest of the 6 h and consisted mainly of the organic metabolites trimethylselenonium ion and U-2. 75 Se excretion remained low in the basal diet group. Liver uptake and release of 75 Se in the 1 h following intraperitoneal 75 SeO 3 2- injection was much greater in the selenium diet rats than in the basal diet rats. These results suggest that the greater excretion of 75 Se by rats fed the selenium diet than that by rats fed the basal diet was due to increased production of organic urinary selenium metabolites by the liver. (U.S.)

The clinical meaningfulness of ADAS-Cog changes in Alzheimer's disease patients treated with donepezil in an open-label trial.

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Rockwood, Kenneth; Fay, Sherri; Gorman, Mary; Carver, Daniel; Graham, Janice E

2007-08-30

In 6-month anti-dementia drug trials, a 4-point change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is held to be clinically important. We examined how this change compared with measures of clinical meaningfulness. This is a secondary analysis of a 12 month open-label study of 100 patients (71 women) diagnosed with mild to moderate AD treated with 5-10 mg of donepezil daily. We studied the observed case, 6-month change from baseline on the ADAS-Cog, the Clinician's Interview Based Impression of Change-Plus Caregiver Input (CIBIC-Plus), patient-Goal Attainment Scaling (PGAS) and clinician-GAS (CGAS). At 6 months, donepezil-treated patients (n = 95) were more likely to show no change (+/- 3 points) on the ADAS-Cog (56%) than to improve (20%) or decline (24%) by 4-points. ADAS-Cog change scores were little correlated with other measures: from -0.09 for PGAS to 0.27 for the CIBIC-Plus. While patients who improved on the ADAS-Cog were less likely to decline on the clinical measures (26%), 43% of patients who declined on the ADAS-Cog improved on at least two of the clinical measures. The ADAS-Cog did not capture all clinically important effects. In general, ADAS-Cog improvement indicates clinical improvement, whereas many people with ADAS-Cog decline do not show clinical decline. The open-label design of this study does not allow us to know whether this is a treatment effect, which requires further investigation.

Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases

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Alvarez, Irene; Iglesias, Olalla; Crespo, Ignacio; Figueroa, Jesus; Aleixandre, Manuel; Linares, Carlos; Granizo, Elias; Garcia-Fantini, Manuel; Marey, Jose; Masliah, Eliezer; Winter, Stefan; Muresanu, Dafin; Moessler, Herbert

2016-01-01

Background: Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer’s disease. Methods: We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer’s disease patients. Results: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy. Conclusion: Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer’s disease cases with apolipoprotein E epsilon-4 allele. PMID:27207906

Detecting effects of donepezil on visual selective attention using signal detection parameters in Alzheimer's disease.

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Foldi, Nancy S; White, Richard E C; Schaefer, Lynn A

2005-05-01

Attentional function is impaired in Alzheimer's disease (AD). Moreover, attention is mediated by acetylcholine. But, despite the widespread use of acetylcholinesterase inhibitors (AChE-I) to augment available acetylcholine in AD, measures of attentional function have not been used to assess the drug response. We hypothesized that as cholinergic augmentation impacts directly on the attentional system, higher-order measures of visual selective attention would be sensitive to effects of treatment using an AChE-I (donepezil hydrochloride). We also sought to determine whether these attentional measures were more sensitive to treatment than other measures of cognitive function. Seventeen patients with AD (8 untreated, 9 treated with donepezil) were contrasted on performance of a selective cancellation task. Two signal detection parameters were used as outcome measures: decision strategy (beta, beta) and discriminability (d-prime, d'). Standard screening and cognitive domain measures of vigilance, language, memory, and executive function were also contrasted. Treated patients judged stimuli more conservatively (p = 0.29) by correctly endorsing targets and rejecting false alarms. They also discriminated targets from distractors more easily (p = 0.58). The screening and neuropsychological measures failed to differentiate the groups. Higher-order attentional measures captured the effects of donepezil treatment in small groups of patients with AD. The results suggest that cholinergic availability may directly affect the attentional system, and that these selective attention measures are sensitive markers to detect treatment response. Copyright 2005 John Wiley & Sons, Ltd.

Sustained release donepezil loaded PLGA microspheres for injection: Preparation, in vitro and in vivo study

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Wenjia Guo

2015-10-01

Full Text Available The purpose of this study was to develop a PLGA microspheres-based donepezil (DP formulation which was expected to sustain release of DP for one week with high encapsulation efficiency (EE. DP derived from donepezil hydrochloride was encapsulated in PLGA microspheres by the O/W emulsion-solvent evaporation method. The optimized formulation which avoided the crushing of microspheres during the preparation process was characterized in terms of particle size, morphology, drug loading and EE, physical state of DP in the matrix and in vitro and in vivo release behavior. DP microspheres were prepared successfully with average diameter of 30 µm, drug loading of 15.92 ± 0.31% and EE up to 78.79 ± 2.56%. Scanning electron microscope image showed it has integrated spherical shape with no drug crystal and porous on its surface. Differential scanning calorimetry and X-ray diffraction results suggested DP was in amorphous state or molecularly dispersed in microspheres. The Tg of PLGA was increased with the addition of DP. The release profile in vitro was characterized with slow but continuous release that lasted for about one week and fitted well with first-order model, which suggested the diffusion governing release mechanism. After single-dose administration of DP microspheres via subcutaneous injection in rats, the plasma concentration of DP reached peak concentration at 0.50 d, and then declined gradually, but was still detectable at 15 d. A good correlation between in vitro and in vivo data was obtained. The results suggest the potential use of DP microspheres for treatment of Alzheimer's disease over long periods.

Multi-target directed donepezil-like ligands for Alzheimer's disease

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Mercedes eUnzeta

2016-05-01

Full Text Available Alzheimer's disease (AD, the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept® but with limited therapeutic success. This might be due to the complex multifactorial nature of AD, a fact that has prompted the design of new Multi-Target-Directed Ligands (MTDL based on the one molecule, multiple targets paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N-benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine or 8-hydroxyquinoline with special emphasis on compound ASS234, an N-propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy.

Rational Design and Multibiological Profiling of Novel Donepezil-Trolox Hybrids against Alzheimer's Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties.

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Cai, Pei; Fang, Si-Qiang; Yang, Xue-Lian; Wu, Jia-Jia; Liu, Qiao-Hong; Hong, Hao; Wang, Xiao-Bing; Kong, Ling-Yi

2017-11-15

A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC 50 = 0.54 μM) and hMAO-B (IC 50 = 4.3 μM), significant antioxidant activity (41.33 μM IC 50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aβ 1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H 2 O 2 , rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl 3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.

Association of plasma IL-6 and Hsp70 with HRV at different levels of PAHs metabolites.

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Jian Ye

Full Text Available Exposure to polycyclic aromatic hydrocarbons (PAHs is associated with reduced heart rate variability (HRV, a strong predictor of cardiovascular diseases, but the mechanism is not well understood.We hypothesized that PAHs might induce systemic inflammation and stress response, contributing to altered cardiac autonomic function.HRV indices were measured using a 3-channel digital Holter monitor in 800 coke oven workers. Plasma levels of interleukin-6 (IL-6 and heat shock protein 70 (Hsp70 were determined using ELISA. Twelve urinary PAHs metabolites (OH-PAHs were measured by gas chromatography-mass spectrometry.We found that significant dose-dependent relationships between four urinary OH-PAHs and IL-6 (all Ptrend<0.05; and an increase in quartiles of IL-6 was significantly associated with a decrease in total power (TP and low frequency (LF (Ptrend = 0.014 and 0.006, respectively. In particular, elevated IL-6 was associated in a dose-dependent manner with decreased TP and LF in the high-PAHs metabolites groups (all Ptrend<0.05, but not in the low-PAHs metabolites groups. No significant association between Hsp70 and HRV in total population was found after multivariate adjustment. However, increased Hsp70 was significantly associated with elevated standard deviation of NN intervals (SDNN, TP and LF in the low-PAHs metabolites groups (all Ptrend<0.05. We also observed that both IL-6 and Hsp70 significantly interacted with multiple PAHs metabolites in relation to HRV.In coke oven workers, increased IL-6 was associated with a dose-response decreased HRV in the high-PAHs metabolites groups, whereas increase of Hsp70 can result in significant dose-related increase in HRV in the low-PAHs metabolites groups.

Effectiveness of donepezil in reducing clinical worsening in patients with mild-to-moderate alzheimer's disease

DEFF Research Database (Denmark)

Wilkinson, David; Schindler, Rachel; Schwam, Elias

2009-01-01

BACKGROUND: Therapeutic endpoints based on reduced clinical worsening represent clinically relevant and realistic goals for patients suffering from progressive neurodegenerative disorders such as Alzheimer's disease (AD). METHODS: Data from 906 patients (388 receiving placebo; 518 receiving...... of declining were significantly reduced for donepezil-treated versus placebo patients (p treatment...

Aquatic toxicity of the macrolide antibiotic clarithromycin and its metabolites.

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Baumann, Michaela; Weiss, Klaus; Maletzki, Dirk; Schüssler, Walter; Schudoma, Dieter; Kopf, Willi; Kühnen, Ute

2015-02-01

The human macrolide antibiotic clarithromycin is widespread in surface waters. Our study shows that its major metabolite 14-hydroxy(R)-clarithromycin is found in surface waters in comparable amounts. This metabolite is known to be pharmacologically active. Additionally, clarithromycin is partly metabolised to N-desmethyl-clarithromycin, which has no antimicrobial activity. For clarithromycin, some ecotoxicological studies on aquatic organisms have been published. However, many of them are not conform with the scientific principles as given in the "Technical guidance for deriving environmental quality standards" (TGD-EQS), because numerous studies were poorly documented and the methods did not contain analytical measurements confirming that the exposure concentrations were in the range of ± 20% of the nominal concentrations. Ecotoxicological effects of clarithromycin and its two metabolites on the zebrafish Danio rerio (embryo test), the microcrustacean Daphnia magna, the aquatic monocotyledonous macrophyte Lemna minor, the freshwater green alga Desmodesmus subspicatus (Chlorophyta) and the cyanobacterium Anabaena flosaquae were investigated in compliance with the TGD-EQS. Environmental risk assessment was performed using ErC10 values of Anabaena, the species most sensitive to clarithromycin and 14-hydroxy(R)-clarithromycin in our testing. Based oncomparable toxicity and similar concentrations of clarithromycin and its active metabolite 14-hydroxy(R)-clarithromycin in surface waters, an additional multiplication factor of 2 to the assessment factor of 10 on the ErC10 of clarithromycin should be used. Consequently, a freshwater quality standard of 0.130 μg L(-1) is proposed for clarithromycin as the "lead substance". Taking this additional multiplication factor of 2 into account, single monitoring of clarithromycin may be sufficient, in order to reduce the number of substances listed for routine monitoring programs. Copyright © 2014 Elsevier Ltd. All rights

Olfactory Deficits in MCI as Predictor of Improved Cognition on Donepezil

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2016-06-01

total recall and modified ADAS-cog) from baseline to 26 weeks and 52 weeks of donepezil treatment. 2. Increase in UPSIT scores from...In  these  models  the  response  was  change  in  score  (either  ADAS-­‐cog  or  SRT   total   recall )   from...decrease  in  UPSIT  score  was  associated  with  change  in  SRT   total   recall  from  baseline   to

Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats.

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Gawel, Kinga; Labuz, Krzysztof; Jenda, Malgorzata; Silberring, Jerzy; Kotlinska, Jolanta H

2014-07-15

The influence of systemic administration of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference (CPP) was examined in rats. Additionally, this study aimed to compare the effects of donepezil, which selectively inhibits acetylcholinesterase, and rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase on morphine reward. Morphine-induced CPP (unbiased method) was induced by four injections of morphine (5 mg/kg, i.p.). Donepezil (0.5, 1, and 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5, and 1 mg/kg, i.p.) were given 20 min before morphine during conditioning phase and 20 min before the expression or reinstatement of morphine-induced CPP. Our results indicated that both inhibitors of cholinesterase attenuated the acquisition and expression of morphine CPP. The results were more significant after rivastigmine due to a broader inhibitory spectrum of this drug. Moreover, donepezil (1 mg/kg) and rivastigmine (0.5 mg/kg) attenuated the morphine CPP reinstated by priming injection of 5mg/kg morphine. These properties of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist but not scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. All effects of cholinesterase inhibitors were observed at the doses that had no effects on locomotor activity of animals. Our results suggest beneficial role of cholinesterase inhibitors in reduction of morphine reward and morphine-induced seeking behavior. Finally, we found that the efficacy of cholinesterase inhibitors in attenuating reinstatement of morphine CPP provoked by priming injection may be due to stimulation of nicotinic acetylcholine receptors. Copyright © 2014 Elsevier B.V. All rights reserved.

Preliminary study to prepare a reference material of toluene metabolite - o-cresol and benzene metabolite-phenol - in human

Czech Academy of Sciences Publication Activity Database

Šperlingová, I.; Dabrowská, L.; Stránský, V.; Kučera, Jan; Tichý, M.

2006-01-01

Roč. 11, č. 5 (2006), s. 231-235 ISSN 0949-1775 R&D Projects: GA MZd NR7831 Institutional research plan: CEZ:AV0Z10480505 Keywords : reference material * toluene metabolites * o-cresol Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 0.640, year: 2006

Quantification of the radio-metabolites of the serotonin-1A receptor radioligand [carbonyl-11C]WAY-100635 in human plasma: An HPLC-assay which enables measurement of two patients in parallel

International Nuclear Information System (INIS)

Nics, L.; Hahn, A.; Zeilinger, M.; Vraka, C.; Ungersboeck, J.; Haeusler, D.; Hartmann, S.; Wagner, K-H.; Lanzenberger, R.; Wadsak, W.; Mitterhauser, M.

2012-01-01

[Carbonyl- 11 C]WAY-100635 is a potent and effective antagonist for the 5-HT 1A receptor subtype. We aimed to assess the status of [carbonyl- 11 C]WAY-100635 and its main radio-metabolites, [carbonyl- 11 C]desmethyl-WAY-100635 and [carbonyl- 11 C]cyclohexanecarboxylic acid, on the basis of an improved radio-HPLC method. Common methods were characterized by preparative HPLC columns with long runtimes and/or high flow rates. Considering the short half-life of C-11, we developed a more rapid and solvent saving HPLC assay, allowing a fast, efficient and reliable quantification of these major metabolites. - Highlights: ► We developed a HPLC assay which allows the measurement of two patients in parallel. ► It allows a fast and efficient quantification of WAY-100635 and its metabolites. ► Better counting statistics with late samples for modeling the input function is achieved. ► The fastest assay so far is about 40% slower in comparison to the presented method.

Routine determination of [18F]-L-6-fluorodopa and its metabolites in blood plasma is essential for accurate positron emission tomography studies

International Nuclear Information System (INIS)

Chan, G.L.Y.; Hewitt, K.A.; Pate, B.D.; Schofield, P.; Adam, M.J.; Ruth, T.J.

1991-01-01

A batch-contact alumina-extraction method has been used to separate [ 18 F]-L-6-fluorodopa (FD) from its principal metabolite, 3-O-methyl-[ 18 F]-6 fluorodopa (3-OMe-FD), in arterial blood plasma samples collected from subjects pretreated with carbidopa during positron emission tomography (PET) scans. The time course of the metabolite-corrected blood plasma activity is then used as an input function for kinetic analysis of striatal FD uptake. Results obtained from using the batch-contact alumina-extraction method were compared with those from high performance liquid chromatography, and also with those from a chromatographic alumina cartridge technique. In 60 human subjects including normal healthy volunteers and patients diagnoses as having a movement disorder, arterial blood plasma samples were collected after FD injection during a two-hour PET scan and analyzed by the batch-contact alumina-extraction method. The activity ratio (metabolites/FD) increased linearly with time for all subjects. However, there was a wide variation in the slope of the plot of the activity ratio versus time among the subjects. No significant linear or curved relationship was observed between the slope and the age of the subject. Separation of FD from its metabolites is therefore, necessary for each PET-FD study conducted

Effect of Metformin on Adult Hippocampal Neurogenesis: Comparison with Donepezil and Links to Cognition.

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Ahmed, Sara; Mahmood, Zahra; Javed, Aneela; Hashmi, Shoaib Naiyer; Zerr, Inga; Zafar, Saima; Zahid, Saadia

2017-05-01

Recent studies have uncovered evidence suggesting that interference with hippocampal adult neurogenesis contributes to neurodegeneration in Alzheimer's disease (AD). Evidence supporting that AD is a metabolic disease with derangements in brain glucose utilization implies the use of anti-diabetics as an alternate therapeutic strategy. The present study drew comparison between the pro-neurogenic potential of metformin and donepezil in AlCl 3 -induced mouse model of neurodegeneration. Morris water maze task and subsequent immunohistochemical evaluation for NeuN was conducted. Expression of neurogenesis markers and hippocampal proteome analysis was determined by qRT-PCR and SDS-PAGE, respectively, followed by ESI-QTOFF MS/MS identification. The results demonstrated impaired spatial memory and differential expression of eight proteins in the AlCl 3 group as compared to the controls. Interestingly, treatment with metformin normalized the proteome profile and expression levels of neurogenesis markers along with improvement in the spatial memory. Moreover, as compared to donepezil, metformin-treated mice exhibited an enhanced number of post-mitotic NeuN-positive neurons. It is suggested that underlying molecular mechanisms of metformin-mediated adult hippocampal neurogenesis may have implications in treatment of neurodegenerative disorders.

Characteristics of MRI features in Alzheimer's disease patients predicting response to donepezil treatment

International Nuclear Information System (INIS)

Tanaka, Yuriko; Hanyu, Haruo; Sakurai, Hirofumi; Shimizu, Souichiro; Takasaki, Masaru

2003-01-01

We attempted to investigate whether morphological features as shown on magnetic resonance imaging (MRI) predict response to donepezil treatment in patients with Alzheimer's disease (AD). Sixty-three patients with AD were divided into responders (n=16) and non-responders (n=47) based on the changes in the mini mental state examinations (MMSE) score between baseline and endpoint. Atrophy of the substantia innominata was more pronounced in responders than non-responders. Although no significant difference in the medial temporal lobe atrophy between responders and non-responders was found, magnetization transfer ratios (MTRs) of the hippocampus and parahippocampus, indicators of structural damage, in the non-responder group were significantly reduced compared to those in the responder group. There were no significant differences in the severity of white matter lesions between the two groups. Logistic regression analysis revealed that the overall discrimination rate was 81%, with 85% of non-responders and 69% of responders, through measurement of the thickness of the substantia innominata and MTR of the hippocampus and parahippocampus. These results suggest that AD patients who show more severe cholinergic dysfunction and less severe structural damage of the hippocampus and parahippocampus as shown on MRI are likely to respond to donepezil treatment. (author)

Donepezil in the Treatment of ADHD-Like Symptoms in Youths with Pervasive Developmental Disorder: A Case Series

Science.gov (United States)

Doyle, Robert L.; Frazier, Jean; Spencer, Thomas J.; Geller, Daniel; Biederman, Joseph; Wilens, Timothy

2006-01-01

Background: Recent studies reported ADHD-like symptoms and cognitive deficits in pervasive developmental disorder (PDD). Because work in dementia documents improvement in executive function deficits with the acetylcholinesterase inhibitor donepezil, the authors reason that similar benefits could be obtained in PDD. Method: The authors describe…

Effectiveness of treatment with donepezil hydrochloride and changes in regional cerebral blood flow in patients with Alzheimer's disease

International Nuclear Information System (INIS)

Yoshida, Tsunetaka; Ha-Kawa, S.; Yoshimura, Masafumi; Nobuhara, Kenji; Kinoshita, Toshihiko; Sawada, Satoshi

2007-01-01

The objective of this study was to elucidate the relationship between the effects of donepezil hydrochloride (donepezil) and cerebral blood flow, and to evaluate the usefulness of cerebral blood flow imaging in assessing and predicting treatment effectiveness. The subjects were 29 outpatients (12 men and 17 women; age 50-82 years; mean age 69.2 years), who had received a diagnosis of Alzheimer's disease (AD). Efficacy was evaluated before donepezil administration; after 1 month, 3 months, and 6 months of drug administration; and at 1 year after completion of administration using the Japanese version of the Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog), as a measure of cognitive function. The ADAS-cog has been frequently used to evaluate cognitive function in AD patients. Patients whose ADAS-cog scores improved by 3 or more points during the observation period were classified as responders, and those with no improvement were classified as nonresponders. 123 I-iofetamine (IMP) was used for single photon emission computed tomography cerebral blood flow scintigraphy. On the basis of ADAS-cog score improvement, 22 of the 29 patients were responders (7 men and 15 women; age 50-82 years; mean age 69.0 years) and seven were nonresponders (5 men and 2 women; age 61-80 years; mean age 70.0 years). The results indicate that a difference in cerebral blood flow responsiveness after 1 month of treatment distinguishes responders from nonresponders. After 1 month, blood flow was significantly decreased in all regions of nonresponders, whereas significant increases in blood flow were seen in the anterior frontal lobe and parietal lobe of responders. At that time point, blood flow in the basal ganglion differed significantly between the two groups, indicating that this difference in responsiveness after 1 month of treatment may distinguish responders from nonresponders. In cognitive function testing, the group that exhibited a complete response showed

Mutagenic azide metabolite is azidoalanine

International Nuclear Information System (INIS)

Owais, W.M.; Rosichan, J.L.; Ronald, R.C.; Kleinhofs, A.; Nilan, R.A.

1981-01-01

Sodium axide produces high mutation rates in a number of species. Azide mutagenicity is mediated through a metabolite in barley and bacteria. Many studies showed that azide affects the L-cysteine biosynthesis pathway. Cell-free extracts of Salmonella typhimurium convert azide and O-acetylserine to the mutagenic metabolite. O-acetylserine sulfhydrylase was identified as the enzyme responsible for the metabolite biosynthesis. To confirm the conclusion that the azide metabolite is formed through the β-substitution pathway of L-cysteine, we radioactively labeled the azide metabolite using 14 C-labeled precursors. Moreover, the mutagenic azide metabolite was purified and identified as azidoalanine based on mass spectroscopy and elemental analysis. 26 refs., 3 figs., 1 tab

Interaction study of aspirin or clopidogrel on pharmacokinetics of donepezil hydrochloride in rats by HPLC-fluorescence detection.

Science.gov (United States)

Wada, Mitsuhiro; Nishiwaki, Junichiro; Yamane, Tomoko; Ohwaki, Yuichi; Aboul-Enein, Hassan Y; Nakashima, Kenichiro

2007-06-01

The present study aims to investigate the possibility of interaction of aspirin (Asp) or clopidogrel (CG) on donepezil (DP) hydrochloride in rats by HPLC-fluorescence detection. The separation of DP was achieved in ca. 13 min without interference of Asp and CG on the chromatogram. DP levels in rat plasma with a single administration of DP (5 mg/kg, i.p., group I) and those with a co-administration of Asp (200 mg/kg, p.o., group II or 200 mg/kg, i.p., group III) or CG (5 mg/kg, p.o., group IV) were monitored. The DP concentrations determined in rat plasma ranged from 25.0 to 336.1 ng/mL. Pharmacokinetic parameters for these groups were calculated and compared with one another. No significant difference was observed on the comparison of group I with other groups except for the mean resident time of group IV (p = 0.012). These basic findings may help clinical inference when DP is co-administered with Asp and CG to human. Copyright 2007 John Wiley & Sons, Ltd.

Effects of donepezil combined with folic acid and vitamin B12 on serum levels of inflammatory factors, HCY, NSE and neurotransmitters in elderly patients with Alzheimer' s disease complicated with hyperhomocysteinemia

Directory of Open Access Journals (Sweden)

Fang-Fang Zheng

2017-08-01

Full Text Available Objective: To investigate the effects of donepezil combined with folic acid and vitamin B12 on the levels of serum inflammatory factors, Hcy, NSE and neurotransmitters in elderly patients with Alzheimer's disease (AD complicated with hyperhomocysteinemia. Methods: A total of 98 elderly patients with AD complicated with hyperhomocysteinemia were randomly divided into control group (n=48 and observation group (n=50 according to the random data table method. Patients in the control group were treated with donepezil. On this basis, the patients in the observation group were treated with folic acid and vitamin B12, all patients were treated for 3 months. Before and after treatment, the levels of serum inflammatory factors (TNF-α, IL-6 and hs-CRP, Hcy, NSE and brain neurotransmitter (5-HT, NE and DA were compared between the two groups. Results: Before treatment, the levels of TNF-α, IL-6, hs-CRP, Hcy, NSE, 5-HT, NE and DA of the control group and the observation group were not statistically significant. Compared with the group before treatment, the levels of TNF-α, IL-6, hs-CRP, Hcy and NSE in the two groups were significantly lower, and the level of the observation group was significantly lower than those of the control group, the difference was statistically significant; Compared with the group before treatment, the levels of 5-HT, NE and DA in the two groups were significantly increased, and the observation group was significantly higher than that of the control group, the difference was statistically significant. Conclusion: Donepezil combined folic acid and vitamin B12 in treatment of AD with hyperhomocysteinemia, which can effectively reduce the body's inflammatory response, reduced Hcy and NSE levels, elevated levels of brain neurotransmitters, has important clinical significance.

The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model.

Science.gov (United States)

Bond, M; Rogers, G; Peters, J; Anderson, R; Hoyle, M; Miners, A; Moxham, T; Davis, S; Thokala, P; Wailoo, A; Jeffreys, M; Hyde, C

2012-01-01

% probability of being the most cost-effective option at a WTP of £’30,000 per QALY (27% at a WTP of £’20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£’69,592 vs £’69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £’30,000 per QALY is 38% (and 28% at a WTP of £’20,000 per QALY). The deterministic ICER for memantine is £’32,100 per/QALY and the probabilistic ICER is £’36,700 per/QALY. Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. The National Institute for Health Research Health Technology Assessment programme.

Evaluation of the therapeutic response to donepezil in patients with dat by 3DSRT

International Nuclear Information System (INIS)

Shigeaki Higashiyama; Terue Okamura; Koichi Koyama Yuichi Inoue; Joji kawabe; Kenji Torii; Susumu Shiomi; Hiroshi Hashimoto; Hisanori Akiyama; Kouki Inoue; Nobuo Kiriike

2004-01-01

Purpose: Alzheimer's disease (AD) is characterized by progressive impairment of memory and cognitive function associated with loss of presynaptic cholinergic function. It has recently been hypothesized that cholinergic agents such as cholinesterase inhibitors or cholinergic agonists may have the potential to improve these symptoms. One such compound is donepezil hydrochloride (Donepezil), which acts by blocking acetylcholinesterase and butyl cholinesterase, which hydoryze acetylcholine. In the diagnosis of AD, brain perfusion scintigraphy is an objective of visualization of brain perfusion. Up to the present, AD has been diagnosed objectively and quantitatively using brain perfusion single photon emission tomography (SPECT). In a quantitative evaluation of therapeutic response of Donepezil in AD, for comparison with regional cerebral blood flow (rCBF) in various lesions before and after treatment, uptake in various cerebral regions of interests (ROIs), such as the frontal lobes, temporo-occipital lobes, parietal lobes and cerebellar hemispheres, were used to be measured, The aim of this study was to investigate the accuratelity of therapeutic response of three-dimensional stereotaxic ROI template (3DSRT), fully automated ROI analysis software, which can objectively estimate rCBF in patients undergoing Donepezil therapy. We compare the effect of therapeutic response of three-dimensional stereotactic surface projections (3D-SSP). 3D-SSP is an image-processing and statistical program allowing pixel-by-pixel analysis of cerebral perfusion, provides a reliable and objective means of evaluation of severity of AD. On 3D-SSP images, we assessed the extent of abnormal region in each segment (rate of coordinates with a Z-value exceeding the.threshold value, of all coordinates within a segment) Methods: Twenty-one patients (15 females, 6 males;age range, 66-83 years old; mean age=69.4 years) diagnosed with AD according to the Diagnostic and Statistical Manual of Mental

Late-onset Rise of 6-MMP Metabolites in IBD Patients on Azathioprine or Mercaptopurine.

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Munnig-Schmidt, Erik; Zhang, Mei; Mulder, Chris J; Barclay, Murray L

2018-03-19

The thiopurines azathioprine and mercaptopurine remain pivotal maintenance treatments in inflammatory bowel disease (IBD); however, up to 15%-20% of patients preferentially produce the hepatotoxic metabolite 6-methylmercaptopurine (6MMP) at the expense of the therapeutic 6-thioguanine nucleotides (6TGN). This metabolic shunting usually begins within 3 months of therapy. We noted patients developing shunting many months or years after starting treatment and aimed to determine how often this late shunting occurs and whether this could be explained by patient factors or concomitant medications. The New Zealand database of thiopurine metabolite results from 2002 to 2016 (19085 6TGN/6MMP pairs from 7130 patients) was interrogated to identify patients developing a 6MMP/6TGN ratio >20 after at least 4 months treatment. Dosing history, concomitant therapy, and comorbidity data were assessed. Fifteen percent of database patients developed preferential 6-MMP production, and of these, 29 patients had late-onset shunting with sufficient data available for validation. This extrapolates to 90 patients in total, representing 1.7% of IBD patients on thiopurines, or 10% of all those with preferential 6-MMP production. Time from starting therapy to shunting was 5 months to 10.4 years (median, 21 months). Eleven patients had abnormal liver function when shunting was recognized, all with 6MMP >5900 pmol/8 × 108 red blood cells. No common factors were found to explain the late onset. Some IBD patients develop preferential 6MMP production many months or years after commencing therapy. This is important when considering frequency of metabolite monitoring, failure of therapy, or abnormal liver function. 10.1093/ibd/izx081_video1izx081.video15746667546001.

Preservation of urine free catecholamines and their free O-methylated metabolites with citric acid as an alternative to hydrochloric acid for LC-MS/MS-based analyses.

Science.gov (United States)

Peitzsch, Mirko; Pelzel, Daniela; Lattke, Peter; Siegert, Gabriele; Eisenhofer, Graeme

2016-01-01

Measurements of urinary fractionated metadrenalines provide a useful screening test to diagnose phaeochromocytoma. Stability of these compounds and their parent catecholamines during and after urine collection is crucial to ensure accuracy of the measurements. Stabilisation with hydrochloric acid (HCl) can promote deconjugation of sulphate-conjugated metadrenalines, indicating a need for alternative preservatives. Urine samples with an intrinsically acidic or alkaline pH (5.5-6.9 or 7.1-8.7, respectively) were used to assess stability of free catecholamines and their free O-methylated metabolites over 7 days of room temperature storage. Stabilisation with HCl was compared with ethylenediaminetetraacetic acid/metabisulphite and monobasic citric acid. Catecholamines and metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Free catecholamines and their O-methylated metabolites were stable in acidic urine samples over 7 days of room temperature storage, independent of the presence or absence of any stabilisation method. In contrast, free catecholamines, but not the free O-methylated metabolites, showed rapid degradation within 24 h and continuing degradation over 7 days in urine samples with an alkaline pH. Adjustment of alkaline urine samples to a pH of 3-5 with HCl or 4.8-5.4 with citric acid completely blocked degradation of catecholamines. Ethylenediaminetetraacetic acid/metabisulphite, although reducing the extent of degradation of catecholamines in alkaline urine, was largely ineffectual as a stabiliser. Citric acid is equally effective as HCl for stabilisation of urinary free catecholamines and minimises hazards associated with use of strong inorganic acids while avoiding deconjugation of sulphate-conjugated metabolites during simultaneous LC-MS/MS measurements of free catecholamines and their free O-methylated metabolites.

[Pharmacological properties of donepezil hydrochloride (Aricept), a drug for Alzheimer's disease].

Science.gov (United States)

Ogura, H; Kosasa, T; Araki, S; Yamanishi, Y

2000-01-01

One of the most consistent changes associated with Alzheimer's disease (AD) is a deficit in central cholinergic neurotransmission. Donepezil hydrochloride (DPZ), a novel class of cholinesterase (ChE) inhibitors, inhibits degradation of acetylcholine (ACh) and activates central cholinergic system. In in vitro studies, DPZ more selectively inhibited acetylcholinesterase (IC50: 6.7 nM) than butyrylcholinesterase (IC50: 7400 nM), while tacrine inhibited both acetylcholinesterase (IC50: 77 nM) and butyrylcholinesterase (IC50: 69 nM). After oral dosing, DPZ (ID50: 2.6 mg/kg) inhibited brain ChE dose-dependently without any remarkable effect on ChE in the heart and small intestine, whereas tacrine (ID50: 9.5 mg/kg) inhibited ChE equally in the brain and peripheral tissues. Brain microdialysis revealed that DPZ (2.5 mg/kg) enhanced extracellular ACh concentrations in the cerebral cortex and hippocampus in rats. In behavioral studies, DPZ counteracted both the deficit in passive avoidance induced by lesioning of the nucleus basalis magnocellularis (0.125-1.0 mg/kg) and the impairment in acquisition of a hidden-platform water maze task after lesioning of the medial septum in rats (0.5 mg/kg). DPZ also inhibited the scopolamine-induced impairment of radial maze performance (0.5 mg/kg). Placebo-controlled clinical studies of 12- and 24-week treatments of DPZ (5 mg, 10 mg/day) clearly showed an improvement in cognitive scores of probable AD patients.

[carbonyl-11C]Desmethyl-WAY-100635 (DWAY) is a potent and selective radioligand for central 5-HT1A receptors in vitro and in vivo

International Nuclear Information System (INIS)

Pike, V.W.; McCarron, J.A.; Hirani, E.; Hume, S.P.; Osman, S.; Poole, K.G.; Wikstroem, H.; Mensonidas, M.

1998-01-01

In this study we set out to assess the ability of DWAY to enter brain in vivo and to elucidate its possible interaction with 5-HT 1A receptors. Desmethyl-WAY-100635 was labelled efficiently with carbon-11 in high specific radioactivity by reaction of its descyclohexanecarbonyl analogue with [carbonyl- 11 C]cyclohexanecarbonyl chloride. The product was separated in high radiochemical purity by HPLC. Rats were injected intravenously with DWAY, sacrificed and dissected to establish radioactivity content in brain tissues. At 60 min after injection, the ratios of radioactivity concentration in each brain region to that in cerebellum correlated with previous in vitro and in vivo measures of 5-HT 1A receptor density. The highest ratio was about 22 in hippocampus. Radioactivity cleared rapidly from plasma; HPLC analysis revealed that DWAY represented 55% of the radioactivity in plasma at 5 min and 33% at 30 min. Only polar radioactive metabolites were detected. Subsequently, a cynomolgus monkey was injected intravenously with DWAY and examined by PET. Maximal whole brain uptake of radioactivity was 5.7% of the administered dose at 5 min after injection. The image acquired between 9 and 90 min showed high radioactivity uptake in brain regions rich in 5-HT 1A receptors, moderate uptake in raphe nuclei and low uptake in cerebellum. A transient equilibrium was achieved in cortical regions at about 60 min, when the ratio of radioactivity concentration in frontal cortex to tcat in cerebellum reached 6. The corresponding ratio for raphe nuclei was about 3. Radioactive metabolites appeared rapidly in plasma, but these were all more polar than DWAY, which represented 52% of the radioactivity in plasma at 4 min and 20% at 55 min. In a second PET experiment, in which a cynomolgus monkey was pretreated with the selective 5-HT 1A receptor antagonist, WAY-100635, at 25 min before DWAY injection, radioactivity in all brain regions was reduced to that in cerebellum. Autoradiography of

New metal-organic frameworks of [M(C6H5O7)(C6H6O7)(C6H7O7)(H2O)] . H2O (M=La, Ce) and [Ce2(C2O4)(C6H6O7)2] . 4H2O

International Nuclear Information System (INIS)

Weng Shengfeng; Wang, Yun-Hsin; Lee, Chi-Shen

2012-01-01

Two novel materials, [M(C 6 H 5 O 7 )(C 6 H 6 O 7 )(C 6 H 7 O 7 )(H 2 O)] . H 2 O (M=La(1a), Ce(1b)) and [Ce 2 (C 2 O 4 )(C 6 H 6 O 7 ) 2 ] . 4H 2 O (2), with a metal-organic framework (MOF) were prepared with hydrothermal reactions and characterized with photoluminescence, magnetic susceptibility, thermogravimetric analysis and X-ray powder diffraction in situ. The crystal structures were determined by single-crystal X-ray diffraction. Compound 1 crystallized in triclinic space group P1-bar (No. 2); compound 2 crystallized in monoclinic space group P2 1 /c (No. 14). The structure of 1 is built from a 1D MOF, composed of deprotonated citric ligands of three kinds. Compound 2 contains a 2D MOF structure consisting of citrate and oxalate ligands; the oxalate ligand arose from the decomposition in situ of citric acid in the presence of Cu II ions. Photoluminescence spectra of compounds 1b and 2 revealed transitions between the 5d 1 excited state and two levels of the 4f 1 ground state ( 2 F 5/2 and 2 F 7/2 ). Compounds 1b and 2 containing Ce III ion exhibit a paramagnetic property with weak antiferromagnetic interactions between the two adjacent magnetic centers. - Graphical Abstract: [M(C 6 H 5 O 7 )(C 6 H 6 O 7 )(C 6 H 7 O 7 )(H 2 O)] . H 2 O (M=La(1a), Ce(1b)) and [Ce 2 (C 2 O 4 )(C 6 H 6 O 7 ) 2 ] . 4H 2 O (2)—with 1D and 2D structures were synthesized and characterized. Highlights: ► Two MOF – [M(C 6 H 5 O 7 )(C 6 H 6 O 7 )(C 6 H 7 O 7 )(H 2 O)] . H 2 O (M=La(1a), Ce(1b)) and [Ce 2 (C 2 O 4 )(C 6 H 6 O 7 ) 2 ] . 4H 2 O (2) – with 1D and 2D structures. ► The adjacent chains of the 1D framework were correlated with each other through an oxalate ligand to form a 2D layer structure. ► The source of the oxalate ligand was the decomposition in situ of citric acid oxidized in the presence of Cu II ions.

[Study on the phase II metabolites of phenoprolamine hydrochloride in rat bile by LC/DAD/MSD].

Science.gov (United States)

Ding, L; Zhang, Z X; Ni, P Z; Wang, G J; An, D K

2001-06-01

To study the phase II metabolites of phenoprolamine hydrochloride (DDPH) in rat bile. DDPH was administered by i.p. to bile duct-cannulated rats. Bile samples were collected before drug administration and up to 12 h after drug administration. After being purified and enriched with C-18 SPE columns the rat bile samples were analyzed by LC/DAD/MSD to identify the peaks of phase II metabolites. The fractions of phase II metabolites were prepared by HPLC and treated with beta-glucuronidase, and then were purified and enriched with C-18 SPE columns and analyzed by LC/DAD/MSD. The corresponding reference standards of DDPH phase I metabolites were analyzed by LC/DAD/MSD under identical conditions. The peaks M7, M8 and M9 in the chromatograms of rat bile samples were the phase II metabolites of DDPH and the enzymatic hydrolysates of M7, M8 and M9 were 1-(2, 6-dimethyl-4-hydroxyphenoxy)-2-(3, 4-methoxyphenylethylamino)-propane (M3), 1-(2, 6-dimethyl-3-hydroxyphenoxy)-2-(3, 4-methoxyphenylethylamino)-propane (M2) and 1-(2,6-dimethylphenoxy)-2-(3-methoxy-4-hydroxyphenylethyl-amino)-propane (M1) respectively. beta-1-O-[3,5-dimethyl-4-[-2-methyl-2-(3,4-dimethoxy-phenylethylamino)- ethoxy]-phenyl]-glucuronic acid (M7, glucuronide of M3), beta-1-O-[2, 4-dimethyl-3-[2-methyl-2-(3, 4-dimethoxy-phenylethylamino)-ethoxy]-phenyl]-glucuronic acid (M8, glucuronide of M2) and beta-1-O-[2-methoxy-4-[1-methyl-2-(2, 6-dimethylphenoxy)-ethylamino-ethyl]-phenyl]-glucuronic acid (M9, glucuronide of M1) were the phase II metabolites of DDPH in rat bile.

The effect of stimulation therapy and donepezil on cognitive function in Alzheimer’s disease. A community based RCT with a two-by-two factorial design

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Andersen Fred

2012-07-01

Full Text Available Abstract Background Progressive neurodegeneration in Alzheimer’s disease (AD induces cognitive deterioration, and there is controversy regarding the optimal treatment strategy in early AD. Stimulation therapy, including physical exercise and cholinesterase inhibitors are both reported to postpone cognitive deterioration in separate studies. We aimed to study the effect of stimulation therapy and the additional effect of donepezil on cognitive function in early AD. Method Design: A two-by-two factorial trial comprising stimulation therapy for one year compared to standard care to which a randomized double-blinded placebo controlled trial with donepezil was added. Setting: Nine rural municipalities in Northern Norway. Participants: 187 participants 65 years and older with a recent diagnosis of mild or moderate AD were included in the study of which 146 completed a one-year follow-up. INTERVENTIONS: In five municipalities the participants received stimulation therapy whereas participants in four received standard care. All participants were randomised double-blindly to donepezil or placebo and tested with three different cognitive tests four times during the one-year study period. Main outcome: Changes in MMSE sum score. Secondary outcome: Changes in ADAS-Cog and Clock Drawing Test. Results MMSE scores remained unchanged amongst AD participants receiving stimulation therapy and those receiving standard care. The results were consistent for ADAS-Cog and Clock Drawing Test. No time trend differences were found during one-year follow-up between groups receiving stimulation therapy versus standard care or between donepezil versus placebo. Conclusion In rural AD patients non-pharmacological and pharmacological therapy did not improve outcome compared with standard care but all groups retained cognitive function during one year follow-up. Other studies are needed to confirm these results. Trial registration ClinicalTrials.gov (Identifier: NCT00443014

Photocatalytic degradation kinetics, mechanism and ecotoxicity assessment of tramadol metabolites in aqueous TiO{sub 2} suspensions

Energy Technology Data Exchange (ETDEWEB)

Antonopoulou, U. [Department of Environmental and Natural Resources Management, University of Patras, 30100 Agrinio (Greece); Department of Chemistry, University of Ioannina, 45110 Ioannina (Greece); Hela, D. [Department of Business Administration of Food and Agricultural Products, University of Patras, Agrinio 30100 (Greece); Konstantinou, I., E-mail: iokonst@cc.uoi.gr [Department of Environmental and Natural Resources Management, University of Patras, 30100 Agrinio (Greece); Department of Chemistry, University of Ioannina, 45110 Ioannina (Greece)

2016-03-01

This study investigated for the first time the photocatalytic degradation of three well-known transformation products (TPs) of pharmaceutical Tramadol, N-desmethyl-(N-DES), N,N-bidesmethyl (N,N-Bi-DES) and N-oxide-tramadol (N-OX-TRA) in two different aquatic matrices, ultrapure water and secondary treated wastewater, with high (10 mg L{sup −1}) and low (50 μg L{sup −1}) initial concentrations, respectively. Total disappearance of the parent compounds was attained in all experiments. For initial concentration of 10 mg L{sup −1}, the target compounds were degraded within 30–40 min and a mineralization degree of more than 80% was achieved after 240 min of irradiation, while the contained organic nitrogen was released mainly as NH{sub 4}{sup +} for N-DES, N,N-Bi-DES and NO{sub 3}{sup −} for N-OX-TRA. The degradation rates of all the studied compounds were considerably decreased in the wastewater due to the presence of inorganic and organic constituents typically found in effluents and environmental matrices which may act as scavengers of the HO{sup •}. The effect of pH (4, 6.7, 10) in the degradation rates was studied and for N-DES-TRA and N,N-Bi-DES-TRA, the optimum pH value was 6.7. In contrast, N-OX-TRA showed an increasing trend in the photocatalytic degradation kinetic in alkaline solutions (pH 10). The major transformation products were identified by high resolution accurate mass spectrometry coupled with liquid chromatography (HR-LC–MS). Scavenging experiments indicated for all studied compounds the important role of HO{sup •} in the photocatalytic degradation pathways that included mainly hydroxylation and further oxidation of the parent compounds. In addition, Microtox bioassay (Vibrio fischeri) was employed for evaluating the ecotoxicity of photocatalytically treated solutions. Results clearly demonstrate the progressive decrease of the toxicity and the efficiency of the photocatalytic process in the detoxification of the irradiated solutions

Assessment of mercaptopurine (6MP) metabolites and 6MP metabolic key-enzymes in childhood acute lymphoblastic leukemia.

Science.gov (United States)

Wojtuszkiewicz, Anna; Barcelos, Ana; Dubbelman, Boas; De Abreu, Ronney; Brouwer, Connie; Bökkerink, Jos P; de Haas, Valerie; de Groot-Kruseman, Hester; Jansen, Gerrit; Kaspers, Gertjan L; Cloos, Jacqueline; Peters, G J

2014-01-01

Pediatric acute lymphoblastic leukemia (ALL) is treated with combination chemotherapy including mercaptopurine (6MP) as an important component. Upon its uptake, 6MP undergoes a complex metabolism involving many enzymes and active products. The prognostic value of all the factors engaged in this pathway still remains unclear. This study attempted to determine which components of 6MP metabolism in leukemic blasts and red blood cells are important for 6MP's sensitivity and toxicity. In addition, changes in the enzymatic activities and metabolite levels during the treatment were analyzed. In a cohort (N=236) of pediatric ALL patients enrolled in the Dutch ALL-9 protocol, we studied the enzymes inosine-5'-monophosphate dehydrogenase (IMPDH), thiopurine S-methyltransferase (TPMT), hypoxanthine guanine phosphoribosyl transferase (HGPRT), and purine nucleoside phosphorylase (PNP) as well as thioguanine nucleotides (TGN) and methylthioinosine nucleotides (meTINs). Activities of selected enzymes and levels of 6MP derivatives were measured at various time points during the course of therapy. The data obtained and the toxicity related parameters available for these patients were correlated with each other. We found several interesting relations, including high concentrations of two active forms of 6MP--TGN and meTIN--showing a trend toward association with better in vitro antileukemic effect of 6MP. High concentrations of TGN and elevated activity of HGPRT were found to be significantly associated with grade III/IV leucopenia. However, a lot of data of enzymatic activities and metabolite concentrations as well as clinical toxicity were missing, thereby limiting the number of assessed relations. Therefore, although a complex study of 6MP metabolism in ALL patients is feasible, it warrants more robust and strict data collection in order to be able to draw more reliable conclusions.

Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron.

Science.gov (United States)

Bloomer, J C; Baldwin, S J; Smith, G J; Ayrton, A D; Clarke, S E; Chenery, R J

1994-01-01

1. The metabolism of granisetron was investigated in human liver microsomes to identify the specific forms of cytochrome P450 responsible. 2. 7-hydroxy and 9'-desmethyl granisetron were identified as the major products of metabolism following incubation of granisetron with human liver microsomes. At low, clinically relevant, concentrations of granisetron the 7-hydroxy metabolite predominated. Rates of granisetron 7-hydroxylation varied over 100-fold in the human livers investigated. 3. Enzyme kinetics demonstrated the involvement of at least two enzymes contributing to the 7-hydroxylation of granisetron, one of which was a high affinity component with a Km of 4 microM. A single, low affinity, enzyme was responsible for the 9'-desmethylation of granisetron. 4. Granisetron caused no inhibition of any of the cytochrome P450 activities investigated (CYP1A2, CYP2A6, CYP2B6, CYP2C9/8, CYP2C19, CYP2D6, CYP2E1 and CYP3A), at concentrations up to 250 microM. 5. Studies using chemical inhibitors selective for individual P450 enzymes indicated the involvement of cytochrome P450 3A (CYP3A), both pathways of granisetron metabolism being very sensitive to ketoconazole inhibition. Correlation data were consistent with the role of CYP3A3/4 in granisetron 9'-desmethylation but indicated that a different enzyme was involved in the 7-hydroxylation. PMID:7888294

Mu receptor binding of some commonly used opioids and their metabolites

International Nuclear Information System (INIS)

Chen, Zhaorong; Irvine, R.J.; Somogyi, A.A.; Bochner, F.

1991-01-01

The binding affinity to the μ receptor of some opioids chemically related to morphine and some of their metabolites was examined in rat brain homogenates with 3 H-DAMGO. The chemical group at position 6 of the molecule had little effect on binding. Decreasing the length of the alkyl group at position 3 decreased the K i values (morphine < codeine < ethylmorphine < pholcodine). Analgesics with high clinical potency containing a methoxyl group at position 3 had relatively weak receptor binding, while their O-demethylated metabolites had much stronger binding. Many opioids may exert their pharmacological actions predominantly through metabolites

Mu receptor binding of some commonly used opioids and their metabolites

Energy Technology Data Exchange (ETDEWEB)

Chen, Zhaorong; Irvine, R.J. (Univ. of Adelaide (Australia)); Somogyi, A.A.; Bochner, F. (Univ. of Adelaide (Australia) Royal Adelaide Hospital (Australia))

1991-01-01

The binding affinity to the {mu} receptor of some opioids chemically related to morphine and some of their metabolites was examined in rat brain homogenates with {sup 3}H-DAMGO. The chemical group at position 6 of the molecule had little effect on binding. Decreasing the length of the alkyl group at position 3 decreased the K{sub i} values (morphine < codeine < ethylmorphine < pholcodine). Analgesics with high clinical potency containing a methoxyl group at position 3 had relatively weak receptor binding, while their O-demethylated metabolites had much stronger binding. Many opioids may exert their pharmacological actions predominantly through metabolites.

Effects of donepezil on activities of daily living: integrated analysis of patient data from studies in mild, moderate and severe Alzheimer's disease

DEFF Research Database (Denmark)

Gauthier, Serge; Lopez, Oscar Lopez; Waldemar, Gunhild

2010-01-01

We aimed to develop a standardization method to pool data recorded on different activities of daily living (ADL) scales in order to reduce variability of functional outcome data from Alzheimer's disease (AD) clinical trials and to better evaluate the effect of donepezil treatment on function...

Chiral analyses of dextromethorphan/levomethorphan and their metabolites in rat and human samples using LC-MS/MS.

Science.gov (United States)

Kikura-Hanajiri, Ruri; Kawamura, Maiko; Miyajima, Atsuko; Sunouchi, Momoko; Goda, Yukihiro

2011-04-01

In order to develop an analytical method for the discrimination of dextromethorphan (an antitussive medicine) from its enantiomer, levomethorphan (a narcotic) in biological samples, chiral analyses of these drugs and their O-demethyl and/or N-demethyl metabolites in rat plasma, urine, and hair were carried out using LC-MS/MS. After the i.p. administration of dextromethorphan or levomethorphan to pigmented hairy male DA rats (5 mg/kg/day, 10 days), the parent compounds and their three metabolites in plasma, urine and hair were determined using LC-MS/MS. Complete chiral separation was achieved in 12 min on a Chiral CD-Ph column in 0.1% formic acid-acetonitrile by a linear gradient program. Most of the metabolites were detected as being the corresponding O-demethyl and N, O-didemethyl metabolites in the rat plasma and urine after the hydrolysis of O-glucuronides, although obvious differences in the amounts of these metabolites were found between the dextro and levo forms. No racemation was observed through O- and/or N-demethylation. In the rat hair samples collected 4 weeks after the first administration, those differences were more clearly detected and the concentrations of the parent compounds, their O-demethyl, N-demethyl, and N, O-didemethyl metabolites were 63.4, 2.7, 25.1, and 0.7 ng/mg for the dextro forms and 24.5, 24.6, 2.6, and 0.5 ng/mg for the levo forms, respectively. In order to fully investigate the differences of their metabolic properties between dextromethorphan and levomethorphan, DA rat and human liver microsomes were studied. The results suggested that there might be an enantioselective metabolism of levomethorphan, especially with regard to the O-demethylation, not only in DA rat but human liver microsomes as well. The proposed chiral analyses might be applied to human samples and could be useful for discriminating dextromethorphan use from levomethorphan use in the field of forensic toxicology, although further studies should be carried out

Human cytochrome-P450 enzymes metabolize N-(2-methoxyphenyl)hydroxylamine, a metabolite of the carcinogens o-anisidine and o-nitroanisole, thereby dictating its genotoxicity.

Science.gov (United States)

Naiman, Karel; Martínková, Markéta; Schmeiser, Heinz H; Frei, Eva; Stiborová, Marie

2011-12-24

N-(2-Methoxyphenyl)hydroxylamine is a component in the human metabolism of two industrial and environmental pollutants and bladder carcinogens, viz. 2-methoxyaniline (o-anisidine) and 2-methoxynitrobenzene (o-nitroanisole), and it is responsible for their genotoxicity. Besides its capability to form three deoxyguanosine adducts in DNA, N-(2-methoxyphenyl)-hydroxylamine is also further metabolized by hepatic microsomal enzymes. To investigate its metabolism by human hepatic microsomes and to identify the major microsomal enzymes involved in this process are the aims of this study. N-(2-Methoxyphenyl)hydroxylamine is metabolized by human hepatic microsomes predominantly to o-anisidine, one of the parent carcinogens from which N-(2-methoxyphenyl)hydroxylamine is formed, while o-aminophenol and two N-(2-methoxyphenyl)hydroxylamine metabolites, whose exact structures have not been identified as yet, are minor products. Selective inhibitors of microsomal CYPs, NADPH:CYP reductase and NADH:cytochrome-b(5) reductase were used to characterize human liver microsomal enzymes reducing N-(2-methoxyphenyl)hydroxylamine to o-anisidine. Based on these studies, we attribute the main activity for this metabolic step in human liver to CYP3A4, 2E1 and 2C (more than 90%). The enzymes CYP2D6 and 2A6 also partake in this N-(2-methoxyphenyl)hydroxylamine metabolism in human liver, but only to ∼6%. Among the human recombinant CYP enzymes tested in this study, human CYP2E1, followed by CYP3A4, 1A2, 2B6 and 2D6, were the most efficient enzymes metabolizing N-(2-methoxyphenyl)hydroxylamine to o-anisidine. The results found in this study indicate that genotoxicity of N-(2-methoxyphenyl)hydroxylamine is dictated by its spontaneous decomposition to nitrenium/carbenium ions generating DNA adducts, and by its susceptibility to metabolism by CYP enzymes. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of donepezil on activities of daily living: integrated analysis of patient data from studies in mild, moderate and severe Alzheimer's disease

DEFF Research Database (Denmark)

Gauthier, Serge; Lopez, Oscar Lopez; Waldemar, Gunhild

2010-01-01

We aimed to develop a standardization method to pool data recorded on different activities of daily living (ADL) scales in order to reduce variability of functional outcome data from Alzheimer's disease (AD) clinical trials and to better evaluate the effect of donepezil treatment on function in p...

Poly[[tetraaqua(μ3-naphthalene-1,6-disulfonato-κ4O1:O6,O6′:O6′′strontium(II] monohydrate

Directory of Open Access Journals (Sweden)

Shan Gao

2011-12-01

Full Text Available In the crystal structure of the polymeric title compound, {[Sr(C10H6O6S2(H2O4]·H2O}n, the naphthalene-1,6-disulfonate dianion uses one –SO3 unit to O,O′-chelate to an SrII cation and its third O atom to bind to another SrII cation. The other –SO3 unit binds to yet another SrII atom. The four coordinated water molecules are monodentate but one is disordered over two positions in a 1:1 ratio. The μ3-bonding mode of the dianion generates a polymeric three-dimensional network; the network is consolidated by O—H...O hydrogen bonds. The SrII cation exists in an undefined eight-coordinate environment.

Taste-masked and affordable donepezil hydrochloride orally disintegrating tablet as promising solution for non-compliance in Alzheimer's disease patients.

Science.gov (United States)

Liew, Kai Bin; Tan, Yvonne Tze Fung; Peh, Kok Khiang

2015-04-01

Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly. The aim of this study was to develop a novel taste masked and affordable donepezil hydrochloride ODT with fast disintegration time and stable to improve medication compliance of Alzheimer's disease patient. The ODT was manufactured using simple wet-granulation method. Crospovidone XL-10 was used as superdisintegrant and optimization was done by comparing the effect of three grades of lactose monohydrate compound as filler: Starlac®, Flowlac® and Tablettose®. Formulations containing higher amount of colloidal silicon dioxide showed increase in hardness, weight, disintegration time and wetting time after stability study. Formulation E which containing 50% of Starlac® was found with shortest in vitro disintegration time (21.7 ± 1.67 s), in vivo disintegration time (24.0 ± 1.05 s) and in vitro disintegration time in artificial salvia (22.5 ± 1.67 s). Physical stability studies at 40 °C/75% RH for 6 months, Fourier transform infrared spectroscopy analysis and X-ray diffraction results showed that the formulation was stable. The drug-released profile showed that 80% of donepezil hydrochloride was released within 1 min. A single-dose, fasting, four-period, seven-treatment, double-blinded study involving 16 healthy human volunteers was performed to evaluate the palatability of ODT. Formulation VII containing 10 mg of ammonium glycyrrhizinate was able to mask the bitter taste of the drug. The product has the potential to be commercialized and it might serve as solution for non-compliance among the Alzheimer's disease patients.

Utility of (11)C-methionine and (11)C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model

DEFF Research Database (Denmark)

Afzelius, Pia; Alstrup, Aage Ko; Schønheyder, Henrik C

2016-01-01

in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, (11)C-methionine and (11)C-donepezil PET, (99m) Tc-DPD and (111)In-labelled leukocytes scintigraphy, and (18)F-FDG PET. This was followed by necropsy of the pigs and gross...

[Pharmacokinetics of (-)-clausenamide and its major metabolite 6-hydroxyl-clausenamide in beagle dogs by HPLC/MS].

Science.gov (United States)

Song, Min; Qian, Wen; Hang, Tai-Jun; Zhang, Zheng-Xing

2005-10-01

To establish a sensitive and accurate method to study the pharmacokinetics of (-)-clausenamide [(-)-clau] and its major metabolite 6-hydroxyl-clausenamide (6-OH-clau) in the plasma of the Beagle dog. (-)-Clau was orally administered to six Beagle dogs at the dose of 30 mg x kg(-1), venous blood from front leg was sampled and plasma was separated for analysis. After extraction with ethyl acetate, the plasma samples were analyzed by HPLC/MS and the mobile phase was a mixture of methanol-water-acetic acid (60: 40: 0. 8) at the flow rate of 1.0 mL x min(-1). The API-ES positive ion SIM detection was carried out for the detection of both (-)-clau ([M + H] (+), m/z 298 ) and 6-OH-clau ([M + H - H2 O](+), m/z 296) with glipzide (glip) ([M + H](+), m/z 446) as internal standard. The pharmacokinetic parameters were calculated by 3P97 software. There was good linear relationship ( r > 0. 999) between the SIM responses and the concentrations for (-)-clau and 6-OH-clau at the range from 1.0 to 200 ng x mL(-1) and 0.2 to 40.0 ng x mL(-1), respectively. The absolute recovery was greater than 85%. The plasma concentration-time curves of (-)-clau and 6-OH-clau were both best fitted to a two-compartment model. The C(max) of (-)-clau and 6-OH-clau were (21 +/- 10) ng x mL(-1) and (3.9 +/- 2.2) ng x mL(-1), T(max) were (0.8 +/- 0.5) h and (1.3 +/- 0.5) h, T 1/2 alpha were (0.9 +/- 0.6) hand (1.4 +/- 0.6) h, T 1/2 beta were (19 +/- 23) hand (13 +/- 12) h, AUC(0-24 h) were (69 +/- 14) h x ng x mL(-1) and (12 +/- 7) h x ng x mL(-1) respectively. The established HPLC/MS method was sensitive and specific for the determination of (-)-clau. It was shown that the absorption and first phase elimination of (-)-clau were very quick in Beagle dogs, but the terminal elimination was very slow. The plasma concentration profile of its major metabolite 6-OH-clau was similar to (-)-clau and the AUC was relatively small in comparison with (-)-clau.

Poly[(6-carboxypicolinato-κ3O2,N,O6(μ3-pyridine-2,6-dicarboxylato-κ5O2,N,O6:O2′:O6′dysprosium(III

Directory of Open Access Journals (Sweden)

Xu Li

2009-11-01

Full Text Available In the title complex, [Dy(C7H3NO4(C7H4NO4]n, one of the ligands is fully deprotonated while the second has lost only one H atom. Each DyIII ion is coordinated by six O atoms and two N atoms from two pyridine-2,6-dicarboxylate and two 6-carboxypicolinate ligands, displaying a bicapped trigonal-prismatic geometry. The average Dy—O bond distance is 2.40 Å, some 0.1Å longer than the corresponding Ho—O distance in the isotypic holmium complex. Adjacent DyIII ions are linked by the pyridine-2,6-dicarboxylate ligands, forming a layer in (100. These layers are further connected by π–π stacking interactions between neighboring pyridyl rings [centroid–centroid distance = 3.827 (3 Å] and C—H...O hydrogen-bonding interactions, assembling a three-dimensional supramolecular network. Within each layer, there are other π–π stacking interactions between neighboring pyridyl rings [centroid–centroid distance = 3.501 (2 Å] and O—H...O and C—H...O hydrogen-bonding interactions, which further stabilize the structure.

Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism.

Science.gov (United States)

Pan, Wei; Bae, Soo-Kyung; Shim, Eon-Jeong; Park, Sung-Eun; Lee, Sang-Seop; Park, Soo-Jin; Yeo, Chang-Woo; Zhou, Hong-Hao; Shon, Ji-Hong; Shin, Jae-Gook

2013-02-01

Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration-time curve (AUC) of sibutramine by 163% and 255%, respectively. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine. These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established.

Unique and common metabolites of thiamethoxam, clothianidin, and dinotefuran in mice.

Science.gov (United States)

Ford, Kevin A; Casida, John E

2006-11-01

The established neonicotinoid insecticides have chloropyridylmethyl (imidacloprid, thiacloprid, acetamiprid, and nitenpyram), chlorothiazolylmethyl (thiamethoxam or TMX and clothianidin or CLO) or tetrahydrofuranylmethyl (dinotefuran or DIN) substituents. We recently reported the metabolic fate of the chloropyridylmethyl neonicotinoids in mice as the first half of a comparative study that now considers the chlorothiazolylmethyl and tetrahydrofuranylmethyl analogues. TMX, CLO, two desmethyl derivatives (TMX-dm and CLO-dm), and DIN were administered ip to mice at 20 mg/kg for characterization of metabolites and pharmacokinetic analysis of brain, liver, plasma, and urine by HPLC/DAD and LC/MSD. Each compound is excreted 19-55% unmetabolized in urine within 24 h, and tissue residues are largely dissipated by 4 h. Thirty-seven metabolites of TMX, TMX-dm, CLO, and CLO-dm are identified by comparison with synthetic standards or their structures are proposed by molecular weights and 35Cl:37Cl ratios often supplemented by previous reports or sequence studies in which intermediates are readministered. A facile reaction sequence involves TMX --> TMX-dm or CLO --> CLO-dm. CLO-dm, reported to be a contributor to TMX hepatocarcinogenesis in mice, is unexpectedly remethylated in part to CLO in brain. The nitrosoguanidine, aminoguanidine, and urea derivatives of the parent compounds are detected in the tissues and methylnitroguanidine, methylguanidine, and nitroguanidine in the urine. Chlorothiazolecarboxaldehyde from oxidative cleavage of TMX and CLO is quite persistent in brain, liver, and particularly plasma compared with chloropyridinecarboxaldehyde and tetrahydrofurancarboxaldehyde from the other neonicotinoids. Chlorothiazolecarboxylic acid is conjugated with glycine or glucuronic acid or converted to S-methyl and mercapturate derivatives. DIN metabolism involves nitro reduction, N-demethylation, N-methylene hydroxylation, and amine cleavage, and tetrahydrofuranylmethyl

Not flavone-8-acetic acid (FAA) but its murine metabolite 6-OH-FAA exhibits remarkable antivascular activities in vitro.

Science.gov (United States)

Pham, Minh Hien; Dauzonne, Daniel; Chabot, Guy G

2016-06-01

Flavone-8-acetic acid (FAA) has been proved to be a potent vascular-disrupting agent in mice. Unfortunately, FAA did not produce any anticancer activity in clinical trials. Previously, we had reported that FAA is metabolized by mouse microsomes into six metabolites, whereas it was poorly metabolized by human microsomes, with fewer metabolites formed in lesser amounts. Especially, 6-OH-FAA was not formed by human microsomes. In this work, two major available metabolites, 4'-OH-FAA and 6-OH-FAA, were tested and compared with the parent compound FAA for their potential antivascular activities in vitro. The ability of the products to induce morphological changes, disrupt preformed capillaries of EA.hy926 endothelial cells and inhibit tubulin polymerization in vitro was assessed. The action mechanism was determined using the RhoA and Rac1 inhibitors. At 25 µg/ml, 6-OH-FAA induced morphological changes and membrane blebbing, whereas 300 µg/ml of FAA and 4'-OH-FAA slightly changed the morphology without inducing membrane blebbing. At 300 µg/ml, 6-OH-FAA produced morphological changes that were 2.1-6.9-fold greater than that produced by FAA and 4'-OH-FAA, an effect that was consistent with its much greater inhibitory effect on tubulin polymerization compared with FAA and 4'-OH-FAA. 6-OH-FAA significantly disrupted the EA.hy926 cell capillaries. 6-OH-FAA activities were prevented in EA.hy926 cells pretreated with RhoA, but not Rac1, inhibitor. In this short communication we report for the first time that, in vitro, 6-OH-FAA, a mouse-specific FAA metabolite, exhibits significantly stronger antivascular activities compared with FAA and 4'-OH-FAA, which are mediated through the RhoA kinase pathway.

Pharmacokinetics of tramadol hydrochloride and its metabolite O-desmethyltramadol in peafowl (Pavo cristatus).

Science.gov (United States)

Black, Peter A; Cox, Sherry K; Macek, Michael; Tieber, Anne; Junge, Randall E

2010-12-01

Tramadol is a centrally acting opiate analgesic that has not been well studied in avian species. Tramadol and its metabolites exert their effects at multiple sites, including opiate (mu, kappa, and delta), adrenergic (alpha-2), and serotonin (5HT) receptors. This multi-receptor mode of action is advantageous for avian patients because the mechanisms for analgesia have not been fully elucidated in all species. The objective of this study was to document the pharmacokinetics of tramadol and its active metabolite O-desmethyltramadol (M1) in common peafowl (Pavo cristatus). Based on results from a pilot animal, six adult peafowl (three male, three female) judged to be clinically healthy based on physical exam and routine bloodwork were selected for this study. Each bird was anesthetized for placement of a jugular catheter, and 7.5 mg/kg tramadol was administered orally via gavage tube. Blood samples were collected just prior to drug administration; at 30 min; and at 1, 2, 3, 4, 6, 8, 10, 12, 24, and 34 hr. Plasma levels of tramadol and M1 were measured and the pharmacokinetics for each drug was calculated. Although tramadol was quickly metabolized, plasma levels of M1 remained at or near human analgesic levels for 12-24 hr. Based on these data, tramadol may be a practical option as an orally administered analgesic agent in avian patients. Further studies, including antinociceptive studies, are needed.

Development and validation of a high performance liquid chromatography quantification method of levo-tetrahydropalmatine and its metabolites in plasma and brain tissues: application to a pharmacokinetic study.

Science.gov (United States)

Abdallah, Inas A; Huang, Peng; Liu, Jing; Lee, David Y; Liu-Chen, Lee-Yuan; Hassan, Hazem E

2017-04-01

Levo-tetrahydropalmatine (l-THP) is an alkaloid isolated from Chinese medicinal herbs of the Corydalis and Stephania genera. It has been used in China for more than 40 years mainly as an analgesic with sedative/hypnotic effects. Despite its extensive use, its metabolism has not been quantitatively studied, nor there a sensitive reliable bioanalytical method for its quantification simultaneously with its metabolites. As such, the objective of this study was to develop and validate a sensitive and selective HPLC method for simultaneous quantification of l-THP and its desmethyl metabolites l-corydalmine (l-CD) and l-corypalmine (l-CP) in rat plasma and brain tissues. Rat plasma and brain samples were processed by liquid-liquid extraction using ethyl acetate. Chromatographic separation was achieved on a reversed-phase Symmetry® C 18 column (4.6 × 150 mm, 5 μm) at 25°C. The mobile phase consisted of acetonitrile-methanol-10 mm ammonium phosphate (pH 3) (10:30:60, v/v) and was used at a flow rate of 0.8 mL/min. The column eluent was monitored at excitation and emission wavelengths of 230 and 315 nm, respectively. The calibration curves were linear over the concentration range of 1-10,000 ng/mL. The intra- and interday reproducibility studies demonstrated accuracy and precision within the acceptance criteria of bioanalytical guidelines. The validated HPLC method was successfully applied to analyze samples from a pharmacokinetic study of l-THP in rats. Taken together, the developed method can be applied for bioanalysis of l-THP and its metabolites in rodents and potentially can be transferred for bioanalysis of human samples. Copyright © 2016 John Wiley & Sons, Ltd.

Changes of primary and secondary metabolites in barley plants exposed to CdO nanoparticles

Czech Academy of Sciences Publication Activity Database

Večeřová, Kristýna; Večeřa, Zbyněk; Dočekal, Bohumil; Oravec, Michal; Pompeiano, Antonio; Tříska, Jan; Urban, Otmar

2016-01-01

Roč. 218, NOV (2016), s. 207-218 ISSN 0269-7491 R&D Projects: GA MŠk(CZ) LO1415; GA ČR(CZ) GAP503/11/2315; GA ČR(CZ) GBP503/12/G147; GA MŠk(CZ) LD15039 Institutional support: RVO:67179843 ; RVO:68081715 Keywords : Barley * CdO nanoparticles * Gas chromatography * High performance liquid chromatography * Mass spectrometry * Plant metabolites Subject RIV: EH - Ecology, Behaviour; CB - Analytical Chemistry, Separation (UIACH-O) Impact factor: 5.099, year: 2016

Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer

International Nuclear Information System (INIS)

Hennig, Ewa E.; Piatkowska, Magdalena; Karczmarski, Jakub; Goryca, Krzysztof; Brewczynska, Elzbieta; Jazwiec, Radoslaw; Kluska, Anna; Omiotek, Robert; Paziewska, Agnieszka; Dadlez, Michal; Ostrowski, Jerzy

2015-01-01

Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy. Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r 2 = 0.23; p < 10 −16 ) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10 −16 ) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10 −43 ). The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard

Prediction of Drug-Drug Interactions with Bupropion and Its Metabolites as CYP2D6 Inhibitors Using a Physiologically-Based Pharmacokinetic Model.

Science.gov (United States)

Xue, Caifu; Zhang, Xunjie; Cai, Weimin

2017-12-21

The potential of inhibitory metabolites of perpetrator drugs to contribute to drug-drug interactions (DDIs) is uncommon and underestimated. However, the occurrence of unexpected DDI suggests the potential contribution of metabolites to the observed DDI. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for bupropion and its three primary metabolites-hydroxybupropion, threohydrobupropion and erythrohydrobupropion-based on a mixed "bottom-up" and "top-down" approach and to contribute to the understanding of the involvement and impact of inhibitory metabolites for DDIs observed in the clinic. PK profiles from clinical researches of different dosages were used to verify the bupropion model. Reasonable PK profiles of bupropion and its metabolites were captured in the PBPK model. Confidence in the DDI prediction involving bupropion and co-administered CYP2D6 substrates could be maximized. The predicted maximum concentration (C max ) area under the concentration-time curve (AUC) values and C max and AUC ratios were consistent with clinically observed data. The addition of the inhibitory metabolites into the PBPK model resulted in a more accurate prediction of DDIs (AUC and C max ratio) than that which only considered parent drug (bupropion) P450 inhibition. The simulation suggests that bupropion and its metabolites contribute to the DDI between bupropion and CYP2D6 substrates. The inhibitory potency from strong to weak is hydroxybupropion, threohydrobupropion, erythrohydrobupropion, and bupropion, respectively. The present bupropion PBPK model can be useful for predicting inhibition from bupropion in other clinical studies. This study highlights the need for caution and dosage adjustment when combining bupropion with medications metabolized by CYP2D6. It also demonstrates the feasibility of applying the PBPK approach to predict the DDI potential of drugs undergoing complex metabolism, especially in the DDI involving inhibitory

Changes in cognitive domains during three years in patients with Alzheimer's disease treated with donepezil

Directory of Open Access Journals (Sweden)

Levander Sten

2009-02-01

Full Text Available Abstract Background The objective was to identify separate cognitive domains in the standard assessment tools (MMSE, ADAS-Cog and analyze the process of decline within domains during three years in Alzheimer's disease (AD patients with donepezil treatment. Method AD patients (n = 421 were recruited from a clinical multi-centre study program in Sweden. Patients were assessed every six months during three years. All patients received donepezil starting directly after study entry. After dropouts, 158 patients remained for analyses over three years. Data for the other patients were analysed until they dropped out (4 groups based on length in study. Results Factor analyses of all items suggested that there were three intercorrelated factors: a General, a Memory and a Spatial factor for which we constructed corresponding domains. Overall there was a cognitive improvement at six months followed by a linear drop over time for the three domains. Some group and domain differences were identified. Patients who remained longer in the study had better initial performance and a slower deterioration rate. The early dropouts showed no improvement at six months and many dropped out due to side effects. The other groups displayed a performance improvement at six months that was less pronounced in the Memory domain. Before dropping out, deterioration accelerated, particularly in the Spatial domain. Conclusion The course of illness in the three domains was heterogeneous among the patients. We were not able to identify any clinically relevant correlates of this heterogeneity. As an aid we constructed three algorithms corresponding to the cognitive domains, which can be used to characterize patients initially, identify rapid decliners and follow the course of the disease.

[Effect of Electroacupuncture at "Neiguan"(PC 6) on Serum and Myocardial Metabolites in Rats with Myocardial Ischemia Reperfusion Injury Based on Nuclear Magnetic Resonance Spectroscopy].

Science.gov (United States)

Tang, Ya-Ni; Tan, Cheng-Fu; Liu, Wei-Wei; Yan, Jie; Wang, Chao; Liu, Mi; Lin, Dong-Hai; Huang, Cai-Hua; Du, Lin; Chen, Mei-Lin; Li, Jiao-Lan; Zhu, Ding-Ming

2018-03-25

We have repeatedly demonstrated that electroacupuncture (EA) of "Neiguan"(PC 6) can improve myocardial ischemia in rats. The present study was designed to investigate the metabolomic profile of peripheral blood se-rum and myocardium involving EA-induced improvement of myocardial ischemia-reperfusion injury (MIRI) in rats by using nuclear magnetic resonance spectroscopy. Thirty male SD rats were equally randomized into blank control, model and EA groups. Rats of the control group were only banded for 20 min, once a day for 7 days. The MIRI model was established by occlusion of the anterior descending branch of the left coronary artery for 40 min, followed by reperfusion for 60 min, and rats of the model group were banded as those in the control group. EA (10 Hz/50 Hz, 1 mA) was applied to bilateral PC 6 for 20 min, once daily for 7 days. The blood samples and left ventricular myocardial tissues were collected for assaying the profiles of differential metabolites using 1 H nuclear magnetic resonance ( 1 H NMR) spectroscopy and multivariate statistical analysis such as the principal components analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and orthogonal PLS-DA (O-PLS-DA) with SIMCA-P software 12.0. A total of 19 differential metabolites (17 down-regulated, 2 up-regulated) in the serum and 14 differential metabolites (13 down-regulated and 1 up-regulated) in the ischemic left myocardium were identified after MIRI. Of the 19 serum differential metabolites, amino acids (leucine, isoleucine, valine,alanine, lysine, glycine, glutamine), 3-hydroxy butyric acid (3-HB), lactic acid, acetate, N-acetyl glycoprotein (NAc), acetone, acetoacetate, succinate, polyunsaturated fatty acids (PUFA), creatine, glycerophosphocholine (GPC) were down-regulated; while low density lipoprotein (LDL), LDL/very low density lipoprotein(LDL/VLDL)and glucose obviously up-regulated. Of the 14 myocardial differential metabolites, amino acids (alanine, lysine, glutamate

Cost Effectiveness of Donepezil in the Treatment of Mild to Moderate Alzheimer's Disease: A UK Evaluation Using Discrete-Event Simulation

OpenAIRE

Denis Getsios; Steve Blume; K. Jack. Ishak; Grant D.H. Maclaine

2010-01-01

Background: Recommendations in the UK suggest restricting treatment of Alzheimer's disease with cholinesterase inhibitors, on cost-effectiveness grounds, to patients with moderate cognitive decline. As the economic analyses that informed these recommendations have been the subject of debate, we sought to address the potential limitations of existing models and produce estimates of donepezil treatment cost effectiveness in the UK using the most recent available data and simulation techniques. ...

Plasma pharmacokinetics of catechin metabolite 4'-O-Me-EGC in healthy humans.

Science.gov (United States)

Renouf, Mathieu; Redeuil, Karine; Longet, Karin; Marmet, Cynthia; Dionisi, Fabiola; Kussmann, Martin; Williamson, Gary; Nagy, Kornél

2011-10-01

Tea is an infusion of the leaves of the Camellia sinensis plant and is the most widely consumed beverage in the world after water. Green tea contains significant amounts of polyphenol catechins and represents a promising dietary component to maintain health and well-being. Epidemiological studies indicate that polyphenol intake may have potential health benefits, such as, reducing the incidence of coronary heart disease, diabetes and cancer. While bioavailability of green tea bioactives is fairly well understood, some gaps still remain to be filled, especially the identification and quantification of conjugated metabolites in plasma, such as, sulphated, glucuronidated or methylated compounds. In the present study, we aimed to quantify the appearance of green tea catechins in plasma with particular emphasis on their methylated forms. After feeding 400 mL of green tea, 1.25% infusion to 9 healthy subjects, we found significant amounts of EC, EGC and EGCg in plasma as expected. EGC was the most bioavailable catechin, and its methylated form (4'-O-Me-EGC) was also present in quantifiable amounts. Its kinetics followed that of its parent compound. However, the relative amount of the methylated form of EGC was lower than that of the parent compound, an important aspect which, in the literature, has been controversial so far. The quantitative results presented in our study were confirmed by co-chromatography and accurate mass analysis of the respective standards. We show that the relative abundance of 4'-O-Me-EGC is ~40% compared to the parent EGC. 4'-O-Me-EGC is an important metabolite derived from catechin metabolism. Its presence in significant amounts should not be overlooked when assessing human bioavailability of green tea.

Detection of stanozolol O- and N-sulfate metabolites and their evaluation as additional markers in doping control.

Science.gov (United States)

Balcells, Georgina; Matabosch, Xavier; Ventura, Rosa

2017-07-01

Stanozolol (STAN) is one of the most frequently detected anabolic androgenic steroids in sports drug testing. STAN misuse is commonly detected by monitoring metabolites excreted conjugated with glucuronic acid after enzymatic hydrolysis or using direct detection by liquid chromatography-tandem mass spectrometry (LC-MS/MS). It is well known that some of the previously described metabolites are the result of the formation of sulfate conjugates in C17, which are converted to their 17-epimers in urine. Therefore, sulfation is an important phase II metabolic pathway of STAN that has not been comprehensively studied. The aim of this work was to evaluate the sulfate fraction of STAN metabolism by LC-MS/MS to establish potential long-term metabolites valuable for doping control purposes. STAN was administered to six healthy male volunteers involving oral or intramuscular administration and urine samples were collected up to 31 days after administration. Sulfation of the phase I metabolites commercially available as standards was performed in order to obtain MS data useful to develop analytical strategies (neutral loss scan, precursor ion scan and selected reaction monitoring acquisitions modes) to detect potential sulfate metabolites. Eleven sulfate metabolites (M-I to M-XI) were detected and characterized by LC-MS/MS. This paper provides valuable data on the ionization and fragmentation of O-sulfates and N-sulfates. For STAN, results showed that sulfates do not improve the retrospectivity of the detection compared to the previously described long-term metabolite (epistanozolol-N-glucuronide). However, sulfate metabolites could be additional markers for the detection of STAN misuse. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

All-Solid-State, PVC Membrane, and Carbon Paste Ion-Selective Electrodes for Determination of Donepezil Hydrochloride in Pharmaceutical Formulation.

Science.gov (United States)

Khamees, Nesreen; Mohamed, Tagreed Abdel-Fattah; Derar, Abeer Rashad; Aziz, Azza

2017-09-01

All-solid-state, polyvinyl chloride (PVC) membrane, and carbon paste potentiometric ion-selective electrodes (ISEs) were proposed for the determination of donepezil hydrochloride (DON) in the drug substance and a pharmaceutical formulation. The potentiometric response toward DON was based on the existence of donepezil-tetraphenyl borate (DON-TPB) in a PVC membrane or a carbon paste in the presence of dioctylphthalate. In contrast, the solid-state electrode was prepared by direct incorporation of DON-TPB into a commercial nail varnish without external additives. The electrodes exhibited Nernstian slopes of 55.0, 57.0, and 53.0 mV/decade over the concentration ranges of 1 × 10-5 to 1 × 10-3, 1 × 10-4 to 10-2, and 1 × 10-4 to 5 × 10-3 for the solid-state, PVC membrane, and carbon paste electrodes, respectively. The response of the electrodes is independent of pH in the range of 2-≤8. The electrodes showed good selectivity for DON with respect to a number of inorganic cations and amino acids. The electrodes were used for the determination of DON in pure solution and in pharmaceutical tablets with high accuracy (±2%) and precision (RSD ≤2%). The solid-state electrode is simple, economical, and rapid when compared to the PVC membrane and carbon paste electrodes.

Donepezil is associated with decreased in-hospital mortality as a result of pneumonia among older patients with dementia: A retrospective cohort study.

Science.gov (United States)

Abe, Yasuko; Shimokado, Kentaro; Fushimi, Kiyohide

2018-02-01

Pneumonia is one of the major causes of mortality in older adults. As the average lifespan has extended and new modalities to prevent or treat pneumonia are developed, the factors that affect the length of hospital stay (LHS) and in-hospital mortality of older patients with pneumonia have changed. The object of the present study was to determine the factors associated with LHS and mortality as a result of pneumonia among older patients with dementia. With a retrospective cohort study design, we used the data derived from the Japanese Administrative Database and diagnosis procedure combination/per diem payment system (DPC/PDPS) database. There were 39 336 admissions of older patients for pneumonia between August 2010 and March 2012. Patients with incomplete data were excluded, leaving 25 602 patients for analysis. Having dementia decreased mortality (OR 0.71, P LHS. Multiple logistic regression analysis identified donepezil as an independent factor that decreased mortality in patients with dementia (OR 0.36, P LHS and mortality were similar to those reported by others. Donepezil seems to decrease in-hospital mortality as a result of pneumonia among older patients with dementia. Geriatr Gerontol Int 2018; 18: 269-275. © 2017 Japan Geriatrics Society.

Generation of novel metabolites of dietary linoleic acid (18:2n6) by guinea pig epidermis

Energy Technology Data Exchange (ETDEWEB)

Chapkin, R.S.; Ziboh, V.A.

1986-03-05

Although the authors have demonstrated the inability of rat and guinea pig (GP) skin enzyme preparations to desaturate 18:2n6 into gammalinolenic acid (18:3n6) using an in vitro microsomal system, the fate of this dietary essential fatty acid in the GP epidermis is unknown. To explore the fate of 18:2n6, intact tissue slices from GP epidermis were incubated with (1-/sup 14/C)18:2n6. After incubation, the extracted lipids were transesterified using methanolic-HCL. The fatty acid methyl esters were analyzed using a combination of (i) argentation TLC, scanned using a proportional TLC radioscanner, and (ii) reverse phase HPLC, equipped with a flow through radioscanner. The results indicate that the intact epidermis metabolized /sup 14/C-18:2n6 to a group of novel products more polar than 18:2n6. In subsequent experiments, /sup 14/C-18:2n6 was either incubated with the 800 xg supernatant, the 105,000 xg pellet or supernatant from GP epidermis. Metabolism of 18:2n6 by the high speed supernatant resulted in the generation of polar products with chromatographic properties of not greater than 2 double bonds. These results indicate that although the GP epidermis lacks the capacity to desaturate 18:2n6 to 18:3n6, it can convert dietary 18:2n6 into a group of novel polar metabolites via a cytosolic mediated process. The function of these metabolites in the GP integumentary system remains to be determined.

Generation of novel metabolites of dietary linoleic acid (18:2n6) by guinea pig epidermis

International Nuclear Information System (INIS)

Chapkin, R.S.; Ziboh, V.A.

1986-01-01

Although the authors have demonstrated the inability of rat and guinea pig (GP) skin enzyme preparations to desaturate 18:2n6 into gammalinolenic acid (18:3n6) using an in vitro microsomal system, the fate of this dietary essential fatty acid in the GP epidermis is unknown. To explore the fate of 18:2n6, intact tissue slices from GP epidermis were incubated with [1- 14 C]18:2n6. After incubation, the extracted lipids were transesterified using methanolic-HCL. The fatty acid methyl esters were analyzed using a combination of (i) argentation TLC, scanned using a proportional TLC radioscanner, and (ii) reverse phase HPLC, equipped with a flow through radioscanner. The results indicate that the intact epidermis metabolized 14 C-18:2n6 to a group of novel products more polar than 18:2n6. In subsequent experiments, 14 C-18:2n6 was either incubated with the 800 xg supernatant, the 105,000 xg pellet or supernatant from GP epidermis. Metabolism of 18:2n6 by the high speed supernatant resulted in the generation of polar products with chromatographic properties of not greater than 2 double bonds. These results indicate that although the GP epidermis lacks the capacity to desaturate 18:2n6 to 18:3n6, it can convert dietary 18:2n6 into a group of novel polar metabolites via a cytosolic mediated process. The function of these metabolites in the GP integumentary system remains to be determined

Morphine metabolites

DEFF Research Database (Denmark)

Christrup, Lona Louring

1997-01-01

, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major metabolites of morphine. The metabolism of morphine occurs not only in the liver, but may also take place in the brain and the kidneys. The glucuronides are mainly eliminated via bile and urine. Glucuronides as a rule...... are considered as highly polar metabolites unable to cross the blood-brain barrier. Although morphine glucuronidation has been demonstrated in human brain tissue, the capacity is very low compared to that of the liver, indicating that the M3G and M6G concentrations observed in the cerebrospinal fluid (CSF) after...... systemic administration reflect hepatic metabolism of morphine and that the morphine glucuronides, despite their high polarity, can penetrate into the brain. Like morphine, M6G has been shown to be relatively more selective for mu-receptors than for delta- and kappa-receptors while M3G does not appear...

Rates of cognitive change in Alzheimer disease: Observations across a decade of placebo-controlled clinical trials with donepezil

DEFF Research Database (Denmark)

Jones, Roy W; Schwam, Elias; Wilkinson, David

2009-01-01

Treatment success in Alzheimer disease (AD) trials is generally based on benefits over placebo-treated controls. Consequently, variation in rates of decline among placebo-treated patients could impact outcomes from AD trials. In the present analyses, individual patient data [baseline Mini......-Mental State Examination (MMSE): 10 to 26] were pooled from randomized, placebo-controlled studies of donepezil for AD conducted during the 1990s, and grouped by initiation year-group 1: 1990 to 1994; group 2: 1996 to 1999. Changes in MMSE and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS...

Simultaneous determination of sibutramine and its active metabolites in human plasma by LC-MS/MS and its application to a pharmacokinetic study.

Science.gov (United States)

Bae, Jung-Woo; Choi, Chang-Ik; Jang, Choon-Gon; Lee, Seok-Yong

2011-11-01

A simple and sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) technique was developed and validated for the determination of sibutramine and its N-desmethyl metabolites (M1 and M2) in human plasma. After extraction with methyl t-butyl ether, chromatographic separation of analytes in human plasma was performed using a reverse-phase Luna C18 column with a mobile phase of acetonitrile-10 mm ammonium formate buffer (50:50, v/v) and quantified by ESI-MS/MS detection in positive ion mode. The flow rate of the mobile phase was 200 μL/min and the retention times of sibutramine, M1, M2 and internal standard (chlorpheniramine) were 1.5, 1.4, 1.3 and 0.9 min, respectively. The calibration curves were linear over the range 0.05-20 ng/mL, for sibutramine, M1 and M2. The lower limit of quantification was 0.05 ng/mL using 500 μL of human plasma. The mean accuracy and the precision in the intra- and inter-day validation for sibutramine, M1 and M2 were acceptable. This LC-MS/MS method showed improved sensitivity and a short run time for the quantification of sibutramine and its two active metabolites in plasma. The validated method was successfully applied to a pharmacokinetic study in human. Copyright © 2011 John Wiley & Sons, Ltd.

Piezoelectric ceramic material, containing PbNb2O6, K2Nb2O6

International Nuclear Information System (INIS)

Fesenko, E.G.; Filip'ev, V.S.; Razumovskaya, O.N.; Cherner, Ya.E.; Rudkovskaya, L.M.; Zav'yalov, V.P.; Molchanova, R.A.; Kryshtop, V.G.; Panich, A.E.; Servuli, V.A.

1984-01-01

A new piezoelectric ceramic material including PbNb 2 O 6 , K 2 Nb 2 O 6 is prepared. Above the new material contains Nb 2 O 5 . The invention relates to piezotechnique. The principal advantage of this material for acoustic converters is high anisotropy of piezoelectric properties as well as high Curie temperature (T C =539-553 deg C). The composition containing 93.96 mole% PbNb 2 O 6 ; 2.48 mole% K 2 Nb 2 O 6 and 3.56 mole% Nb 2 O 5 has optimum content of parameters

Identification, synthesis, and biological evaluation of the metabolites of 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36), a promising rexinoid lead compound for the development of cancer chemotherapeutic and chemopreventive agents.

Science.gov (United States)

Chen, Lian; Conda-Sheridan, Martin; Reddy, P V Narasimha; Morrell, Andrew; Park, Eun-Jung; Kondratyuk, Tamara P; Pezzuto, John M; van Breemen, Richard B; Cushman, Mark

2012-06-28

Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36) (3) is among the few RXR ligands known. The presently reported studies of 3 include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound 3 was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatocytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NFκB.

Acquisition and reinstatement of ethanol-induced conditioned place preference in rats: Effects of the cholinesterase inhibitors donepezil and rivastigmine.

Science.gov (United States)

Gawel, Kinga; Labuz, Krzysztof; Gibula-Bruzda, Ewa; Jenda, Malgorzata; Marszalek-Grabska, Marta; Silberring, Jerzy; Kotlinska, Jolanta H

2016-07-01

The present study examined the influence of the cholinesterase inhibitors donepezil (a selective inhibitor of acetylcholinesterase) and rivastigmine (also an inhibitor of butyrylcholinesterase) on the acquisition and reinstatement of ethanol-induced conditioned place preference (CPP) in rats. Before the CPP procedure, animals received a single injection of ethanol (0.5 g/kg, 10% w/v, intraperitoneally [i.p.]) for 15 days. The ethanol-induced CPP (biased method) was developed by four injections of ethanol (0.5 g/kg, 10% w/v, i.p.) every second day. Control rats received saline instead of ethanol. Donepezil (0.5, 1 or 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5 or 1 mg/kg, i.p.) were administered before ethanol during conditioning or before the reinstatement of ethanol-induced CPP. The cholinesterase inhibitors were equally effective in increasing (dose dependently) the acquisition of ethanol-induced CPP. Furthermore, priming injections of both inhibitors reinstated (cross-reinstatement) the ethanol-induced CPP with similar efficacy. These effects of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist, but not by scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. Thus, our results show that the cholinergic system is involved in the reinforcing properties of ethanol, and nicotinic acetylcholine receptors play an important role in the relapse to ethanol-seeking behaviour. © The Author(s) 2016.

Quantification of sibutramine and its two metabolites in human plasma by LC–ESI-MS/MS and its application in a bioequivalence study

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Venkata Suresh Ponnuru

2012-08-01

Full Text Available Obesity can be considered as a chronic illness of epidemic proportion and its incidents have increased exponentially in recent years. The use of anti-obesity drugs such as sibutramine is somewhat helpful. There is a need to quantify such drugs in biological samples, which is generally quite difficult. In this report, we developed and validated a simple, sensitive and specific liquid chromatography–tandem mass spectrometry (LC–MS/MS method for the quantification of sibutramine (SB and its two metabolites N-des methyl sibutramine (DSB and N-di desmethyl sibutramine (DDSB in human plasma. Zorbax SB-C18 (4.6 mm×75 mm, 3.5 μm, 80 Å analytical column and 5 mM ammonium formate:acetonitrile (10:90, v/v mobile phase were used for chromatographic separation of SB, DSB and DDSB. Multiple reaction monitoring (MRM in the positive mode was used to detect SB, DSB and DDSB at m/z 280.3/124.9, 266.3/125.3 and 252.2/124.9, respectively. Liquid–liquid extraction was used for the extraction of analytes and internal standard from human plasma. This method was validated over a linear concentration range of 10.0–10,000.0 pg/mL for SB, DSB and DDSB with correlation coefficients (r of ≥0.9997. The drug and the two metabolites were stable in plasma samples. The validated method was successfully applied in a bioequivalence and pharmacokinetic study with human volunteers under fasting condition. Keywords: LC–ESI-MS/MS, Sibutramine, Human plasma, Bioequivalence, Pharmacokinetic study

Simvastatin (SV) metabolites in mouse tissues

International Nuclear Information System (INIS)

Duncan, C.A.; Vickers, S.

1990-01-01

SV, a semisynthetic analog of lovastatin, is hydrolyzed in vivo to its hydroxy acid (SVA), a potent inhibitor of HMG CoA reductase (HR). Thus SV lowers plasma cholesterol. SV is a substrate for mixed function oxidases whereas SVA undergoes lactonization and β-oxidation. Male CD-1 mice were dosed orally with a combination of ( 14 C)SV and ( 3 H)SVA at 25 mg/kg of each, bled and killed at 0.5, 2 and 4 hours. Labeled SV, SVA, 6'exomethylene SV (I), 6'CH 2 OH-SV (II), 6'COOH-SV (III) and a β-oxidized metabolite (IV) were assayed in liver, bile, kidneys, testes and plasma by RIDA. Levels of potential and active HR inhibitors in liver were 10 to 40 fold higher than in other tissues. II and III, in which the configuration at 6' is inverted, may be 2 metabolites of I. Metabolites I-III are inhibitors of HR in their hydroxy acid forms. Qualitatively ( 14 C)SV and ( 3 H)SVA were metabolized similarly (consistent with their proposed interconversion). However 3 H-SVA, I-III (including hydroxy acid forms) achieved higher concentrations than corresponding 14 C compounds (except in gall bladder bile). Major radioactive metabolites in liver were II-IV (including hydroxy acid forms). These metabolites have also been reported in rat tissues. In bile a large fraction of either label was unidentified polar metabolites. The presence of IV indicated that mice (like rats) are not good models for SV metabolism in man

Structural phase transitions of NaV6O11 and SrV6O11

International Nuclear Information System (INIS)

Kanke, Yasushi; Izumi, Fujio; Kato, Katsuo; Morii, Yukio; Funahashi, Satoru; Akiba, Etsuo.

1993-01-01

Crystal structures of NaV 6 O 11 at several temperatures were studied by either Rietveld analyses of both neutron and X-ray powder diffraction data, or an analysis of X-ray single crystal diffraction data. At 200 K, NaV 6 O 11 loses the center of symmetry, and its space group changes from P6 3 /mmc to P6 3 mc. Consequently, V(2) splits into two sites. At 30 K, NaV 6 O 11 was transformed from the hexagonal form to the orthorhombic one (Cmc2 1 ), and V(1) splits into two sites. These results indicate that magnetic phase transitions of NaV 6 O 11 at 245 K and 64.2 K are accompanied by structural phase transitions. On the other hand, no structural phase transition was detected in SrV 6 O 11 . (author)

Metabolites of 2,4,4'-tribrominated diphenyl ether (BDE-28) in pumpkin after in vivo and in vitro exposure.

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Yu, Miao; Liu, Jiyan; Wang, Thanh; Sun, Jianteng; Liu, Runzeng; Jiang, Guibin

2013-01-01

There is currently limited knowledge on PBDE metabolism in plants although they could play an important role in the environmental transformation of these persistent organic pollutants. In this study, pumpkin (Cucurbita maxima × C. moschata) was chosen as the model to understand the fate of BDE-28 in plants. MeO-tri-BDEs, OH-tri-BDEs, and OH-tri-BDEs were found as metabolites in plant samples of both in vivo hydroponic and in vitro tissue culture exposure. Three MeO-tri-BDEs were further identified as para-substituted metabolites. MeO-BDEs and OH-BDEs, respectively, accounted for about 1.6% and 1.5% (recovery corrected) of initial amount of BDE-28 according to the semiquantitative results. Other PBDEs, especially less brominated PBDEs as impurities in the standard of BDE-28, were also detected. The impurities and evaporation of the standard must be considered when trace metabolites are studied in exposure experiments.

Metabolites of cannabidiol identified in human urine.

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Harvey, D J; Mechoulam, R

1990-03-01

1. Urine from a dystonic patient treated with cannabidiol (CBD) was examined by g.l.c.-mass spectrometry for CBD metabolites. Metabolites were identified as their trimethylsilyl (TMS), [2H9]TMS, and methyl ester/TMS derivatives and as the TMS derivatives of the product of lithium aluminium deuteride reduction. 2. Thirty-three metabolites were identified in addition to unmetabolized CBD, and a further four metabolites were partially characterized. 3. The major metabolic route was hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups to give 1"-, 2"-, 3"-, 4"- and 10-hydroxy derivatives of CBD-7-oic acid. Other metabolites, mainly acids, were formed by beta-oxidation and related biotransformations from the pentyl side-chain and these were also hydroxylated at C-6 or C-7. The major oxidized metabolite was CBD-7-oic acid containing a hydroxyethyl side-chain. 4. Two 8,9-dihydroxy compounds, presumably derived from the corresponding epoxide were identified. 5. Also present were several cyclized cannabinoids including delta-6- and delta-1-tetrahydrocannabinol and cannabinol. 6. This is the first metabolic study of CBD in humans; most observed metabolic routes were typical of those found for CBD and related cannabinoids in other species.

Roles of different forms of cytochrome P450 in the activation of the promutagen 6-aminochrysene to genotoxic metabolites in human liver microsomes.

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Yamazaki, H; Mimura, M; Oda, Y; Inui, Y; Shiraga, T; Iwasaki, K; Guengerich, F P; Shimada, T

1993-07-01

We reported previously that the potent mutagen 6-aminochrysene is catalyzed principally by rat liver microsomal P4501A and P4502B enzymes to reactive metabolites that induce umu gene expression in O-acetyltransferase-over-expressing strain Salmonella typhimurium NM2009; the proposal was made that there are different mechanisms in the formation of reactive N-hydroxylated and diolepoxide metabolites by P450 enzymes (Yamazaki, H. and Shimada, T., Biochem. Pharmacol., 44, 913-920, 1992). Here we further examined the roles of human liver P450 enzymes and the mechanism of activation of 6-aminochrysene by rat and human P450 enzymes in the Salmonella tester strains. Liver microsomes from 18 different human samples catalyzed activation of 6-aminochrysene more efficiently in S. typhimurium NM2009 than in the original strain of S. typhimurium TA1535/pSK1002. The rates of 6-aminochrysene activation in 18 human liver samples showed good correlation to the contents of P4502B6 as well as contents of P4503A4 and the respective mono-oxygenase activities catalyzed by P4503A4. Among purified P450 enzymes examined, P4501A2 as well as P4503A4 were highly active in transforming 6-amino-chrysene to reactive metabolites, suggesting the involvement of different human P450 enzymes in the reaction. Four human samples that contained relatively high levels of particular P450 enzymes in their microsomes were selected and used for further characterization. Liver microsomes from human samples HL-13 and HL-4 that contained the highest levels of P4502B6 and P4503A4 respectively, were sensitive to the respective antibodies raised against monkey P4502B and human P4503A4; the activity in sample HL-16 having the highest level of P4501A2 was inhibited by anti-P4501A2 IgG. alpha-Naphthoflavone enhanced the activation of 6-aminochrysene very significantly in human liver microsomes enriched in P4503A4 and P4502B6 enzymes. Pentachlorophenol, an inhibitor of acetyltransferase activity, suppressed the

Primary, Secondary Metabolites, H2O2, Malondialdehyde and Photosynthetic Responses of Orthosiphon stimaneus Benth. to Different Irradiance Levels

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Mohd Hafiz Ibrahim

2012-01-01

Full Text Available The resource availability hypothesis predicts an increase in the allocation to secondary metabolites when carbon gain is improved relative to nutrient availability, which normally occurs during periods of low irradiance. The present work was carried out to confirm this hypothesis by investigating the effects of decreasing irradiance on the production of plant secondary metabolites (flavonoids and phenolics in the herbal plant Orthosiphon stamineus, and to characterize this production by carbohydrate, H2O2, and malondialdehyde (MDA levels, net photosynthesis, leaf chlorophyll content and carbon to nitrogen ratio (C/N. Four levels of irradiance (225, 500, 625 and 900 µmol/m2/s were imposed onto two-week old seedlings for 12 weeks in a randomized complete block design experiment. Peak production of total flavonoids, phenolics, soluble sugar, starch and total non-structural carbohydrate ocurred under low irradiance of 225 µmol/m2/s, and decreased with increasing irradiance. The up-regulation of secondary metabolites could be explained by the concomitant increases in H2O2 and MDA activities under low irradiance. This condition also resulted in enhanced C/N ratio signifying a reduction in nitrogen levels, which had established significant negative correlations with net photosynthesis, total biomass and total chlorophyll content, indicating the possible existence of a trade-off between growth and secondary metabolism under low irradiance with reduced nitrogen content. The competition between total chlorophyll and secondary metabolites production, as exhibited by the negative correlation coefficient under low irradiance, also suggests a sign of gradual switch of investment from chlorophyll to polyphenols production.

Metabolism of Lutein and Zeaxanthin in Rhesus Monkeys: Identification of (3R,6′R)- and (3R,6′S)-3′-Dehydro-lutein as Common Metabolites and Comparison to Humans

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Albert, Gesa I.; Hoeller, Ulrich; Schierle, Joseph; Neuringer, Martha; Johnson, Elizabeth J.; Schalch, Wolfgang

2012-01-01

Lutein and zeaxanthin are xanthophylls that can be found highly concentrated in the macula of the retina. They are thought to protect the macula through their role as blue-light filters and because of their antioxidant and singlet oxygen quenching properties. Examination of metabolites unique to lutein and zeaxanthin such as 3′-dehydro-lutein, and of their stereochemistry may provide insight to the mechanism by which they are formed and by which they exert protection. To evaluate the formation of such metabolites, eleven monkeys were raised on a xanthophyll-free diet, and supplemented with pure lutein or pure zeaxanthin (2.2 mg/kg body weight/d). The period of supplementation ranged between 12 to 92 weeks. At study start and throughout the study, serum samples were taken and analyzed for xanthophylls using different HPLC systems. Xanthophyll metabolites were identified using UV/VIS and HR-MS detection. Lutein and zeaxanthin metabolites were found in detectable amounts with 3′-dehydro-lutein being a common metabolite of both. Using chiral-phase HPLC, two diastereomers, (3R,6′R)-3′-dehydro-lutein and (3R,6′S)-3′-dehydro-lutein, were identified and shown to be present in nearly equimolar amounts. A pathway for their formation from either lutein or zeaxanthin is proposed. These finding were comparable to results obtained with human plasma. PMID:18582588

Circulating prostacyclin metabolites in the dog

International Nuclear Information System (INIS)

Taylor, B.M.; Shebuski, R.J.; Sun, F.F.

1983-01-01

The present study was designed to determine the concentration of prostacyclin (PGI2) metabolites in the blood of the dog. After a bolus i.v. dose of [11 beta- 3 H]PGI2 (5 micrograms/kg) into each of five dogs, blood samples were withdrawn at 0.33, 0.67, 1, 3, 5, 20, 30, 60 and 120 min postdrug administration. Plasma samples were extracted and the radioactive components were analyzed by two-dimensional thin-layer chromatography with autoradiofluorography and radio-high-performance liquid chromatography. The compounds were identified by comparing their mobility with synthetic standards; only parallel responses observed in both tests constituted positive identification. Seven metabolites were identified by these two techniques: 6-keto-prostaglandin (PG)F1 alpha; 6-keto-PGE1; 2,3-dinor-6-keto-PGF 1 alpha; 2,3-dinor-13,14-dihydro-6,15-diketo-20-carboxyl PGF 1 alpha; and 2,3,18,19-tetranor-13,14-dihydro-6,15-diketo-20-carboxyl PGF 1 alpha. Several additional compounds, both polar and nonpolar in nature, which did not co-chromatograph with any of our standards were also detected. Early samples consisted predominantly of 6-keto-PGF 1 alpha and other 20-carbon metabolites. By 30 min, the predominant metabolites were the 16- and 18-carbon dicarboxylic acids. By 60 min, 85% of the radioactivity was associated with two unidentified polar compounds. The evidence suggests that 6-keto-PGF 1 alpha probably reflects only the transient levels of freshly entering PGI2 in the circulation, whereas levels of the most polar metabolites (e.g., dihydro-diketo-carboxyl tetranor-PGF 2 alpha) may be a better measure of the overall PGI2 presence due to its longer half-life in circulation

Effect of CYP2B6 genotype on the pharmacokinetics of sibutramine and active metabolites in healthy subjects.

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Chung, Jae Yong; Jang, Seong Bok; Lee, Yoon Jung; Park, Min Soo; Park, Kyungsoo

2011-01-01

Sibutramine is a pharmacologic intervention for the treatment of obesity. The effect of CYP2B6 genotypes on the pharmacokinetics of sibutramine and its active metabolites (desmethylsibutramine [M1] and didesmethylsibutramine [M2]) was evaluated in 57 healthy subjects. Each subject received a single oral dose of 10 or 15 mg sibutramine, and blood samples were collected up to 72 hours after dosing. The relationship between the genotypes and the pharmacokinetics of sibutramine, M1, and M2 was examined. A statistically significant difference in the elimination half-life (t(1/2)) of sibutramine M1 was found among the 3 genotype groups (P = .0006), between the *1/*1 and *1/*6 groups (P = .0001), and between the *1/*4 and *1/*6 groups (P = .012). The mean value of M1 t(1/2) in *1/*6 (33.3 ± 10.5 hours) was about 58% and 61% greater than that of the *1/*1 group (21.0 ± 7.4 hours) and the *1/*4 group (20.7 ± 9.8 hours), respectively. No significant differences in area under the concentration-time curve or maximum plasma drug concentration were observed between the groups. The CYP2B6*6 allele may be associated with a lower metabolic clearance of the M1 metabolite of sibutramine in human subjects.

Physicochemical investigation of Bi2MoO6 solid-phase interaction with Sm2MoO6

International Nuclear Information System (INIS)

Khajkina, E.G.; Kovba, L.M.; Bazarova, Zh.G.; Khal'baeva, K.M.; Khakhinov, V.V.; Mokhosoev, M.V.

1986-01-01

Bi 2 MoO 6 -Sm 2 MoO 6 interaction in the temperature range of 700-1000 deg C is studied using X-ray phase analysis and vibrational spectroscopy. Formation of monoclinic solid solutions based on γ'-Bi 2 MoO 6 and B 2-x Sm x MoO 6 varied composition phase with α-Ln 2 MoO 6 structure which homogeneity region extent at 1000 deg C constitutes ∼ 50 mol % (0.7≤x≤1.7) is stated. Crystallographic characteristics of the synthesized phases are determined

PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE AND ITS METABOLITE O-DESMETHYLTRAMADOL FOLLOWING A SINGLE, ORALLY ADMINISTERED DOSE IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

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Boonstra, Jennifer L; Barbosa, Lorraine; Van Bonn, William G; Johnson, Shawn P; Gulland, Frances M D; Cox, Sherry K; Martin-Jimenez, Tomas

2015-09-01

Tramadol is a synthetic, centrally acting, opiate-like analgesic that is structurally related to codeine and morphine. The objective of this study was to determine the pharmacokinetics of tramadol hydrochloride and its major active metabolite O-desmethyltramadol (M1) in the California sea lion (Zalophus californianus). A single dose of tramadol was administered orally in fish at 2 mg/kg to a total of 15 wild California sea lions admitted for rehabilitation. Twenty-four total blood samples were collected post drug administration at 10, 20, 30, and 45 min and at 1, 3, 5, 6, 8, 12, and 24 hr. Blood plasma was separated and stored at -80°C until analysis with high-performance liquid chromatography was performed to determine levels of tramadol and M1, the major active metabolite. The results indicate that the plasma levels of parent tramadol are low or negligible during the first 30-45 min and then reach the predicted mean maximum plasma concentration of 358 ng/ml at 1.52 hr. The M1 metabolite was not detectable in 21 of 24 plasma samples, below the level of quantification of 5 ng/ml in one sample, and detectable at 11 and 17 ng/ml in two of the samples. This study suggests that a 2 mg/kg dose would need to be administered every 6-8 hr to maintain concentrations of tramadol above the minimum human analgesic level for mild to moderate pain. Based on dosing simulations, a dose of 4 mg/kg q8 hr or q12 hr, on average, may represent an adequate compromise, but further studies are needed using a larger sample size. Pharmacodynamic studies are warranted to determine if tramadol provides analgesic effects in this species. The potential for tramadol toxicosis at any dose also has not been determined in this species.

Simultaneous determination of 7-O-succinyl macrolactin A and its active major metabolite, macrolactin A in dog plasma using high-performance liquid chromatography with UV detection.

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Kim, Eunyoung; Shin, Beomsoo; Kwon, Kwang-il; Bang, Joon Seok; Kang, Wonku

2014-10-01

We developed a method for the simultaneous quantification of 7-O-succinyl macrolactin A and its active metabolite, macrolactin A, in dog plasma. After protein precipitation with acetonitrile including flufenamic acid as an internal standard, 7-O-succinyl macrolactin A, macrolactin A, and flufenamic acid were chromatographed on a reverse-phase C18 analytical column. The mobile phase, consisting of 20 mM acetate buffer and acetonitrile, was eluted using a gradient program at 1 mL/min, and the UV absorbance was measured at 230 nm. The retention times of 7-O-succinyl macrolactin A, flufenamic acid, and macrolactin A were 3.4, 4.8, and 6.9 min, respectively. The coefficient of variation in the assay precision for both substances was less than 6%, and the accuracy ranged from 96 to 105%. This method was used to measure the concentrations of 7-O-succinyl macrolactin A and macrolactin A in dog plasma following an intravenous administration of a single dose (25 mg/kg) of 7-O-succinyl macrolactin A salt. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The influence of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite.

Science.gov (United States)

Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Chira, Ruxandra; Briciu, Corina

2015-01-01

To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers. 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period. Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively. Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry for Identification of In Vitro and In Vivo Metabolites of Bornyl Gallate in Rats

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Wei Lan

2013-01-01

Full Text Available Bornyl gallate (BG is a potential drug candidate synthesized by the reaction of two natural products, gallic acid and borneol. Previous studies have strongly suggested that BG is worthy of further investigation due to antioxidant, antiatherosclerosis activities, and obvious activity of stimulating intersegmental vessel growth in zebrafish. This work was designed to elucidate the metabolic profile of BG through analyzing its metabolites in vitro and in vivo by a chromatographic separation coupled with a mass spectrometry. The metabolites of BG were characterized from the rat liver microsome incubation solution, as well as rat urine and plasma after oral administration. Chromatographic separation was performed on an Agilent TC-C18 column (250 mm × 4.6 mm, 5 μm with gradient elution using methanol and water containing 0.2% (V : V formic acid as the mobile phase. Metabolites identification involved analyzing the retention behaviors, changes of molecular weights and MS/MS fragment patterns of BG and the metabolites. Five compounds were identified as isomers of hydroxylated BG metabolites in vitro. The major metabolites of BG in rat urine and plasma proved to be BG-O-glucuronide and O-methyl BG-O-glucuronide. The proposed method confirmed to be a reliable and sensitive alternative for characterizing metabolic pathways of BG.

Urinary Polycyclic Aromatic Hydrocarbon Metabolites and Attention/Deficit Hyperactivity Disorder, Learning Disability, and Special Education in U.S. Children Aged 6 to 15

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Zaynah Abid

2014-01-01

Full Text Available Exposure to polycyclic aromatic hydrocarbons (PAHs adversely affects child neurodevelopment, but little is known about the relationship between PAHs and clinically significant developmental disorders. We examined the relationship between childhood measures of PAH exposure and prevalence of attention deficit/hyperactivity disorder (ADHD, learning disability (LD, and special education (SE in a nationally representative sample of 1,257 U.S. children 6–15 years of age. Data were obtained from the National Health and Nutrition Examination Survey (NHANES 2001–2004. PAH exposure was measured by urinary metabolite concentrations. Outcomes were defined by parental report of (1 ever doctor-diagnosed ADHD, (2 ever doctor- or school representative-identified LD, and (3 receipt of SE or early intervention services. Multivariate logistic regression accounting for survey sampling was used to determine the associations between PAH metabolites and ADHD, LD, and SE. Children exposed to higher levels of fluorine metabolites had a 2-fold increased odds (95% C.I. 1.1, 3.8 of SE, and this association was more apparent in males (OR 2.3; 95% C.I. 1.2, 4.1 than in females (OR 1.8; 95% C.I. 0.6, 5.4. No other consistent pattern of developmental disorders was associated with urinary PAH metabolites. However, concurrent exposure to PAH fluorine metabolites may increase use of special education services among U.S. children.

The Daidzein Metabolite, 6,7,4'-Trihydroxyisoflavone, Is a Novel Inhibitor of PKCα in Suppressing Solar UV-Induced Matrix Metalloproteinase 1

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Tae-Gyu Lim

2014-11-01

Full Text Available Soy isoflavone is an attractive source of functional cosmetic materials with anti-wrinkle, whitening and skin hydration effects. After consumption, the majority of soy isoflavones are converted to their metabolites in the human gastrointestinal tract. To understand the physiological impact of soy isoflavone on the human body, it is necessary to evaluate and address the biological function of its metabolites. In this study, we investigated the effect of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF, a major metabolite of daidzein, against solar UV (sUV-induced matrix metalloproteinases (MMPs in normal human dermal fibroblasts. MMPs play a critical role in the degradation of collagen in skin, thereby accelerating the aging process of skin. The mitogen-activated protein/extracellular signal-regulated kinase (MEK/extracellular signal-regulated kinase (ERK, mitogen-activated protein kinase (MKK3/6/p38 and MKK4/c-Jun N-terminal kinases (JNK signaling pathways are known to modulate MMP-1 function, and their activation by sUV was significantly reduced by 6,7,4'-THIF pretreatment. Our results also indicated that the enzyme activity of protein kinase C (PKCα, an upstream regulator of MKKs signaling, is suppressed by 6,7,4'-THIF using the in vitro kinase assay. Furthermore, the direct interaction between 6,7,4'-THIF and endogenous PKCα was confirmed using the pull-down assay. Not only sUV-induced MMP-1 expression, but also sUV-induced signaling pathway activation were decreased in PKCα knockdown cells. Overall, we elucidated the inhibitory effect of 6,7,4'-THIF on sUV-induced MMPs and suggest PKCα as its direct molecular target.

Combined effects of O3 and UV radiation on secondary metabolites and endogenous hormones of soybean leaves.

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Bing Mao

Full Text Available Enhanced ultraviolet radiation (UV and elevated tropospheric ozone (O3 may individually cause reductions in the growth and productivity of important agricultural crops. However, research regarding their combined effects on important agricultural crops is still scarce, especially on changes in secondary metabolites and endogenous hormones, which are important protective substances and signal components that control plant responses to environment stresses. In this study, using an experimental setup of open top chambers, we monitored the responses of seed yield per plant, leaf secondary metabolites and leaf endogenous hormones under the stress of elevated O3 and enhanced UV radiation individually, as well as their combined stress. The results indicated that elevated O3 (110 ± 10 nmol mol-1 for 8 hours per day and enhanced UV radiation (1.73 kJ h-1 m-2 significantly decreased seed yield per plant. Concentrations of rutin, queretin and total flavonoids were significantly increased under the elevated O3 treatment or the enhanced UV radiation treatment or the combination treatment at flowering and podding stages, and concentrations of rutin, queretin and total flavonoids showed significant correlations with seed yield per plant. Concentrations of ABA and IAA decreased under the three treatments. There was a significant positive correlation between the ABA concentration and seed yield and a negative correlation between the IAA concentration and seed yield. We concluded that the combined stress of elevated O3 and UV radiation significantly decreased seed yield per plant. Yield reduction was associated with changes in the concentrations of flavonoids, ABA and IAA in soybean leaves. The effects of the combined O3 and UV stress were always greater than those of the individual stresses alone.

TREATMENT OF RESISTANT DEPRESSIONS AND CASE OF SUCCESSFUL USE OF DONEPEZIL HCl IN THEIR THERAPY

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Dragan Terzič

2001-07-01

Full Text Available Background. In this article some approaches how to treat a stadium of resistant depression are described. There is also a description of the successful use of inhibitors acetylholinesterase donepezil hydrochloride (Aricept in treatment of this kind of depression. Taking into account a great number of depressive patients who are resistant to usual antidepressivs these new approaches to treatment are of a great importance due to the fact that in many cases previous treatments of a depressive patients proved to be unsuccessful. This article is considered to be one of the first description in respect of the use of inhibitors of acetylcholinesterase in treatment of resistant depressions.Conclusions. In case of resistant depressions, one of the possibilities of its treatment is the use of inhibitors of acetylcholinesterase (and may be others in combination with antidepressants.

Secondary metabolites from Ganoderma.

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Baby, Sabulal; Johnson, Anil John; Govindan, Balaji

2015-06-01

Ganoderma is a genus of medicinal mushrooms. This review deals with secondary metabolites isolated from Ganoderma and their biological significance. Phytochemical studies over the last 40years led to the isolation of 431 secondary metabolites from various Ganoderma species. The major secondary compounds isolated are (a) C30 lanostanes (ganoderic acids), (b) C30 lanostanes (aldehydes, alcohols, esters, glycosides, lactones, ketones), (c) C27 lanostanes (lucidenic acids), (d) C27 lanostanes (alcohols, lactones, esters), (e) C24, C25 lanostanes (f) C30 pentacyclic triterpenes, (g) meroterpenoids, (h) farnesyl hydroquinones (meroterpenoids), (i) C15 sesquiterpenoids, (j) steroids, (k) alkaloids, (l) prenyl hydroquinone (m) benzofurans, (n) benzopyran-4-one derivatives and (o) benzenoid derivatives. Ganoderma lucidum is the species extensively studied for its secondary metabolites and biological activities. Ganoderma applanatum, Ganoderma colossum, Ganoderma sinense, Ganoderma cochlear, Ganoderma tsugae, Ganoderma amboinense, Ganoderma orbiforme, Ganoderma resinaceum, Ganoderma hainanense, Ganoderma concinna, Ganoderma pfeifferi, Ganoderma neo-japonicum, Ganoderma tropicum, Ganoderma australe, Ganoderma carnosum, Ganoderma fornicatum, Ganoderma lipsiense (synonym G. applanatum), Ganoderma mastoporum, Ganoderma theaecolum, Ganoderma boninense, Ganoderma capense and Ganoderma annulare are the other Ganoderma species subjected to phytochemical studies. Further phytochemical studies on Ganoderma could lead to the discovery of hitherto unknown biologically active secondary metabolites. Copyright © 2015 Elsevier Ltd. All rights reserved.

The In Vivo Quantitation of Diazinon, chlorpyrifos, and Their Major Metabolites in Rat Blood for the Refinement of a Physiologically-Based Pharmacokinetic/Pharmacodynamic Models

Energy Technology Data Exchange (ETDEWEB)

Busby, A.; Kousba, A.; Timchalk, C.

2004-01-01

Chlorpyrifos (CPF)(O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate, CAS 2921-88-2), and diazinon (DZN)(O,O-diethyl-O-2-isopropyl-4-methyl-6-pyrimidyl thiophosphate, CAS 333-41-5) are commonly encountered organophosphorus insecticides whose oxon metabolites (CPF-oxon and DZN-oxon) have the ability to strongly inhibit acetylcholinesterase, an enzyme responsible for the breakdown of acetylcholine at nerve synapses. Chlorpyrifos-oxon and DZN-oxon are highly unstable compounds that degrade via hepatic, peripheral blood, and intestinal metabolism to the more stable metabolites, TCP (3,5,6-trichloro-2-pyridinol, CAS not assigned) and IMHP (2-isopropyl-6-methyl-4-pyrimidinol, CAS 2814-20-2), respectively. Studies have been performed to understand and model the chronic and acute toxic effects of CPF and DZN individually but little is known about their combined effects. The purpose of this study was to improve physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) computational models by quantifying concentrations of CPF and DZN and their metabolites TCP and IMHP in whole rat blood, following exposure to the chemicals individually or as a mixture. Male Sprague-Dawley rats were orally dosed with 60 mg/kg of CPF, DZN, or a mixture of these two pesticides. When administered individually DZN and CPF were seen to reach their maximum concentration at ~3 hours post-dosing. When given as a mixture, both DZN and CPF peak blood concentrations were not achieved until ~6 hours post-dosing and the calculated blood area under the curve (AUC) for both chemicals exceeded those calculated following the single dose. Blood concentrations of IMHP and TCP correlated with these findings. It is proposed that the higher AUC obtained for both CPF and DZN as a mixture resulted from competition for the same metabolic enzyme systems.

Quantitative determination of regorafenib and its two major metabolites in human plasma with high-performance liquid chromatography and ultraviolet detection.

Science.gov (United States)

Fujita, Kazuma; Miura, Masatomo; Shibata, Hiroyuki

2016-10-01

A simple, highly sensitive and specific high-performance liquid chromatography (HPLC) method was developed for the simultaneous quantitation of regorafenib, N-oxidemetabolite (M-2) and the desmethyl N-oxide metabolite (M-5) in human plasma. Regorafenib, M-2, M-5 and the internal standard sorafenib were separated using a mobile phase of 0.5% KH2 PO4 (pH 3.5)-acetonitrile (30:70, v/v), on a Capcell PAK MG II column at a flow rate of 0.5 mL/min and measurement at UV 260 nm. The lower limits of quantification for regorafenib, M-2 and M-5 were 10 ng/mL for each analyte. A procedure using solid-phase extraction required only a small amount of plasma (100 μL) for one analysis while providing high extraction recovery (>81% for all compounds) and good selectivity. Coefficients of variation for intra- and inter-day assays were HPLC assay is suitable for clinical pharmacokinetic studies of regorafenib. The present HPLC method is currently in use for our observational studies of patients under treatment. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Remoção de atrazina e metabólitos pela filtração lenta com leito de areia e carvão ativado granular Removal of atrazine and metabolites through slow filtration by sand and granular activated carbon

Directory of Open Access Journals (Sweden)

Edumar Ramos Cabral Coelho

2012-09-01

Full Text Available A atrazina (ATZé um herbicida largamente utilizado no mundo, sendo encontrada associada aos seus produtos de degradação em águas superficiais e subterrâneas. Pertence à classe das s-triazinas e, juntamente com os metabólitos clorados deetilatrazina (DEA e deisopropilatrazina (DIA, possui potencial carcinogênico e toxicidade como disruptores endócrinos. A limitação dos processos que empregam a coagulação química na remoção de ATZ, a conhecida capacidade do carvão ativado em remover microcontaminantes em água e o risco que a ATZ e seus metabólitos apresentam à saúde motivaram o estudo da filtração lenta com leito de areia e carvão ativado granular. Os resultados apontaram a eficiência do processo de filtração lenta com camada intermediária de carvão ativado granular na remoção de ATZ e a limitação deste na remoção dos metabólitos DEA, DIA e deetilhidroxiatrazina (DEHA.Atrazine (ATZ is widely used as herbicide, commonly found in association to its degradation products in surface water and groundwater. It belongs to the class of s-triazines and together with the chlorinated metabolites dieethylatrazine (DEA and deisopropilatrazine (DIA have carcinogenic potential and toxicity as endocrine disruptors. The limitation of the processes employing chemical coagulation in the removal of atrazine, the known ability of activated carbon to remove microcontaminants in water and the risk that atrazine and the potential toxicity to human health of its metabolits motivated the study of slow sand filtration bed combined with granular activated carbon. The results showed the high efficiency of the slow filtration process with intermediate layer of granular activated carbon in the removal of atrazine and its limitation on the removal of the metabolites DEA, DIA and diethylhidroxiatrazine (DEHA.

Kinetic Modelling of Infection Tracers [¹⁸F]FDG, [⁶⁸Ga]Ga-Citrate, [¹¹C]Methionine, and [¹¹C]Donepezil in a Porcine Osteomyelitis Model

DEFF Research Database (Denmark)

Jødal, Lars; Jensen, Svend Borup; Nielsen, Ole Lerberg

2017-01-01

Introduction. Positron emission tomography (PET) is increasingly applied for infection imaging using [18F]FDG as tracer, but uptake is unspecific. The present study compares the kinetics of [18F]FDG and three other PET tracers with relevance for infection imaging. Methods. A juvenile porcine...... osteomyelitis model was used. Eleven pigs underwent PET/CT with 60-minute dynamic PET imaging of [18F]FDG, [68Ga]Ga-citrate, [11C]methionine, and/or [11C]donepezil, along with blood sampling. For infectious lesions, kinetic modelling with one- and two-tissue-compartment models was conducted for each tracer...... for the analysis. Conclusions. The kinetics of the four studied tracers in infection was characterized. For clinical applications, [18F]FDG remains the first-choice PET tracer. [11C]methionine may have a potential for detecting soft tissue infections. [68Ga]Ga-citrate and [11C]donepezil were not found useful...

Synthesis of an Albendazole Metabolite: Characterization and HPLC Determination

Science.gov (United States)

Mahler, Graciela; Davyt, Danilo; Gordon, Sandra; Incerti, Marcelo; Nunez, Ivana; Pezaroglo, Horacio; Scarone, Laura; Serra, Gloria; Silvera, Mauricio; Manta, Eduardo

2008-01-01

In this laboratory activity, students are introduced to the synthesis of an albendazole metabolite obtained by a sulfide oxidation reaction. Albendazole as well as its metabolite, albendazole sulfoxide, are used as anthelmintic drugs. The oxidation reagent is H[subscript 2]O[subscript 2] in acetic acid. The reaction is environmental friendly,…

Natural metabolites for parasitic weed management.

Science.gov (United States)

Vurro, Maurizio; Boari, Angela; Evidente, Antonio; Andolfi, Anna; Zermane, Nadjia

2009-05-01

Compounds of natural origin, such as phytotoxins produced by fungi or natural amino acids, could be used in parasitic weed management strategies by interfering with the early growth stages of the parasites. These metabolites could inhibit seed germination or germ tube elongation, so preventing attachment to the host plant, or, conversely, stimulate seed germination in the absence of the host, contributing to a reduction in the parasite seed bank. Some of the fungal metabolites assayed were very active even at very low concentrations, such as some macrocyclic trichothecenes, which at 0.1 microM strongly suppressed the germination of Orobanche ramosa L. seeds. Interesting results were also obtained with some novel toxins, such as phyllostictine A, highly active in reducing germ tube elongation and seed germination both of O. ramosa and of Cuscuta campestris Yuncker. Among the amino acids tested, methionine and arginine were particularly interesting, as they were able to suppress seed germination at concentrations lower than 1 mM. Some of the fungal metabolites tested were also able to stimulate the germination of O. ramosa seeds. The major findings in this research field are described and discussed.

Characterisation of the appearance of radioactive metabolites in monkey and human plasma from the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635 - explanation of high signal contrast in PET and an aid to biomathematical modelling

International Nuclear Information System (INIS)

Osman, Safiye; Lundkvist, Camilla; Pike, Victor W.; Halldin, Christer; McCarron, Julie A.; Swahn, Carl-Gunnar; Farde, Lars; Ginovart, Nathalie; Luthra, Sajinder K.; Gunn, Roger N.; Bench, Christopher J.; Sargent, Peter A.; Grasby, Paul M.

1998-01-01

N-(2-(4-(2-Methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), labelled in its amido carbonyl group with 11 C (t 1/2 = 20.4 min), is a promising radioligand for the study of brain 5-HT 1A receptors with positron emission tomography (PET). Thus, in PET experiments in six cynomolgus monkeys and seven healthy male volunteers, [carbonyl- 11 C]WAY-100635 was taken up avidly by brain. Radioactivity was retained in regions rich in 5-HT 1A receptors, such as occipital cortex, temporal cortex and raphe nuclei, but cleared rapidly from cerebellum, a region almost devoid of 5-HT 1A receptors. [Carbonyl- 11 C]WAY-100635 provides about 3- and 10-fold higher signal contrast (receptor-specific to nonspecific binding) than [O-methyl- 11 C]WAY-100635 in receptor-rich areas of monkey and human brain, respectively. To elucidate the effect of label position on radioligand behaviour and to aid in the future biomathematical interpretation of the kinetics of regional cerebral radioactivity uptake in terms of receptor-binding parameters, HPLC was used to measure [carbonyl- 11 C]WAY-100635 and its radioactive metabolites in plasma at various times after intravenous injection. Radioactivity cleared rapidly from monkey and human plasma. Parent radioligand represented 19% of the radioactivity in monkey plasma at 47 min and 8% of the radioactivity in human plasma at 40 min. [Carbonyl- 11 C]desmethyl-WAY-100635 was below detectable limits in monkey plasma and at most a very minor radioactive metabolite in human plasma. [ 11 C]Cyclohexanecarboxylic acid was identified as a significant radioactive metabolite. In human plasma this maximally represented 21% of the radioactivity at 10 min after radioligand injection. All other major radioactive metabolites in monkey and human plasma were even more polar. No-carrier-added [carbonyl- 11 C]cyclohexanecarboxylic acid was prepared in the laboratory and after intravenous administration into cynomolgus monkey was

O6-ethylguanine carcinogenic lesions in DNA: An NMR study of O6etG·T pairing in dodecanucloetide duplexes

International Nuclear Information System (INIS)

Kalnik, M.W.; Li, B.F.L.; Swann, P.F.; Patel, D.J.

1989-01-01

High-resolution two-dimensional NMR studies are reported on the self-complementary d-(C1-G2-C3-O 6 etG4-A5-G6-C7-T8-T9-G10-C11-G12) duplex (designated O 6 etG·T 12-mer) containing two symmetrically related O 6 etG·T lesion sites located four base pairs in from either end of the duplex. Parallel studies were undertaken on a related sequence containing O 6 meG·T lesion sites (designated O 6 meG·T 12-mer) in order to evaluate the influence of the size of the alkyl substituent on the structure of the duplex and were undertaken on a related sequence containing G·T mismatch sites (designated G·T 12-mer duplex), which served as the control duplex. The exchangeable and nonexchangeable proton and the phosphorus nuclei have been assigned from an analysis of two-dimensional nuclear Overhauser enhancement (NOE) and correlated spectra of the O 6 etG·T 12-mer, O 6 meG·T 12-mer, and G·T 12-mer duplexes in H 2 O and D 2 O solutions. The distance connectivities observed in the NOESY spectra of the O 6 alkG·T 12-mer duplexes establish that the helix is right-handed and all of the bases adopt an anti conformation of the glycosidic torsion angle including the O 6 alkG4 and T9 bases at the lesion site. These observations establish that the O 6 alkG4 and T9 residues are stacked into the duplex and that the O 6 CH 3 and O 6 CH 2 CH 3 groups of O 6 alkG4 adopt a syn orientation with respect to the N 1 of the alkylated guanine. Since the O 6 -alkyl group adopts a syn orientation, the separation between the O 6 of O 6 alkG4 and the O 4 of T9 in the major groove is increased, preventing the formation of a short hydrogen bond between the N 1 ring nitrogen of O 6 alkG4 and the imino proton of T9

Trapping {BW12}2 tungstoborate: synthesis and crystal structure of hybrid [{(H2BW12O42)2O}{Mo6O6S6(OH)4(H2O)2}]14- anion.

Science.gov (United States)

Korenev, V S; Abramov, P A; Vicent, C; Mainichev, D A; Floquet, S; Cadot, E; Sokolov, M N; Fedin, V P

2012-12-28

Reaction between monolacunary {BW(11)} tungstoborate and oxothiocationic building block, {Mo(2)O(2)S(2)}, results in the formation of a new polyoxothiometalate with a unique architecture in which two [H(2)BW(12)O(43)](9-) tungstoborate subunits are linked together with a hexamolybdate [Mo(V)(6)O(6)S(6)(OH)(4)(H(2)O)(2)](2+) bridge.

Detection of Volatile Metabolites of Garlic in Human Breast Milk

Science.gov (United States)

Scheffler, Laura; Sauermann, Yvonne; Zeh, Gina; Hauf, Katharina; Heinlein, Anja; Sharapa, Constanze; Buettner, Andrea

2016-01-01

The odor of human breast milk after ingestion of raw garlic at food-relevant concentrations by breastfeeding mothers was investigated for the first time chemo-analytically using gas chromatography−mass spectrometry/olfactometry (GC-MS/O), as well as sensorially using a trained human sensory panel. Sensory evaluation revealed a clear garlic/cabbage-like odor that appeared in breast milk about 2.5 h after consumption of garlic. GC-MS/O analyses confirmed the occurrence of garlic-derived metabolites in breast milk, namely allyl methyl sulfide (AMS), allyl methyl sulfoxide (AMSO) and allyl methyl sulfone (AMSO2). Of these, only AMS had a garlic-like odor whereas the other two metabolites were odorless. This demonstrates that the odor change in human milk is not related to a direct transfer of garlic odorants, as is currently believed, but rather derives from a single metabolite. The formation of these metabolites is not fully understood, but AMSO and AMSO2 are most likely formed by the oxidation of AMS in the human body. The excretion rates of these metabolites into breast milk were strongly time-dependent with large inter-individual differences. PMID:27275838

Forkhead Box O6 (FoxO6) Depletion Attenuates Hepatic Gluconeogenesis and Protects against Fat-induced Glucose Disorder in Mice*

Science.gov (United States)

Calabuig-Navarro, Virtu; Yamauchi, Jun; Lee, Sojin; Zhang, Ting; Liu, Yun-Zi; Sadlek, Kelsey; Coudriet, Gina M.; Piganelli, Jon D.; Jiang, Chun-Lei; Miller, Rita; Lowe, Mark; Harashima, Hideyoshi; Dong, H. Henry

2015-01-01

Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice. PMID:25944898

Forkhead Box O6 (FoxO6) Depletion Attenuates Hepatic Gluconeogenesis and Protects against Fat-induced Glucose Disorder in Mice.

Science.gov (United States)

Calabuig-Navarro, Virtu; Yamauchi, Jun; Lee, Sojin; Zhang, Ting; Liu, Yun-Zi; Sadlek, Kelsey; Coudriet, Gina M; Piganelli, Jon D; Jiang, Chun-Lei; Miller, Rita; Lowe, Mark; Harashima, Hideyoshi; Dong, H Henry

2015-06-19

Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites.

Science.gov (United States)

Byeon, Ji-Yeong; Kim, Young-Hoon; Na, Han-Sung; Jang, Jong-Hwa; Kim, Se-Hyung; Lee, Yun-Jeong; Bae, Jung-Woo; Kim, In Su; Jang, Choon-Gon; Chung, Myeon-Woo; Lee, Seok-Yong

2015-11-01

To investigate the effect of the variant CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (NAT), in healthy subjects, a single oral dose of atomoxetine was administered to 62 subjects with a CYP2D6*wt/*wt (*wt = *1 or *2, n = 22), CYP2D6*wt/*10 (n = 22) or CYP2D6*10/*10 (n = 18) genotype. Plasma samples were then collected for 24 h after atomoxetine administration. The concentrations of atomoxetine and its metabolites were assayed using LC-MS/MS. For atomoxetine, the Cmax, AUC0-∞, t1/2 and CL/F showed genotype-dependent differences. The CYP2D6*10/*10 and CYP2D6*wt/*10 groups showed 1.74- and 1.15-fold higher Cmax, 3.40- and 1.33-fold higher AUC0-∞, and 69.7 and 24.6 % lower CL/F, compared to those of the CYP2D6*wt/*wt group, respectively. The Cmax and t1/2 for 4-HAT were lower and longer in the CYP2D6*10/*10 group than those in the CYP2D6*wt/*wt group, but the AUC0-∞ was not different between these groups. The Cmax, AUC0-∞ and t1/2 for NAT were profoundly greater in the CYP2D6*10/*10 group than they were in the CYP2D6*wt/*wt group. The concentration of active moieties of atomoxetine (atomoxetine + 4-HAT) in the CYP2D6*10/*10 group was 3.32-fold higher than that in the CYP2D6*wt/*wt group. The mean exposure to active moieties of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6*wt/*wt genotype. The higher systemic exposure of the active atomoxetine moieties in CYP2D6*10/*10 individuals may increase the risk of concentration-related adverse events of atomoxetine, although this has not yet been clinically confirmed.

O6-ethylguanine carcinogenic lesions in DNA: An NMR study of O6etG·C pairing in dodecanucleotide duplexes

International Nuclear Information System (INIS)

Kalnik, M.W.; Li, B.F.L.; Swann, P.F.; Patel, D.J.

1989-01-01

The pairing of O 6 etG with C located four base pairs in from either end of the self-complementary d(C1-G2-C3-O 6 etG4-A5-G6-C7-T8-C9-G10-C11-G12) duplex (designated O 6 etG·C 12-mer) has been investigated from an analysis of proton and phosphorus two-dimensional NMR experiments. The structural consequences of increasing the alkyl group size were elucidated from a comparative study of the pairing of O 6 meG4 with C9 in a related sequence (designated O 6 meG·C 12-mer). The NMR parameters for both O 6 alkG-containing dodecanucleotides are also compared with those of the control sequence containing G4·C9 base pairs (designated G·C 12-mer). The NOE cross-peaks detected in the two-dimensional NOESY spectra of the O 6 alkG·C 12-mer duplexes in H 2 O solution establish that the O 6 etG4/O 6 meG4 and C9 bases at the lesion site stack into the helix between the flanking C3·G10 and A5·T8 Watson-Crick base pairs. The observed NOEs between the amino protons of C9 and the CH 3 protons of O 6 alkG4 establish a syn orientation of the O 6 -alkyl group with respect to the N 1 of alkylated guanine. A wobble alignment of the O 6 alkG4·C9 base pair stabilized by two hydrogen bonds, one between the amino group of C9 and N 1 of O 6 alkG and the other between the amino group of O 6 alkG and N 3 of C9, is tentatively proposed on the basis of the NOEs between the amino protons of C9 at the lesion site and the imino protons of flanking Watson-Crick base pairs

Role of O6-alkylguanine-DNA alkyltransferase in the resistance of mouse spermatogenic cells to O6-alkylating agents.

Science.gov (United States)

Thompson, M J; Abdul-Rahman, S; Baker, T G; Rafferty, J A; Margison, G P; Bibby, M C

2000-07-01

The O(6)-alkylguanine-DNA alkyltransferase inactivator O(6)-benzylguanine was administered to BALB/c mice either alone or before exposure to 1,3-bis(2-chloroethyl)-1-nitrosourea to study the role of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase in the protection of the testis against anti-cancer O(6)-alkylating agents. Exposure of the mice to 1, 3-bis(2-chloroethyl)-1-nitrosourea or O(6)-benzylguanine alone did not produce any marked testicular toxicity at the times studied. Testicular O(6)-alkylguanine-DNA alkyltransferase concentrations were assayed between 0 and 240 min after O(6)-benzylguanine treatment and were shown to be > 95% depleted 15 min after treatment with O(6)-benzylguanine and remained at > 95% at all the times assayed. Histological examination, the reduction in testicular mass and the induction of spermatogenic cell apoptosis showed that this depletion significantly potentiated 1, 3-bis(2-chloroethyl)-1-nitrosourea-induced testicular damage after treatment. Major histological damage was apparent 42 days after treatment, demonstrating that the stem spermatogonia were significantly affected by the combination. These results demonstrate that O(6)-alkylguanine-DNA alkyltransferase plays a significant role in protecting the spermatogenic cells from damage caused by DNA alkylation and indicate that the observed toxicity may result from damage to stem spermatogonia.

6-Peroxo-6-zirconium crown and its hafnium analogue embedded in a triangular polyanion: [M6(O2)6(OH)6(gamma-SiW10O36)3]18- (M = Zr, Hf).

Science.gov (United States)

Bassil, Bassem S; Mal, Sib Sankar; Dickman, Michael H; Kortz, Ulrich; Oelrich, Holger; Walder, Lorenz

2008-05-28

We have synthesized and structurally characterized the unprecedented peroxo-zirconium(IV) containing [Zr6(O2)6(OH)6(gamma-SiW10O36)3]18- (1). Polyanion 1 comprises a cyclic 6-peroxo-6-zirconium core stabilized by three decatungstosilicate units. We have also prepared the isostructural hafnium(IV) analogue [Hf6(O2)6(OH)6(gamma-SiW10O36)3]18- (2). We investigated the acid/base and redox properties of 1 by UV-vis spectroscopy and electrochemistry studies. Polyanion 1 represents the first structurally characterized Zr-peroxo POM with side-on, bridging peroxo units. The simple, one-pot synthesis of 1 and 2 involving dropwise addition of aqueous hydrogen peroxide could represent a general procedure for incorporating peroxo groups into a large variety of transition metal and lanthanide containing POMs.

Metabolite Damage and Metabolite Damage Control in Plants

Energy Technology Data Exchange (ETDEWEB)

Hanson, Andrew D. [Horticultural Sciences Department and; Henry, Christopher S. [Mathematics and Computer Science Division, Argonne National Laboratory, Argonne, Illinois 60439, email:; Computation Institute, University of Chicago, Chicago, Illinois 60637; Fiehn, Oliver [Genome Center, University of California, Davis, California 95616, email:; de Crécy-Lagard, Valérie [Microbiology and Cell Science Department, University of Florida, Gainesville, Florida 32611, email: ,

2016-04-29

It is increasingly clear that (a) many metabolites undergo spontaneous or enzyme-catalyzed side reactions in vivo, (b) the damaged metabolites formed by these reactions can be harmful, and (c) organisms have biochemical systems that limit the buildup of damaged metabolites. These damage-control systems either return a damaged molecule to its pristine state (metabolite repair) or convert harmful molecules to harmless ones (damage preemption). Because all organisms share a core set of metabolites that suffer the same chemical and enzymatic damage reactions, certain damage-control systems are widely conserved across the kingdoms of life. Relatively few damage reactions and damage-control systems are well known. Uncovering new damage reactions and identifying the corresponding damaged metabolites, damage-control genes, and enzymes demands a coordinated mix of chemistry, metabolomics, cheminformatics, biochemistry, and comparative genomics. This review illustrates the above points using examples from plants, which are at least as prone to metabolite damage as other organisms.

The mercury chromates Hg6Cr2O9 and Hg6Cr2O10-Preparation and crystal structures, and thermal behaviour of Hg6Cr2O9

International Nuclear Information System (INIS)

Weil, Matthias; Stoeger, Berthold

2006-01-01

The basic mercury(I) chromate(VI), Hg 6 Cr 2 O 9 (=2Hg 2 CrO 4 .Hg 2 O), has been obtained under hydrothermal conditions (200deg. C, 5 days) in the form of orange needles as a by-product from reacting elemental mercury and K 2 Cr 2 O 7 . Hydrothermal treatment of microcrystalline Hg 6 Cr 2 O 9 in demineralised water at 200deg. C for 3 days led to crystal growth of red crystals of the basic mercury(I, II) chromate(VI), Hg 6 Cr 2 O 10 (=2Hg 2 CrO 4 .2HgO). The crystal structures were solved and refined from single crystal X-ray data sets. Hg 6 Cr 2 O 9 : space group P2 1 2 1 2 1 , Z=4, a=7.3573(12), b=8.0336(13), c=20.281(3)A, 3492 structure factors, 109 parameters, R[F 2 >2σ(F 2 )]=0.0371, wR(F 2 all)=0.0517; Hg 6 Cr 2 O 10 : space group Pca2 1 , Z=4, a=11.4745(15), b=9.4359(12), c=10.3517(14)A, 3249 structure factors, 114 parameters, R[F 2 >2σ(F 2 )]=0.0398, wR(F 2 all)=0.0625. Both crystal structures are made up of an intricate mercury-oxygen network, subdivided into single building blocks [O-Hg-Hg-O] for the mercurous compound, and [O-Hg-Hg-O] and [O-Hg-O] for the mixed-valent compound. Hg 6 Cr 2 O 9 contains three different Hg 2 2+ dumbbells, whereas Hg 6 Cr 2 O 10 contains two different Hg 2 2+ dumbbells and two Hg 2+ cations. The Hg I -Hg I distances are characteristic and range between 2.5031(15) and 2.5286(9)A. All Hg 2 2+ groups exhibit an unsymmetrical oxygen environment. The oxygen coordination of the Hg 2+ cations is nearly linear with two tightly bonded O atoms at distances around 2.07A. For both structures, the chromate(VI) anions reside in the vacancies of the Hg-O network and deviate only slightly from the ideal tetrahedral geometry with average Cr-O distances of ca. 1.66A. Upon heating at temperatures above 385deg. C, Hg 6 Cr 2 O 9 decomposes in a four-step mechanism with Cr 2 O 3 as the end-product at temperatures above 620 deg. C

2,6-Diaminopyridinium bis(4-hydroxypyridine-2,6-dicarboxylato-κ3O2,N,O6ferrate(III dihydrate

Directory of Open Access Journals (Sweden)

Andya Nemati

2008-10-01

Full Text Available The reaction of iron(II sulfate heptahydrate with the proton-transfer compound (pydaH(hypydcH (pyda = pyridine-2,6-diamine; hypydcH2 = 4-hydroxypyridine-2,6-dicarboxylic acid in an aqueous solution led to the formation of the title compound, (C5H8N3[Fe(C7H3NO52]·2H2O. The anion is a six-coordinated complex with a distorted octahedral geometry around the FeIII atom. Extensive intermolecular O—H...O, N—H...O and C—H...O hydrogen bonds, involving the complex anion, (pydaH+ counter-ion and two uncoordinated water molecules, and π–π [centroid-to-centroid distance 3.323 (11 Å] and C—O...π [O–centroid distance 3.150 (15 Å] interactions connect the various components into a supramolecular structure.

Hepatic Disposition of Gemfibrozil and Its Major Metabolite Gemfibrozil 1-O-β-Glucuronide.

Science.gov (United States)

Kimoto, Emi; Li, Rui; Scialis, Renato J; Lai, Yurong; Varma, Manthena V S

2015-11-02

Gemfibrozil (GEM), which decreases serum triglycerides and low density lipoprotein, perpetrates drug-drug interactions (DDIs) with several drugs. These DDIs are primarily attributed to the inhibition of drug transporters and metabolic enzymes, particularly cytochrome P450 (CYP) 2C8 by the major circulating metabolite gemfibrozil 1-O-β-glucuronide (GG). Here, we characterized the transporter-mediated hepatic disposition of GEM and GG using sandwich-cultured human hepatocytes (SCHH) and transporter-transfect systems. Significant active uptake was noted in SCHH for the metabolite. GG, but not GEM, showed substrate affinity to organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1. In SCHH, glucuronidation was characterized affinity constants (Km) of 7.9 and 61.4 μM, and biliary excretion of GG was observed. Furthermore, GG showed active basolateral efflux from preloaded SCHH and ATP-dependent uptake into membrane vesicles overexpressing multidrug resistance-associated protein (MRP) 2, MRP3, and MRP4. A mathematical model was developed to estimate hepatic uptake and efflux kinetics of GEM and GG based on SCHH studies. Collectively, the hepatic transporters play a key role in the disposition and thus determine the local concentrations of GEM and more so for GG, which is the predominant inhibitory species against CYP2C8 and OATP1B1.

Volatiles from the fungal microbiome of the marine sponge Callyspongia cf. flammea.

Science.gov (United States)

Barra, Lena; Barac, Paul; König, Gabriele M; Crüsemann, Max; Dickschat, Jeroen S

2017-09-13

The volatiles emitted by five fungal strains previously isolated from the marine sponge Callyspongia cf. flammea were captured with a closed-loop stripping apparatus (CLSA) and analyzed by GC-MS. Besides several widespread compounds, a series of metabolites with interesting bioactivities were found, including the quorum sensing inhibitor protoanemonin, the fungal phytotoxin 3,4-dimethylpentan-4-olide, and the insect attractant 1,2,4-trimethoxybenzene. In addition, the aromatic polyketides isotorquatone and chartabomone that are both known from Eucalyptus and a new O-desmethyl derivative were identified. The biosynthesis of isotorquatone was studied by feeding experiments with isotopically labeled precursors and its absolute configuration was determined by enantioselective synthesis of a reference compound. Bioactivity testings showed algicidal activity for some of the identified compounds, suggesting a potential ecological function in sponge defence.

Benzene metabolite levels in blood and bone marrow of B6C3F{sub 1} mice after low-level exposure

Energy Technology Data Exchange (ETDEWEB)

Bechtold, W.E.; Strunk, M.R.; Thornton-Manning, J.R. [and others

1995-12-01

Studies at the Inhalation Toxicology Research Institute (ITRI) have explored the species-specific uptake and metabolism of benzene. Results have shown that metabolism is dependent on both dose and route of administration. Of particular interest were shifts in the major metabolic pathways as a function of exposure concentration. In these studies, B6C3F{sub 1} mice were exposed to increasing levels of benzene by either gavage or inhalation. As benzene internal dose increased, the relative amounts of muconic acid and hydroquinone decreased. In contrast, the relative amount of catechol increased with increasing exposure. These results show that the relative levels of toxic metabolites are a function of exposure level. Based on these results and assuming a linear relationship between exposure concentration and levels of bone marrow metabolites, it would be difficult to detect an elevation of any phenolic metabolites above background after occupational exposures to the OSHA Permissible Exposure Limit of 1 ppm benzene.

Metabolite profiling of carbamazepine and ibuprofen in Solea senegalensis bile using high-resolution mass spectrometry.

Science.gov (United States)

Aceña, Jaume; Pérez, Sandra; Eichhorn, Peter; Solé, Montserrat; Barceló, Damià

2017-09-01

The widespread occurrence of pharmaceuticals in the aquatic environment has raised concerns about potential adverse effects on exposed wildlife. Very little is currently known on exposure levels and clearance mechanisms of drugs in marine fish. Within this context, our research was focused on the identification of main metabolic reactions, generated metabolites, and caused effects after exposure of fish to carbamazepine (CBZ) and ibuprofen (IBU). To this end, juveniles of Solea senegalensis acclimated to two temperature regimes of 15 and 20 °C for 60 days received a single intraperitoneal dose of these drugs. A control group was administered the vehicle (sunflower oil). Bile samples were analyzed by ultra-high-performance liquid chromatography-high-resolution mass spectrometry on a Q Exactive (Orbitrap) system, allowing to propose plausible identities for 11 metabolites of CBZ and 13 metabolites of IBU in fish bile. In case of CBZ metabolites originated from aromatic and benzylic hydroxylation, epoxidation, and ensuing O-glucuronidation, O-methylation of a catechol-like metabolite was also postulated. Ibuprofen, in turn, formed multiple hydroxyl metabolites, O-glucuronides, and (hydroxyl)-acyl glucuronides, in addition to several taurine conjugates. Enzymatic responses after drug exposures revealed a water temperature-dependent induction of microsomal carboxylesterases. The metabolite profiling in fish bile provides an important tool for pharmaceutical exposure assessment. Graphical abstract Studies of metabolism of carbamazepine and ibuprofen in fish.

Two structure types based on Si6O15 rings: synthesis and structural and spectroscopic characterisation of Cs1.86K1.14DySi6O15 and Cs1.6K1.4SmSi6O15

International Nuclear Information System (INIS)

Wierzbicka-Wieczorek, Maria; Goeckeritz, Martin; Kolitsch, Uwe; Lenz, Christoph; Giester, Gerald

2015-01-01

The silicate Cs 1.86 K 1.14 DySi 6 O 15 represents a mixed tetrahedral-octahedral framework structure type based on roughly circular Si 6 O 15 rings and isolated DyO 6 octahedra. The silicate Cs 1.6 K 1.4 SmSi 6 O 15 has a layered atomic arrangement built from corrugated Si 6 O 15 layers containing four-, six- and eight-membered rings. The layers are connected by isolated SmO 6 octahedra to form a mixed tetrahedral-octahedral framework. This structure shows a close structural relationship to β-K 3 NdSi 6 O 15 and a less close one to dehydrated elpidite (Na 2 ZrSi 6 O 15 ). In both structures, Cs/K atoms occupy large voids. The silicates were obtained through high-temperature flux syntheses. Their crystal structures have been determined from single-crystal X-ray diffraction data. Cs 1.86 K 1.14 DySi 6 O 15 crystallises in R32 (no. 155) with a = 13.896(2), c = 35.623(7) Aa and V = 5957.2(17) Aa 3 , whereas Cs 1.6 K 1.4 SmSi 6 O 15 crystallises in Cmca (no. 64) with a = 14.474(3), b = 14.718(3), c = 15.231(3) Aa and V = 3244.7(11) Aa 3 . The Dy 3+ and Sm 3+ cations present in the silicates cause PL emission bands in the visible yellow-to-orange spectral range. (Copyright copyright 2015 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

Degradation of 2,4,6-trinitrotoluene by P. aeruginosa and characterization of some metabolites

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Hatice Aysun Mercimek

2015-03-01

Full Text Available Degradation of 2,4,6-trinitrotoluene (TNT, a nitroaromatic explosive found in the soil and ground water, was investigated using Pseudomonas aeruginosa in in vitroexperiments. Biodegradable abilitiy of this bacteria was performed with 50 and 75 mg L−1 TNT concentrations in a defined liquid medium for 96 h time period. Treatment of TNT in supernatant samples taken at 0, 6, 12, 24, 48, 72 and 96 h from agitated vessels was followed by reverse-phase high-performance liquid chromatography (HPLC. In cultures supplemented with 50 and 75 mgL−1 TNT, after 96 h of incubation 46% and 59% reduction were detected respectively. Two metabolites as degradation intermediates with nitrite release into the medium, 2,4-dinitrotoluene (2,4-DNT and 4-aminodinitrotoluene (4-ADNT, were elucidated by thin layer chromatography (TLC and gas chromatography-mass spectrometry (GC-MS. These findings clearly indicate that Pseudomonas aeruginosa can be used in bioremediation of TNT contaminated sites.

β-Orcinol Metabolites from the Lichen Hypotrachyna revoluta

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Panagiota Papadopoulou

2007-05-01

Full Text Available Four new β-orcinol metabolites, hypotrachynic acid (1, deoxystictic acid (2, cryptostictinolide (3 and 8 ́-methylconstictic acid (4 along with the metabolites 8 ́-methylstictic acid (5, 8 ́-methylmenegazziaic acid (6, stictic acid (7, 8 ́-ethylstictic acid (8 and atranorin (9, that have been previously described, were isolated for the first time from the tissue extracts of the lichen Hypotrachyna revoluta (Flörke Hale. The structures of the new metabolites were elucidated on the basis of extensive spectroscopic analyses. Radical scavenging activity (RSA of the metabolites isolated in adequate amounts, was evaluated using luminol chemiluminescence and comparison with Trolox®.

Simultaneous Determination of 6-Mercaptopurine and its Oxidative Metabolites in Synthetic Solutions and Human Plasma using Spectrophotometric Multivariate Calibration Methods

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Mohammad-Reza Rashidi

2011-06-01

Full Text Available Introduction: 6-Mercaptopurine (6MP is an important chemotherapeutic drug in the conventional treatment of childhood acute lymphoblastic leukemia (ALL. It is catabolized to 6-thiouric acid (6TUA through 8-hydroxo-6-mercaptopurine (8OH6MP or 6-thioxanthine (6TX intermediates. Methods: High-performance liquid chromatography (HPLC is usually used to determine the contents of therapeutic drugs, metabolites and other important biomedical analytes in biological samples. In the present study, the multivariate calibration methods, partial least squares (PLS-1 and principle component regression (PCR have been developed and validated for the simultaneous determination of 6MP and its oxidative metabolites (6TUA, 8OH6MP and 6TX without analyte separation in spiked human plasma. Mixtures of 6MP, 8-8OH6MP, 6TX and 6TUA have been resolved by PLS-1 and PCR to their UV spectra. Results: Recoveries (% obtained for 6MP, 8-8OH6MP, 6TX and 6TUA were 94.5-97.5, 96.6-103.3, 95.1-96.9 and 93.4-95.8, respectively, using PLS-1 and 96.7-101.3, 96.2-98.8, 95.8-103.3 and 94.3-106.1, respectively, using PCR. The NAS (Net analyte signal concept was used to calculate multivariate analytical figures of merit such as limit of detection (LOD, selectivity and sensitivity. The limit of detections for 6MP, 8-8OH6MP, 6TX and 6TUA were calculated to be 0.734, 0.439, 0.797 and 0.482 µmol L-1, respectively, using PLS and 0.724, 0.418, 0783 and 0.535 µmol L-1, respectively, using PCR. HPLC was also applied as a validation method for simultaneous determination of these thiopurines in the synthetic solutions and human plasma. Conclusion: Combination of spectroscopic techniques and chemometric methods (PLS and PCR has provided a simple but powerful method for simultaneous analysis of multicomponent mixtures.

Do the metabolites of 6-[F-18]fluoro-L-dopa and of [F-18]fluoro-meta-L-tyrosine contribute to the F-18 accumulation in the human brain?

International Nuclear Information System (INIS)

Firnau, G.; Chirakal, R.; Nahmias, C.; Garnett, E.S.

1990-01-01

The purpose of this study was to determine if the metabolites of 6-[F-18]fluoro-L-dopa (F-dopa) and of [F-18]fluoro-meta-L-tyrosine (FmLtyr) contribute to the accumulation of fluorine-18 in the brain through unspecific retention. PET studies were conducted on a healthy human subject who was treated with both of the radiopharmaceuticals and their labelled metabolites. Results indicated that in contrast to F-dopa, the metabolite of FmLtyr does not 'contaminate' the brain with extraneous fluorine-18

Species-specific differences in the accumulation features of organohalogen contaminants and their metabolites in the blood of Japanese terrestrial mammals

International Nuclear Information System (INIS)

Mizukawa, Hazuki; Nomiyama, Kei; Nakatsu, Susumu; Yachimori, Shuuji; Hayashi, Terutake; Tashiro, Yutaka; Nagano, Yasuko; Tanabe, Shinsuke

2013-01-01

Residue levels and patterns of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), their hydroxylated metabolites (OH-PCBs, OH-PBDEs), and methoxylated PBDEs (MeO-PBDEs) in the blood of various terrestrial mammals in Japan, including cats, raccoon dogs, dogs, masked palm civets, foxes, raccoons, badgers, and mongooses were determined. Tri- through penta-chlorinated OH-PCBs were predominant in cat blood, whereas hexa- through octa-chlorinated OH-PCBs were found in other species. High proportion of BDE209 was found in all species, suggesting exposure to municipal waste and soil containing higher levels of deca-BDE products. 6OH-/MeO-BDE47 and 2′OH-/MeO-BDE68 were dominant in all terrestrial mammals. This is first report on the detection of OH-/MeO-PBDEs in the blood of terrestrial mammals. High concentrations of OH-/MeO-PBDEs were found in cats, suggesting the intake of these compounds from seafood. Cats exhibited higher accumulation and specific patterns of OH-PCBs, OH-PBDEs, and MeO-PBDEs, they may be at a high risk from these metabolites. -- Highlights: ► Analysis of organohalogen metabolites in the blood of Japanese terrestrial mammals. ► First study on analysis of OH-/MeO-PBDEs in terrestrial mammals. ► Cats showed specific residue pattern of OH-PCBs compare to other species. ► Metabolic capacities of PCBs in carnivore were higher than marine mammals. ► Marine natural occurrence OH-/MeO-PBDEs were found in terrestrial mammals. -- Cats showed specific residue pattern of OH-PCBs compare to other species and marine natural occurrence OH-/MeO-PBDEs were detected in terrestrial mammals

Structuring effects of [Ln6O(OH)8(NO3)6(H2O)12]2+ entities

International Nuclear Information System (INIS)

Guillou, O.; Daiguebonne, C.; Calvez, G.; Le Dret, F.; Car, P.-E.

2008-01-01

In order to obtain highly porous lanthanide-based coordination polymers we are currently investigating reactions between [Ln 6 O(OH) 8 (NO 3 ) 6 (H 2 O) 12 ] 2+ di-cationic hexanuclear entities and sodium salts of benzene-poly-carboxylic acids. Two new coordination polymers obtained during this study are reported here. In both cases, the hexanuclear entity has been destroyed during the reaction. However the resulting compounds are original thanks to a structuring effect of the poly-metallic complex. The first compound of chemical formula [Y 2 (C 8 H 4 O 4 ) 3 (DMF)(H 2 O)],2DMF crystallizes in the monoclinic system, space group P121/n (n o 14) with a = 16.0975(3) A, b = 14.4605(3) A, c = 17.7197(4) A, β = 92.8504(9) o and Z = 4. The second compound of chemical formula Y 2 (NO 3 ) 2 (C 10 H 2 O 8 )(DMF) 4 crystallizes in the triclinic system, space group P-1 (n o 2) with a = 7.5312(3) A, b = 9.0288(3) A, c = 13.1144(6) A, α = 92.6008(14) o , β = 94.9180(14) o , γ = 112.1824(16) o and Z = 2. Both crystal structures are 2D. Both crystal structures are described and the original structural features are highlighted and related to a potential structuring effect of the hexanuclear precursor

Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron.

OpenAIRE

Bloomer, J C; Baldwin, S J; Smith, G J; Ayrton, A D; Clarke, S E; Chenery, R J

1994-01-01

1. The metabolism of granisetron was investigated in human liver microsomes to identify the specific forms of cytochrome P450 responsible. 2. 7-hydroxy and 9'-desmethyl granisetron were identified as the major products of metabolism following incubation of granisetron with human liver microsomes. At low, clinically relevant, concentrations of granisetron the 7-hydroxy metabolite predominated. Rates of granisetron 7-hydroxylation varied over 100-fold in the human livers investigated. 3. Enzyme...

Stability of tetrachlorvinphos residues in faba beans and soya bean oil towards different processing procedures

International Nuclear Information System (INIS)

Zayed, S.M.A.D.; Farghaly, M.

1987-01-01

Cooking of contaminated faba beans did not degrade the originally present potentially toxic residues, namely, tetrachlorvinphos and its desmethyl derivative to any appreciable extent. Processing of contaminated soya bean oil, on the other hand, led to degradation of tetrachlorvinphos and its metabolites to give mono and dimethyl phosphates. Feeding of mice with bound residues of tetrachlorvinphos in beans for 90 days led to an apparent decrease in the rate of body weight gain. (author)

Carbon allocation to major metabolites in illuminated leaves is not just proportional to photosynthesis when gaseous conditions (CO2 and O2 ) vary.

Science.gov (United States)

Abadie, Cyril; Bathellier, Camille; Tcherkez, Guillaume

2018-04-01

In gas-exchange experiments, manipulating CO 2 and O 2 is commonly used to change the balance between carboxylation and oxygenation. Downstream metabolism (utilization of photosynthetic and photorespiratory products) may also be affected by gaseous conditions but this is not well documented. Here, we took advantage of sunflower as a model species, which accumulates chlorogenate in addition to sugars and amino acids (glutamate, alanine, glycine and serine). We performed isotopic labelling with 13 CO 2 under different CO 2 /O 2 conditions, and determined 13 C contents to compute 13 C-allocation patterns and build-up rates. The 13 C content in major metabolites was not found to be a constant proportion of net fixed carbon but, rather, changed dramatically with CO 2 and O 2 . Alanine typically accumulated at low O 2 (hypoxic response) while photorespiratory intermediates accumulated under ambient conditions and at high photorespiration, glycerate accumulation exceeding serine and glycine build-up. Chlorogenate synthesis was relatively more important under normal conditions and at high CO 2 and its synthesis was driven by phosphoenolpyruvate de novo synthesis. These findings demonstrate that carbon allocation to metabolites other than photosynthetic end products is affected by gaseous conditions and therefore the photosynthetic yield of net nitrogen assimilation varies, being minimal at high CO 2 and maximal at high O 2 . © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

Ground and excited states of the [Fe(H2O)6]2+ and [Fe(H2O)6]3+ clusters: Insight into the electronic structure of the [Fe(H2O)6]2+ – [Fe(H2O)6]3+ complex

Energy Technology Data Exchange (ETDEWEB)

Miliordos, Evangelos; Xantheas, Sotiris S.

2015-04-14

We report the ground and low lying electronically excited states of the [Fe(H2O)6]2+ and [Fe(H2O)6]3+ clusters using multi-configuration electronic structure theory. In particular, we have constructed the Potential Energy Curves (PECs) with respect to the iron-oxygen distance when removing all water ligands at the same time from the cluster minima and established their correlation to the long range dissociation channels. Due to the fact that both the second and third ionization potentials of iron are larger than the one for water, the ground state products asymptotically correlate with dissociation channels that are repulsive in nature at large separations as they contain at least one H2O+ fragment and a positive metal center. The most stable equilibrium structures emanate – via intersections and/or avoided crossings – from the channels consisting of the lowest electronic states of Fe2+(5D; 3d6) or Fe3+(6S; 3d5) and six neutral water molecules. Upon hydration, the ground state of Fe2+(H2O)6 is a triply (5Tg) degenerate one with the doubly (5Eg) degenerate state lying slightly higher in energy. Similarly, Fe3+(H2O)6 has a ground state of 6Ag symmetry under Th symmetry. We furthermore examine a multitude of electronically excited states of many possible spin multiplicities, and report the optimized geometries for several selected states. The PECs for those cases are characterized by a high density of states. Focusing on the ground and the first few excited states of the [Fe(H2O)6]2+ and [Fe(H2O)6]3+ clusters, we studied their mutual interaction in the gas phase. We obtained the optimal geometries of the Fe2+(H2O)6 – Fe3+(H2O)6 gas phase complex for different Fe–Fe distances. For distances shorter than 6.0 Å, the water molecules in the respective first solvation shells located between the two metal centers were found to interact via weak hydrogen bonds. We examined a total of ten electronic states for this complex, including those corresponding to the

Method for simultaneous imaging of endogenous low molecular weight metabolites in mouse brain using TiO2 nanoparticles in nanoparticle-assisted laser desorption/ionization-imaging mass spectrometry.

Science.gov (United States)

Shrivas, Kamlesh; Hayasaka, Takahiro; Sugiura, Yuki; Setou, Mitsutoshi

2011-10-01

We report the detection of a group of endogenous low molecular weight metabolites (LMWM) in mouse brain (80-500 Da) using TiO(2) nanoparticles (NPs) in nanoparticle-assisted laser desorption/ionization-imaging mass spectrometry (Nano-PALDI-IMS) without any washing and separation step prior to MS analysis. The identification of metabolites using TiO(2) NPs was compared with a conventional organic matrix 2,5-dihydroxybenzoic acid (DHB) where signals of 179 molecules were specific to TiO(2) NPs, 4 were specific to DHB, and 21 were common to both TiO(2) NPs and DHB. The use of TiO(2) NPs enabled the detection of a higher number of LMWM as compared to DHB and gold NPs as a matrix. This approach is a simple, inexpensive, washing, and separation free for imaging and identification of LMWM in mouse brain. We believe that the biochemical information from distinct regions of the brain using a Nano-PALDI-IMS will be helpful in elucidating the imbalances linked with diseases in biomedical samples.

Ruta graveolens Extracts and Metabolites against Spodoptera frugiperda.

Science.gov (United States)

Ayil-Gutiérrez, Benjamin A; Villegas-Mendoza, Jesús M; Santes-Hernndez, Zuridai; Paz-González, Alma D; Mireles-Martínez, Maribel; Rosas-García, Ninfa M; Rivera, Gildardo

2015-11-01

The biological activity of Ruta graveolens leaf tissue extracts obtained with different solvents (ethyl acetate, ethanol, and water) and metabolites (psoralen, 2- undecanone and rutin) against Spodoptera frugiperda was evaluated. Metabolites levels in extracts were quantified by HPLC and GC. Ethyl acetate and ethanol extracts showed 94% and 78% mortality, respectively. Additionally, psoralen metabolite showed a high mortality as cypermethrin. Metabolite quantification in extracts shows the presence of 2-undecanone (87.9 µmoles mg(-1) DW), psoralen (3.6 µmoles mg(-1) DW) and rutin (0.001 pmoles mg(-1) DW). We suggest that these concentrations of 2-undecanone and psoralen in R. graveolens leaf tissue extracts could be responsible for S. frugiperda mortality.

Immunological detection of O6-methylguanine in alkylated DNA

International Nuclear Information System (INIS)

Briscoe, W.T.; Spizizen, J.; Tan, E.M.

1978-01-01

Antibodies to O 6 -methyldeoxyguanosine were produced in rabbits and utilized in a radioimmunoassay to detect this nucleoside at picomole levels. The specificity of the antibodies was demonstrated by the use of nucleoside analogues as inhibitors in the radioimmunoassay. The antibodies cross-reacted with O 6 -methylguanosine, O 6 -methylguanine, and O 6 -ethylguanosine. There was 10 4 to 10 6 times less sensitivity to inhibition by deoxyadenosine, deoxyguanosine, and guanosine than by O 6 -methyldeoxyguanosine. The radioimmunoassay also detected O 6 -methylguanine in DNA alkylated by agents known to produce O 6 -methylguanine, such as N'-methyl-N-nitrosourea. DNA alkylated with dimethyl sulfate, which does not produce O 6 -methylguanine in DNA, cross-reacted with the antibodies to a very limited extent. Such an assay system for modified nucleic acid components would be very useful in following the production, persistence, and repair of these lesions in a variety of cells and tissues treated with a broad spectrum of carcinogens and suspected carcinogens

Synthesis of carbon-11-labeled 5-HT6R antagonists as new candidate PET radioligands for imaging of Alzheimer's disease.

Science.gov (United States)

Wang, Xiaohong; Dong, Fugui; Miao, Caihong; Li, Wei; Wang, Min; Gao, Mingzhang; Zheng, Qi-Huang; Xu, Zhidong

2018-06-01

Carbon-11-labeled serotonin (5-hydroxytryptamine) 6 receptor (5-HT 6 R) antagonists, 1-[(2-bromophenyl)sulfonyl]-5-[ 11 C]methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole (O-[ 11 C]2a) and 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-[ 11 C]methyl-1-piperazinyl)methyl]-1H-indole (N-[ 11 C]2a), 5-[ 11 C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (O-[ 11 C]2b) and 5-methoxy-3-((4-[ 11 C]methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (N-[ 11 C]2b), 1-((4-isopropylphenyl)sulfonyl)-5-[ 11 C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[ 11 C]2c) and 1-((4-isopropylphenyl)sulfonyl)-5-methoxy-3-((4-[ 11 C]methylpiperazin-1-yl)methyl)-1H-indole (N-[ 11 C]2c), 1-((4-fluorophenyl)sulfonyl)-5-[ 11 C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[ 11 C]2d) and 1-((4-fluorophenyl)sulfonyl)-5-methoxy-3-((4-[ 11 C]methylpiperazin-1-yl)methyl)-1H-indole (N-[ 11 C]2d), were prepared from their O- or N-desmethylated precursors with [ 11 C]CH 3 OTf through O- or N-[ 11 C]methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370-740 GBq/μmol with a total synthesis time of ∼40-min from EOB. Copyright © 2018 Elsevier Ltd. All rights reserved.

ISOTOPE-DILUTION AMMONIA CHEMICAL-IONIZATION MASS FRAGMENTOGRAPHIC ANALYSIS OF URINARY 3-O-METHYLATED CATECHOLAMINE METABOLITES - RAPID SAMPLE CLEANUP BY DERIVATIZATION AND EXTRACTION OF LYOPHILIZED SAMPLES

NARCIS (Netherlands)

KEMA, IP; MEIBORG, G; NAGEL, GT; STOB, GJ; MUSKIET, FAJ

1993-01-01

We developed a method for simultaneous quantification of the urinary 3-O-methylated catecholamine metabolites 3-methoxytyramine, normetanephrine and metanephrine by stable isotope-dilution ammonia chemical ionization mass fragmentography. Prepurification of lyophilized samples was done by

Secondary metabolites from the endophytic fungus Talaromyces pinophilus.

Science.gov (United States)

Vinale, F; Nicoletti, R; Lacatena, F; Marra, R; Sacco, A; Lombardi, N; d'Errico, G; Digilio, M C; Lorito, M; Woo, S L

2017-08-01

Endophytic fungi have a great influence on plant health and growth, and are an important source of bioactive natural compounds. Organic extracts obtained from the culture filtrate of an endophytic strain of Talaromyces pinophilus isolated from strawberry tree (Arbutus unedo) were studied. Metabolomic analysis revealed the presence of three bioactive metabolites, the siderophore ferrirubin, the platelet-aggregation inhibitor herquline B and the antibiotic 3-O-methylfunicone. The latter was the major metabolite produced by this strain and displayed toxic effects against the pea aphid Acyrthosiphon pisum (Homoptera Aphidiidae). This toxicity represents an additional indication that the widespread endophytic occurrence of T. pinophilus may be related to a possible role in defensive mutualism. Moreover, the toxic activity on aphids could promote further study on 3-O-methylfunicone, or its derivatives, as an alternative to synthetic chemicals in agriculture.

Metabolism of metofluthrin in rats: I. Identification of metabolites.

Science.gov (United States)

Abe, Jun; Nagahori, Hirohisa; Tarui, Hirokazu; Tomigahara, Yoshitaka; Isobe, Naohiko

2018-02-01

1. Metofluthrin (2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (Z/E)-(1R)-trans-2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate) is a novel pyrethroid insecticide, which has E/Z isomers at prop-1-enyl group. 2. Rats were orally dosed with each [ 14 C]-labelled E/Z isomer, and the excreta were collected for isolation and identification of metabolites. Analysis of the excreta by LC/MS and NMR revealed formation of 33 and 23 (total 42) metabolites from rats dosed with Z-isomer and E-isomer, respectively. 3. Major metabolic reactions were cleavage of ester linkage, O-demethylation, hydroxylation, epoxidation or reduction of double bond, glutathione conjugation and its further metabolism, hydroxylation of epoxide and formation of lactone ring. Notably, the acid side, 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylic acid, was much more variously metabolised compared to chrysanthemic acid, the acid side of the known pyrethroids. 4. Major metabolites for Z-isomer mostly retained ester linkage with 1,2-dihydroxypropyl group and/or 2-methylalcohol of cyclopropane ring, while most of those for E-isomer received hydrolysis of the ester linkage without oxidation at the 1-propenyl group or the gem-methyl groups, suggesting epoxidation and hydroxylation could occur more easily on Z-isomer. 5. As the novel metabolic pathways for pyrethroids, isomerisation of ω-carboxylic acid moiety, reduction or hydration of double bond and cleavage of cyclopropane ring via epoxidation were suggested.

Single Crystal Growth of Multiferroic Double Perovskites: Yb2CoMnO6 and Lu2CoMnO6

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Hwan Young Choi

2017-02-01

Full Text Available We report on the growth of multiferroic Yb2CoMnO6 and Lu2CoMnO6 single crystals which were synthesized by the flux method with Bi2O3. Yb2CoMnO6 and Lu2CoMnO6 crystallize in a double-perovskite structure with a monoclinic P21/n space group. Bulk magnetization measurements of both specimens revealed strong magnetic anisotropy and metamagnetic transitions. We observed a dielectric anomaly perpendicular to the c axis. The strongly coupled magnetic and dielectric states resulted in the variation of both the dielectric constant and the magnetization by applying magnetic fields, offering an efficient approach to accomplish intrinsically coupled functionality in multiferroics.

Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids.

Science.gov (United States)

Bautista-Aguilera, Oscar M; Esteban, Gerard; Chioua, Mourad; Nikolic, Katarina; Agbaba, Danica; Moraleda, Ignacio; Iriepa, Isabel; Soriano, Elena; Samadi, Abdelouahid; Unzeta, Mercedes; Marco-Contelles, José

2014-01-01

The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer's disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700±2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950±940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13-15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective h

Metabolites inhibiting germination of Orobanche ramosa seeds produced by Myrothecium verrucaria and Fusarium compactum.

Science.gov (United States)

Andolfi, Anna; Boari, Angela; Evidente, Antonio; Vurro, Maurizio

2005-03-09

Myrothecium verrucaria and Fusarium compactum were isolated from diseased Orobanche ramosa plants collected in southern Italy to find potential biocontrol agents of this parasitic weed. Both fungi grown in liquid culture produced metabolites that inhibited the germination of O. ramosa seeds at 1-10 muM. Eight metabolites were isolated from M. verrucaria culture extracts. The main metabolite was identified as verrucarin E, a disubstituted pyrrole not belonging to the trichothecene group. Seven compounds were identified by spectroscopic methods as macrocyclic trichothecenes, namely, verrucarins A, B, M, and L acetate, roridin A, isotrichoverrin B, and trichoverrol B. The main metabolite produced by F. compactum was neosoloaniol monoacetate, a trichothecene. All the trichothecenes proved to be potent inhibitors of O. ramosa seed germination and possess strong zootoxic activity when assayed on Artemia salina brine shrimps. Verrucarin E is inactive on both seed germination and zootoxic assay.

Secondary metabolites from Sida rhombifolia L. (Malvaceae) and the vasorelaxant activity of cryptolepinone.

Science.gov (United States)

Chaves, Otemberg Souza; Gomes, Roosevelt Albuquerque; Tomaz, Anna Cláudia de Andrade; Fernandes, Marianne Guedes; das Graças Mendes, Leônidas; de Fátima Agra, Maria; Braga, Valdir Andrade; de Fátima Vanderlei de Souza, Maria

2013-03-01

The phytochemical study of Sida rhombifolia L. (Malvaceae) led to the isolation through chromatographic techniques of eleven secondary metabolites: sitosterol (1a) and stigmasterol (1b), sitosterol-3-O-b-D-glucopyranoside (2a) and stigmasterol-3-O-b-D-glucopyranoside (2b), phaeophytin A (3), 17³-ethoxypheophorbide A (4), 13²-hydroxy phaeophytin B (5), 17³-ethoxypheophorbide B (6), 5,7-dihydroxy-4'-methoxyflavone (7), cryptolepinone (8) and a salt of cryptolepine (9). Their structures were identified by ¹H- and ¹³C-NMR using one- and two-dimensional techniques. In addition, the vasorelaxant activity of cryptolepinone in rat mesenteric artery rings is reported herein for the first time.

Secondary Metabolites from Sida rhombifolia L. (Malvaceae and the Vasorelaxant Activity of Cryptolepinone

Directory of Open Access Journals (Sweden)

Maria de Fátima Vanderlei de Souza

2013-03-01

Full Text Available The phytochemical study of Sida rhombifolia L. (Malvaceae led to the isolation through chromatographic techniques of eleven secondary metabolites: sitosterol (1a and stigmasterol (1b, sitosterol-3-O-b-D-glucopyranoside (2a and stigmasterol-3-O-b-D-glucopyranoside (2b, phaeophytin A (3, 173-ethoxypheophorbide A (4, 132-hydroxy phaeophytin B (5, 173-ethoxypheophorbide B (6, 5,7-dihydroxy-4'-methoxyflavone (7, cryptolepinone (8 and a salt of cryptolepine (9. Their structures were identified by 1H- and 13C-NMR using one- and two-dimensional techniques. In addition, the vasorelaxant activity of cryptolepinone in rat mesenteric artery rings is reported herein for the first time.

Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

Directory of Open Access Journals (Sweden)

Bautista-Aguilera OM

2014-10-01

Full Text Available Oscar M Bautista-Aguilera,1,* Gerard Esteban,2,* Mourad Chioua,1 Katarina Nikolic,3 Danica Agbaba,3 Ignacio Moraleda,4 Isabel Iriepa,4 Elena Soriano,5 Abdelouahid Samadi,1 Mercedes Unzeta,2 José Marco-Contelles1 1Laboratory of Medicinal Chemistry (Institute of General Organic Chemistry [IQOG], National Research Council [CSIC], Madrid, Spain; 2Department of Biochemistry and Molecular Biology, Institute of Neurosciences, Autonomous Barcelona University, Barcelona, Spain; 3Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia; 4Department of Organic Chemistry, Faculty of Pharmacy, University of Alcalá, Ctra Barcelona, Alcalá de Henares, Spain; 5Synthesis, and Structure of Organic Compounds (SEPCO (IQOG, CSIC, Madrid, Spain *These authors have equally contributed to this work Abstract: The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs as multipotent cholinesterase (ChE and monoamine oxidase (MAO inhibitors for the potential treatment of Alzheimer’s disease (AD is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE, and butyrylcholinesterase (BuChE enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (­Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE. Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for h

Tratamento da doença de Alzheimer: avaliação crítica sobre o uso de anticolinesterásicos Update on anticholinesterase treatment of Alzheimer's disease

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OSVALDO P. ALMEIDA

1998-09-01

Full Text Available A demência do tipo Alzheimer (DA é uma doença degenerativa que há até pouco tempo não tinha nenhum tratamento eficaz. Pesquisas realizadas a partir da década de 70 revelaram que os sistemas cerebrais que utilizam acetilcolina encontram-se gravemente comprometidos nesses pacientes, o que serviu de base para a introdução da terapêutica de base colinérgica da doença. Os inibidores da acetilcolinesterase foram os primeiros medicamentos que demonstraram ser úteis para o tratamento da DA em ensaios clínicos controlados contra placebo. Este artigo revê os principais estudos desenhados para investigar a eficácia e efeitos adversos da tacrina, donepezil, rivastigmina, e metrifonato em pacientes com DA. Discutem-se, ainda, os fatores que podem interferir na resposta do paciente ao tratamento com anticolinesterásicos, bem como as limitações inerentes a esse tipo de abordagem terapêutica.Alzheimer's disease (AD is a neurogenerative disorder that had no effective treatment until a few years ago. Many studies published during the past 20 years showed that the disease is associated with the disruption of brain systems that use acetilcholine. These findings shaped the development of the cholinergic treatment strategies for AD. The cholinesterase inhibitors were the first class of drugs to show positive results in double-blind placebo controlled studies for the treatment of AD. This paper reviews efficacy and safety studies of tacrine, donepezil, rivastigmine, and metrifonate in patients with AD. Factors that may interfere with patients' response to treatment are also discussed, as well as the limitations associated with the use of this class of drugs.

Structure of Ga2O3(ZnO)6: a member of the homologous series Ga2O3(ZnO)m

International Nuclear Information System (INIS)

Michiue, Yuichi; Kanke, Yasushi; Kimizuka, Noboru

2008-01-01

The structure of Ga 2 O 3 (ZnO) 6 was determined using singlecrystal X-ray diffraction techniques in the space group Cmcm. The metal ion sublattice resembles some of the Zn ions in the wurtzite ZnO structure. The oxygen ion sublattice in Ga 2 O 3 (ZnO) 6 also resembles some of the O ions in ZnO. Structural relationships between Ga 2 O 3 (ZnO) 6 and ZnO are discussed, illustrating the process for obtaining the centrosymmetric Ga 2 O 3 (ZnO) 6 structure from the noncentrosymmetric ZnO. Structures of phases in the homologous series Ga 2 O 3 (ZnO) m are predicted on the basis of the structural data for Ga 2 O 3 (ZnO) 6 . The structures of even m are constructed by simply extending the structure units seen in Ga 2 O 3 (ZnO) 6 , while those of odd m consist of structure units which are of different types from those used for even m. (orig.)

Impacts of rising tropospheric ozone on photosynthesis and metabolite levels on field grown soybean.

Science.gov (United States)

Sun, Jindong; Feng, Zhaozhong; Ort, Donald R

2014-09-01

The response of leaf photosynthesis and metabolite profiles to ozone (O3) exposure ranging from 37 to 116 ppb was investigated in two soybean cultivars Dwight and IA3010 in the field under fully open-air conditions. Leaf photosynthesis, total non-structural carbohydrates (TNC) and total free amino acids (TAA) decreased linearly with increasing O3 levels in both cultivars with average decrease of 7% for an increase in O3 levels by 10 ppb. Ozone interacted with developmental stages and leaf ages, and caused higher damage at later reproductive stages and in older leaves. Ozone affected yield mainly via reduction of maximum rate of Rubisco carboxylation (Vcmax) and maximum rates of electron transport (Jmax) as well as a shorter growing season due to earlier onset of canopy senescence. For all parameters investigated the critical O3 levels (∼50 ppb) for detectable damage fell within O3 levels that occur routinely in soybean fields across the US and elsewhere in the world. Strong correlations were observed in O3-induced changes among yield, photosynthesis, TNC, TAA and many metabolites. The broad range of metabolites that showed O3 dose dependent effect is consistent with multiple interaction loci and thus multiple targets for improving the tolerance of soybean to O3. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A non-radioactive assay for precise determination of intracellular levels of imatinib and its main metabolite in Bcr-Abl positive cells

Czech Academy of Sciences Publication Activity Database

Mlejnek, P.; Novák, Ondřej; Doležel, P.

2011-01-01

Roč. 83, č. 5 (2011), s. 1466-1471 ISSN 0039-9140 R&D Projects: GA ČR GA301/08/1649 Institutional research plan: CEZ:AV0Z50380511 Keywords : K562 cells * P-glycoprotein * Multidrug resistance * N-desmethyl imatinib * CGP 74588 Subject RIV: EF - Botanics Impact factor: 3.794, year: 2011

Comparative study of potentially J{sub eff} = 0 ground state iridium(V) in SrLaNiIrO{sub 6}, SrLaMgIrO{sub 6}, and SrLaZnIrO{sub 6}

Energy Technology Data Exchange (ETDEWEB)

Wolff, Klaus K.; Agrestini, Stefano; Tjeng, Liu Hao [Max Planck Institute for Chemical Physics of Solids, Dresden (Germany); Tanaka, Arata [Department of Quantum Matter, AdSM, Hiroshima University, Higashi-Hiroshima (Japan); Jansen, Martin [Max Planck Institute for Chemical Physics of Solids, Dresden (Germany); Max Planck Institute for Solid State Research, Stuttgart (Germany)

2017-12-13

A series of polycrystalline double perovskites SrLaBIrO{sub 6} (B = Ni, Mg, Zn) containing Ir{sup 5+} (5d{sup 4}) was synthesized by solid state reactions, and structural, magnetic and electronic properties were investigated. The isotypic fully ordered double perovskites crystallize in space group P2{sub 1}/n and show semiconducting behavior with estimated bandgaps of approximately 0.2 eV for SrLaNiIrO{sub 6} and SrLaZnIrO{sub 6}, and 0.4 eV for SrLaMgIrO{sub 6}. SrLaNiIrO{sub 6} is an antiferromagnet with a Neel temperature of 74 K (μ{sub eff} = 3.3 μ{sub B}, θ{sub W} = -90 K), whereas SrLaMgIrO{sub 6} and SrLaZnIrO{sub 6} are weakly paramagnetic. All title compounds exhibit a temperature-independent contribution to the measured magnetic susceptibility, which supports the notion for a van-Vleck-type response originating from the Ir{sup 5+} (5d{sup 4}, J{sub eff} = 0) ions. (copyright 2017 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

A novel HPLC-MS/MS method for the simultaneous determination of astemizole and its major metabolite in dog or monkey plasma and application to pharmacokinetics.

Science.gov (United States)

Back, Hyun-moon; Lee, Jong-Hwa; Chae, Jung-woo; Song, Byungjeong; Seo, Joung-Wook; Yun, Hwi-yeol; Kwon, Kwang-il

2015-10-10

Astemizole (AST), a second-generation antihistamine, is metabolized to desmethyl astemizole (DEA), and although it has been removed from the market for inducing QT interval prolongation, it has reemerged as a potential anticancer and antimalarial agent. This report describes a novel high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneously determining the concentrations of AST and DEA in beagle dog and cynomolgus monkey plasma with simple preparation method and short retention time. Prior to HPLC analyses, the plasma samples were extracted with simple liquid-liquid extraction method. The isocratic mobile phase was 0.025% trifluoroacetic acid (TFA dissolved in acetonitrile) and 20 mM ammonium acetate (94:6) at a flow rate of 0.25 mL/min and diphenhydramine used as internal standard. In MS/MS analyses, precursor ions of the analytes were optimized as protonated molecular ions: [M+H](+). The lower limit of quantification of astemizole was 2.5 ng/mL in both species and desmethyl astemizole were 7.5 ng/mL and 10 ng/mL in dog and monkey plasma, respectively. The accuracy, precision, and stability of the method were in accordance with FDA guidelines for the validation of bioanalytical methods. Finally this validated method was successfully applied to a pharmacokinetic study in dogs and monkeys after oral administration of 10 mg/kg AST. Copyright © 2015 Elsevier B.V. All rights reserved.

Radioimmunoassay for metabolites of 9,3''-diacetylmidecamycin, a macrolide antibiotic

International Nuclear Information System (INIS)

Shimada, N.; Ueda, T.; Yokoshima, T.; Umemura, K.; Shomura, T.

1982-01-01

A radioimmunoassay system has been developed for the measurement of two major metabolites of 9,3''-diacetylmidecamycin, Mb-6 and Mb-12. A radioimmunoassay for Mb-6 was performed by using anti-Mb-6 serum and a [ 125 I]tyramined Mb-6 derivative as a radiolabeled antigen. The labeled antigen was prepared by the chloramine T method. The antiserum was obtained from a rabbit immunized with Mb-6 conjugated to bovine serum albumin. The obtained antiserum was cross-reactive with two other metabolites of 9,3''-diacetylmidecamycin, Mb-2 and Mb-12, in addition to Mb-6. This Mb-6 radioimmunoassay system could detect Mb-6 concentrations as low as 100 pg/ml of serum. The coefficients of variation were 4.5% (intra-assay) and 5.1% (inter-assay). A radioimmunoassay for Mb-12, using anti-midecamycin serum and a [ 125 I]tyramined-Mb-12 derivative, has also been developed. The antiserum was cross-reactive only with Mb-12 among the 9,3''-diacetylmidecamycin metabolites. This Mb-12 radioimmunoassay system could detect Mb-12 concentrations as low as 2 ng/ml. The intra- and inter-assay variances were 5.9 and 5.8%, respectively

Influence of O-methylated metabolite penetrating the blood-brain barrier to estimation of dopamine synthesis capacity in human L-[β-(11)C]DOPA PET.

Science.gov (United States)

Matsubara, Keisuke; Ikoma, Yoko; Okada, Maki; Ibaraki, Masanobu; Suhara, Tetsuya; Kinoshita, Toshibumi; Ito, Hiroshi

2014-02-01

O-methyl metabolite (L-[β-(11)C]OMD) of (11)C-labeled L-3,4-dihydroxyphenylalanine (L-[β-(11)C]DOPA) can penetrate into brain tissue through the blood-brain barrier, and can complicate the estimation of dopamine synthesis capacity by positron emission tomography (PET) study with L-[β-(11)C]DOPA. We evaluated the impact of L-[β-(11)C]OMD on the estimation of the dopamine synthesis capacity in a human L-[β-(11)C]DOPA PET study. The metabolite correction with mathematical modeling of L-[β-(11)C]OMD kinetics in a reference region without decarboxylation and further metabolism, proposed by a previous [(18)F]FDOPA PET study, were implemented to estimate radioactivity of tissue L-[β-(11)C]OMD in 10 normal volunteers. The component of L-[β-(11)C]OMD in tissue time-activity curves (TACs) in 10 regions were subtracted by the estimated radioactivity of L-[β-(11)C]OMD. To evaluate the influence of omitting blood sampling and metabolite correction, relative dopamine synthesis rate (kref) was estimated by Gjedde-Patlak analysis with reference tissue input function, as well as the net dopamine synthesis rate (Ki) by Gjedde-Patlak analysis with the arterial input function and TAC without and with metabolite correction. Overestimation of Ki was observed without metabolite correction. However, the kref and Ki with metabolite correction were significantly correlated. These data suggest that the influence of L-[β-(11)C]OMD is minimal for the estimation of kref as dopamine synthesis capacity.

2,2′,3,5′,6-PENTACHLOROBIPHENYL (PCB 95) AND ITS HYDROXYLATED METABOLITES ARE ENANTIOMERICALLY ENRICHED IN FEMALE MICE

Science.gov (United States)

Kania-Korwel, Izabela; Barnhart, Christopher D.; Stamou, Marianna; Truong, Kim M.; El-Komy, Mohammed H.M.E.; Lein, Pamela J.; Veng-Pedersen, Peter; Lehmler, Hans-Joachim

2012-01-01

Epidemiological and laboratory studies link polychlorinated biphenyls and their metabolites to adverse neurodevelopmental outcomes. Several neurotoxic PCB congeners are chiral and undergo enantiomeric enrichment in mammalian species, which may modulate PCB developmental neurotoxicity. This study measures levels and enantiomeric enrichment of PCB 95 and its hydroxylated metabolites (OH-PCBs) in adult female C57Bl/6 mice following subchronic exposure to racemic PCB 95. Tissue levels of PCB 95 and OH-PCBs increased with increasing dose. Dose-dependent enantiomeric enrichment of PCB 95 was observed in brain and other tissues. OH-PCBs also displayed enantiomeric enrichment in blood and liver, but were not detected in adipose and brain. In light of data suggesting enantioselective effects of chiral PCBs on molecular targets linked to PCB developmental neurotoxicity, our observations highlight the importance of accounting for PCB and OH-PCB enantiomeric enrichment in the assessment of PCB developmental neurotoxicity. PMID:22974126

Preparation of human drug metabolites using fungal peroxygenases

Science.gov (United States)

Marzena Poraj-Kobielska; Matthias Kinne; René Ullrich; Katrin Scheibner; Gernot Kayser; Kenneth E. Hammel; Martin Hofrichter

2011-01-01

The synthesis of hydroxylated and O- or N-dealkylated human drug metabolites (HDMs) via selective monooxygenation remains a challenging task for synthetic organic chemists. Here we report that aromatic peroxygenases (APOs; EC 1.11.2.1) secreted by the agaric fungi Agrocybe aegerita and Coprinellus...

Differentiation-Dependent Energy Production and Metabolite Utilization: A Comparative Study on Neural Stem Cells, Neurons, and Astrocytes

Science.gov (United States)

Jády, Attila Gy.; Nagy, Ádám M.; Kőhidi, Tímea; Ferenczi, Szilamér; Tretter, László

2016-01-01

While it is evident that the metabolic machinery of stem cells should be fairly different from that of differentiated neurons, the basic energy production pathways in neural stem cells (NSCs) or in neurons are far from clear. Using the model of in vitro neuron production by NE-4C NSCs, this study focused on the metabolic changes taking place during the in vitro neuronal differentiation. O2 consumption, H+ production, and metabolic responses to single metabolites were measured in cultures of NSCs and in their neuronal derivatives, as well as in primary neuronal and astroglial cultures. In metabolite-free solutions, NSCs consumed little O2 and displayed a higher level of mitochondrial proton leak than neurons. In stem cells, glycolysis was the main source of energy for the survival of a 2.5-h period of metabolite deprivation. In contrast, stem cell-derived or primary neurons sustained a high-level oxidative phosphorylation during metabolite deprivation, indicating the consumption of own cellular material for energy production. The stem cells increased O2 consumption and mitochondrial ATP production in response to single metabolites (with the exception of glucose), showing rapid adaptation of the metabolic machinery to the available resources. In contrast, single metabolites did not increase the O2 consumption of neurons or astrocytes. In “starving” neurons, neither lactate nor pyruvate was utilized for mitochondrial ATP production. Gene expression studies also suggested that aerobic glycolysis and rapid metabolic adaptation characterize the NE-4C NSCs, while autophagy and alternative glucose utilization play important roles in the metabolism of stem cell-derived neurons. PMID:27116891

The oxygen-centered radicals scavenging activity of sulfasalazine and its metabolites. A direct protection of the bowel.

Science.gov (United States)

Prónai, L; Yukinobu, I; Láng, I; Fehér, J

1992-01-01

Oxygen-centered radicals, such as superoxide (O2-) and hydroxyl radicals (.OH) generated by phagocytes have been suggested to be involved in the pathogenesis of chronic inflammations of the bowel, such as Crohn's disease and colitis ulcerosa. Recently, sulfasalazine (SASP) and its metabolites have been reported to exert their effects as a direct scavenger of oxygen-centered radicals in the bowel. To scavenge oxygen-centered radicals in vivo, however, SASP and its metabolites have to react with O2- and/or .OH in vitro very rapidly, furthermore they have to reach an appropriate (possible millimolar) concentration range at the site of inflammation. To test this possibility, we investigated the direct O2- and .OH scavenging activity of SASP and its metabolites using the specific electron paramagnetic resonance/spin trapping method, and we compared the 50% inhibition rates of SASP and its metabolites with their known concentrations in the bowel and in the human plasma. It was found that SASP and its metabolites, such as 5-amino-salicylic acid (5-ASA), and acetyl-5-amino-salicylic acid (AC-5-ASA), but not sulfapyridine (SP) and acetyl-sulfapyridine (Ac-SP) have a direct O2- and .OH scavenging activity in vitro systems. Among the compounds, SASP and 5-ASA can reach a concentration which is appropriate to scavenge oxygen-centered radicals in the bowel but not in the human plasma. It was concluded that the in vivo antiinflammatory effects of SASP and its metabolites are, at least partly, due to the direct oxygen-centered scavenging activity of these drugs.

The synthesis of [O-methyl-{sup 11}C]venlafaxine: a non-classical, fast-acting antidepressant

Energy Technology Data Exchange (ETDEWEB)

Gee, A.D.; Gjedde, A. [Aarhus Univ. Hospital, PET Center, Aarhus (Denmark); Smith, D.F. [Aarhus Univ. Psychiatric Hospital, Inst. for Biological Psychiatry, Risskov (Denmark)

1997-01-01

As part of our program to develop PET tracers for the 5-HT reuptake site, venlafaxine, a non-classical, fast-acting antidepressant, was selected as a candidate for labelling with {sup 11}C for in vivo evaluation. [O-methyl-{sup 11}C]venlafaxine was produced by the alkylation of O-desmethyl venlafaxine with [{sup 11}C]methyl iodide followed by HPLC purification and formulation. Radiochemically pure [O-methyl-{sup 11}C]venlafaxine was obtained in a 30 {+-} 5% decay corrected radiochemical yield and a specific activity > 50 GBq/{mu}mol(1.4 Ci/{mu}mol) at the end of synthesis. For a typical production starting with 46 GBq (1.3 Ci) [{sup 11}C]CO{sub 2}, 5.2 GBq (140 mCi) [O-methyl-{sup 11}C]venlafaxine was obtained as a sterile, formulated solution in a synthesis time of 30 min (counted from EOB). (Author).

Synthesis and thermal stability of the sodalite Na6Zn2[Al6Si6O24](SO4)2 and its reaction with hydrogen

DEFF Research Database (Denmark)

Heiden, Frank; Nielsen, Ulla Gro; Warner, Terence Edwin

2012-01-01

Ca2[Al6Si6O24](SO4)2. Na6Zn2[Al6Si6O24](SO4)2 was shown to be largely immiscible with nosean, Na8[Al6Si6O24]SO4 in the solid-state. Na6Zn2[Al6Si6O24](SO4)2 decomposes above 700 °C, yielding nosean, Na8[Al6Si6O24]SO4; willemite, Zn2SiO4; gahnite, ZnAl2O4; and presumably a glass phase, 2Na2O•9SiO2...

Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D3-3-O-Sulfate, a Major Circulating Vitamin D Metabolite in Humans.

Science.gov (United States)

Wong, Timothy; Wang, Zhican; Chapron, Brian D; Suzuki, Mizuki; Claw, Katrina G; Gao, Chunying; Foti, Robert S; Prasad, Bhagwat; Chapron, Alenka; Calamia, Justina; Chaudhry, Amarjit; Schuetz, Erin G; Horst, Ronald L; Mao, Qingcheng; de Boer, Ian H; Thornton, Timothy A; Thummel, Kenneth E

2018-04-01

Metabolism of 25-hydroxyvitamin D 3 (25OHD 3 ) plays a central role in regulating the biologic effects of vitamin D in the body. Although cytochrome P450-dependent hydroxylation of 25OHD 3 has been extensively investigated, limited information is available on the conjugation of 25OHD 3 In this study, we report that 25OHD 3 is selectively conjugated to 25OHD 3 -3- O -sulfate by human sulfotransferase 2A1 (SULT2A1) and that the liver is a primary site of metabolite formation. At a low (50 nM) concentration of 25OHD 3 , 25OHD 3 -3- O -sulfate was the most abundant metabolite, with an intrinsic clearance approximately 8-fold higher than the next most efficient metabolic route. In addition, 25OHD 3 sulfonation was not inducible by the potent human pregnane X receptor agonist, rifampicin. The 25OHD 3 sulfonation rates in a bank of 258 different human liver cytosols were highly variable but correlated with the rates of dehydroepiandrosterone sulfonation. Further analysis revealed a significant association between a common single nucleotide variant within intron 1 of SULT2A1 (rs296361; minor allele frequency = 15% in whites) and liver cytosolic SULT2A1 content as well as 25OHD 3 -3- O -sulfate formation rate, suggesting that variation in the SULT2A1 gene contributes importantly to interindividual differences in vitamin D homeostasis. Finally, 25OHD 3 -3- O -sulfate exhibited high affinity for the vitamin D binding protein and was detectable in human plasma and bile but not in urine samples. Thus, circulating concentrations of 25OHD 3 -3- O -sulfate appear to be protected from rapid renal elimination, raising the possibility that the sulfate metabolite may serve as a reservoir of 25OHD 3 in vivo, and contribute indirectly to the biologic effects of vitamin D. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Direct Fermi-surface image of hidden nesting for NaMo6O17 and KMo6O17

International Nuclear Information System (INIS)

Gweon, G.-.; Allen, J.W.; Clack, J.A.; Zhang, Y.X.; Poirier, D.M.; Benning, P.J.; Olson, C.G.; Marcus, J.; Schlenker, C.

1997-01-01

We report direct Fermi-surface images obtained with angle-resolved photoemission spectroscopy (ARPES) for NaMo 6 O 17 and KMo 6 O 17 above the charge-density wave transition temperatures. We also report ARPES spectra of the valence band of NaMo 6 O 17 . The images imply a Fermi surface (FS) based on three underlying quasi-one-dimensional (quasi-1D) surfaces. Thus it agrees in detail with that expected in the hidden nesting picture of Whangbo et al. [Science 252, 96 (1991)], but differs greatly from a FS deduced in a previous study by Breuer et al. [Phys. Rev. Lett. 76, 3172 (1996)], which found only two underlying quasi-1D surfaces. copyright 1997 The American Physical Society

Enantiomeric profiling of a chemically diverse mixture of chiral pharmaceuticals in urban water

International Nuclear Information System (INIS)

Evans, S.; Bagnall, J.; Kasprzyk-Hordern, B.

2017-01-01

Due to concerns regarding the release of pharmaceuticals into the environment and the understudied impact of stereochemistry of pharmaceuticals on their fate and biological potency, we focussed in this paper on stereoselective transformation pathways of selected chiral pharmaceuticals (16 pairs) at both microcosm (receiving waters and activated sludge wastewater treatment simulating microcosms) and macrocosm (wastewater treatment plant (WWTP) utilising activated sludge technology and receiving waters) scales in order to test the hypothesis that biodegradation of chiral drugs is stereoselective. Our monitoring programme of a full scale activated sludge WWTP and receiving environment revealed that several chiral drugs, those being marketed mostly as racemates, are present in wastewater and receiving waters enriched with one enantiomeric form (e.g. fluoxetine, mirtazapine, salbutamol, MDMA). This is most likely due to biological metabolic processes occurring in humans and other organisms. Both activated sludge and receiving waters simulating microcosms confirmed our hypothesis that chiral drugs are subject to stereoselective microbial degradation. It led, in this research, to preferential degradation of S-(+)-enantiomers of amphetamines, R-(+)-enantiomers of beta-blockers and S-(+)-enantiomers of antidepressants. In the case of three parent compound – metabolite pairs (venlafaxine – desmethylvenlafaxine, citalopram – desmethylcitalopram and MDMA - MDA), while parent compounds showed higher resistance to both microbial metabolism and photodegradation, their desmethyl metabolites showed much higher degradation rate both in terms of stereoselective metabolic and non-stereoselective photochemical processes. It is also worth noting that metabolites tend to be, as expected, enriched with enantiomers of opposite configuration to their parent compounds, which might have significant toxicological consequences when evaluating the metabolic residues of chiral pollutants

Salicylic acid treatment reduces the rot of postharvest citrus fruit by inducing the accumulation of H2O2, primary metabolites and lipophilic polymethoxylated flavones.

Science.gov (United States)

Zhu, Feng; Chen, Jiajing; Xiao, Xue; Zhang, Mingfei; Yun, Ze; Zeng, Yunliu; Xu, Juan; Cheng, Yunjiang; Deng, Xiuxin

2016-09-15

To comprehensively analyze the effects of salicylic acid (SA) on the storability of Satsuma mandarin (Citrus unshiu), fruits were treated with 2mM SA. The disease incidence of control/SA-treated fruit at 50d and 120d after treatment was 23.3%/10% and 67.3%/23.3%, respectively, suggesting that SA treatment can significantly reduce the rot rate of postharvest citrus fruit. Fruit quality assays revealed that the treatment can maintain fruit firmness without affecting the inner quality. Furthermore, the contents of H2O2 and some defense-related metabolites, such as ornithine and threonine, in citrus pericarp, were significantly increased by SA treatment. Moreover, it was lipophilic polymethoxylated flavones, rather than flavanone glycosides, that accumulated in SA-treated fruits and these can directly inhibit pathogen development. These results suggest that the effects of SA on postharvest citrus fruit may be attributed to the accumulation of H2O2 and defense-related metabolites. Copyright © 2016. Published by Elsevier Ltd.

Metoprolol induces oxidative damage in common carp (Cyprinus carpio).

Science.gov (United States)

Martínez-Rodríguez, Héctor; Donkor, Kingsley; Brewer, Sharon; Galar-Martínez, Marcela; SanJuan-Reyes, Nely; Islas-Flores, Hariz; Sánchez-Aceves, Livier; Elizalde-Velázquez, Armando; Gómez-Oliván, Leobardo Manuel

2018-04-01

During the last decade, β-blockers such as metoprolol (MTP) have been frequently detected in surface water, aquatic systems and municipal water at concentrations of ng/L to μg/L. Only a small number of studies exist on the toxic effects induced by this group of pharmaceuticals on aquatic organisms. Therefore, the present study aimed to evaluate the oxidative damage induced by MTP in the common carp Cyprinus carpio, using oxidative stress biomarkers. To this end, indicators of cellular oxidation such as hydroperoxide content (HPC), lipid peroxidation (LPX) and protein carbonyl content (PCC) were determined, as well as the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT). Also, concentrations of MTP and its metabolite O-desmethyl metoprolol were determined in water as well as carp gill, liver, kidney, brain and blood, along with the partial uptake pattern of these compounds. Results show that carp takes up MTP and its metabolite in the different organs evaluated, particularly liver and gill. The oxidative stress biomarkers, HPC, LPX, and PCC, as well as SOD and CAT activity all increased significantly at most exposure times in all organs evaluated. Results indicate that MTP and its metabolite induce oxidative stress on the teleost C. carpio and that the presence of these compounds may constitute a risk in water bodies for aquatic species. Copyright © 2018 Elsevier B.V. All rights reserved.

Comparative Study of Electronic Structure and Magnetic Properties of Osmate Double Perovskites: Ca2FeOsO6 versus Ca2Co(Ni)OsO6

Science.gov (United States)

Samanta, Kartik; Saha-Dasgupta, Tanusri

2018-04-01

Employing density functional theory, we study the trend in the electronic and magnetic properties of 3d-5d double perovskites, upon varying the 3d element for a fixed choice of 5d element, namely Ca2BOsO6 (B = Fe/Co/Ni). While all three compounds are reported to be ferrimagnets, the magnetic transition temperature of Ca2FeOsO6 is reported to be 2-2.4 times larger than that of Ca2CoOsO6 or Ca2NiOsO6. Our first-principles study provides microscopic insight into this trend. This trend is found to be caused by the downward shift in the position of d level energies of the B site element with respect to that of the Os t2g level upon moving across the 3d series from Fe to Co and Ni. This in turn changes the nominal valence of the Os ion from 5+ in Ca2FeOsO6 to 6+ in Ca2CoOsO6 and Ca2NiOsO6, resulting in differing superexchange paths between Ca2FeOsO6 and Ca2Co(Ni)OsO6, and additionally enabling the hybridization-mechanism-driven magnetism in Ca2FeOsO6. These together significantly enhance the magnetic transition temperature in Ca2FeOsO6 compared with that in Ca2Co(Ni)OsO6.

Identification of natural metabolites in mixture: a pattern recognition strategy based on (13)C NMR.

Science.gov (United States)

Hubert, Jane; Nuzillard, Jean-Marc; Purson, Sylvain; Hamzaoui, Mahmoud; Borie, Nicolas; Reynaud, Romain; Renault, Jean-Hugues

2014-03-18

Because of their highly complex metabolite profile, the chemical characterization of bioactive natural extracts usually requires time-consuming multistep purification procedures to achieve the structural elucidation of pure individual metabolites. The aim of the present work was to develop a dereplication strategy for the identification of natural metabolites directly within mixtures. Exploiting the polarity range of metabolites, the principle was to rapidly fractionate a multigram quantity of a crude extract by centrifugal partition extraction (CPE). The obtained fractions of simplified chemical composition were subsequently analyzed by (13)C NMR. After automatic collection and alignment of (13)C signals across spectra, hierarchical clustering analysis (HCA) was performed for pattern recognition. As a result, strong correlations between (13)C signals of a single structure within the mixtures of the fraction series were visualized as chemical shift clusters. Each cluster was finally assigned to a molecular structure with the help of a locally built (13)C NMR chemical shift database. The proof of principle of this strategy was achieved on a simple model mixture of commercially available plant secondary metabolites and then applied to a bark extract of the African tree Anogeissus leiocarpus Guill. & Perr. (Combretaceae). Starting from 5 g of this genuine extract, the fraction series was generated by CPE in only 95 min. (13)C NMR analyses of all fractions followed by pattern recognition of (13)C chemical shifts resulted in the unambiguous identification of seven major compounds, namely, sericoside, trachelosperogenin E, ellagic acid, an epimer mixture of (+)-gallocatechin and (-)-epigallocatechin, 3,3'-di-O-methylellagic acid 4'-O-xylopyranoside, and 3,4,3'-tri-O-methylflavellagic acid 4'-O-glucopyranoside.

Novel urinary metabolite of d-delta-tocopherol in rats

International Nuclear Information System (INIS)

Chiku, S.; Hamamura, K.; Nakamura, T.

1984-01-01

A novel metabolite of d-delta-tocopherol was isolated from the urine of rats given d-3,4-[ 3 H 2 ]-delta-tocopherol intravenously. The metabolite was collected from the urine of rats given d-delta-tocopherol in the same manner as that of the labeled compound. It was found that the metabolites consisted of sulfate conjugates. The portion of the major metabolite released with sulfatase was determined to be 2,8-dimethyl-2-(2'-carboxyethyl)-6-chromanol by infrared spectra, nuclear magnetic resonance spectra, and mass spectra. The proposed structure was confirmed by comparing the analytical results with those of a synthetically derived compound. As a result of the structural elucidation of this novel metabolite, a pathway for the biological transformation of delta-tocopherol is proposed which is different from that of alpha-tocopherol. A characteristic feature of the pathway is the absence of any opening of the chroman ring throughout the sequence

A new paradigm for known metabolite identification in metabonomics/metabolomics: metabolite identification efficiency.

Science.gov (United States)

Everett, Jeremy R

2015-01-01

A new paradigm is proposed for assessing confidence in the identification of known metabolites in metabonomics studies using NMR spectroscopy approaches. This new paradigm is based upon the analysis of the amount of metabolite identification information retrieved from NMR spectra relative to the molecular size of the metabolite. Several new indices are proposed including: metabolite identification efficiency (MIE) and metabolite identification carbon efficiency (MICE), both of which can be easily calculated. These indices, together with some guidelines, can be used to provide a better indication of known metabolite identification confidence in metabonomics studies than existing methods. Since known metabolite identification in untargeted metabonomics studies is one of the key bottlenecks facing the science currently, it is hoped that these concepts based on molecular spectroscopic informatics, will find utility in the field.

A New Paradigm for Known Metabolite Identification in Metabonomics/Metabolomics: Metabolite Identification Efficiency

Directory of Open Access Journals (Sweden)

Jeremy R. Everett

2015-01-01

Full Text Available A new paradigm is proposed for assessing confidence in the identification of known metabolites in metabonomics studies using NMR spectroscopy approaches. This new paradigm is based upon the analysis of the amount of metabolite identification information retrieved from NMR spectra relative to the molecular size of the metabolite. Several new indices are proposed including: metabolite identification efficiency (MIE and metabolite identification carbon efficiency (MICE, both of which can be easily calculated. These indices, together with some guidelines, can be used to provide a better indication of known metabolite identification confidence in metabonomics studies than existing methods. Since known metabolite identification in untargeted metabonomics studies is one of the key bottlenecks facing the science currently, it is hoped that these concepts based on molecular spectroscopic informatics, will find utility in the field.

Thermoelectric properties of Ba3Co2O6(CO3)0.7 containing one-dimensional CoO6 octahedral columns

OpenAIRE

Iwasaki, Kouta; Yamamoto, Teruhisa; Yamane, Hisanori; Takeda, Takashi; Arai, Shigeo; Miyazaki, Hidetoshi; Tatsumi, Kazuyoshi; Yoshino, Masahito; Ito, Tsuyoshi; Arita, Yuji; Muto, Shunsuke; Nagasaki, Takanori; Matsui, Tsuneo

2009-01-01

The thermoelectric properties of Ba3Co2O6(CO3)0.7 have been investigated using prismatic single crystals elongated along the c axis. Ba3Co2O6(CO3)0.7 has a pseudo-one-dimensional structure similar to that of 2H perovskite-type BaCoO3 and contains CoO6 octahedral columns running parallel to the c axis. The prismatic crystals are grown by a flux method using a K2CO3–BaCl2 flux. The electrical conductivity(σ) along the columns (c axis) exhibits a metallic behavior (670–320 S cm−1 in the temperat...

FoxO6 Integrates Insulin Signaling With Gluconeogenesis in the Liver

Science.gov (United States)

Kim, Dae Hyun; Perdomo, German; Zhang, Ting; Slusher, Sandra; Lee, Sojin; Phillips, Brett E.; Fan, Yong; Giannoukakis, Nick; Gramignoli, Roberto; Strom, Stephen; Ringquist, Steven; Dong, H. Henry

2011-01-01

OBJECTIVE Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism. RESEARCH DESIGN AND METHODS We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver. RESULTS FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice. CONCLUSIONS Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes. PMID:21940782

Identification of the principal biliary metabolite of 4'-(9-acridinylamino)methanesulfon-m-anisidide in rats

International Nuclear Information System (INIS)

Shoemaker, D.D.; Cysyk, R.L.; Padmanabhan, S.; Bhat, H.B.; Malspeis, L.

1982-01-01

m-AMSA [4'-(9-acridinylamino)methanesulfon-m-anisidide] labeled in either the acridine or anilino portion was used to investigate the disposition of this antitumor agent in rats. The principal biliary metabolite, which accounts for approximately 80% of the total biliary radioactivity for 90 min after administration and greater than 50% of the administered dose by 180 min after administration, had both the acridine and the anilino portions intact. Isolation and purification of the principal metabolite was achieved by preparative thin-layer chromatography on silica gel and column chromatography on Amberlite XAD-2 resin. A nuclear magnetic resonance (NMR) spectrum of the CID salt in D 2 O showed that the metabolite is the m-AMSA-glutathione conjugate in which the thioether linkage occurs at the 5'-position of the anilino ring. Synthesis of the metabolite was achieved by oxidizing m-AMSA with active MnO 2 to -methanesulfonyl - - (9-acridinyl)-3'-methoxy - 2',5' - cyclohexadiene-1',4'-diimine (m-AQDI) followed by reaction of m-AQDI with glutathione. The 1 H-NMR spectrum of the synthetic product proved identical with that of the isolated metabolite. The demonstration that the principal biliary metabolite on m-AMSA involves glutathione bound to the 9-anilino ring suggests that m-AMSA may be bioactivated in vivo to the quinoidal diimine, m-AQDI

Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women.

Science.gov (United States)

da Silva, Vanessa R; Rios-Avila, Luisa; Lamers, Yvonne; Ralat, Maria A; Midttun, Øivind; Quinlivan, Eoin P; Garrett, Timothy J; Coats, Bonnie; Shankar, Meena N; Percival, Susan S; Chi, Yueh-Yun; Muller, Keith E; Ueland, Per Magne; Stacpoole, Peter W; Gregory, Jesse F

2013-11-01

Suboptimal vitamin B-6 status, as reflected by low plasma pyridoxal 5'-phosphate (PLP) concentration, is associated with increased risk of vascular disease. PLP plays many roles, including in one-carbon metabolism for the acquisition and transfer of carbon units and in the transsulfuration pathway. PLP also serves as a coenzyme in the catabolism of tryptophan. We hypothesize that the pattern of these metabolites can provide information reflecting the functional impact of marginal vitamin B-6 deficiency. We report here the concentration of major constituents of one-carbon metabolic processes and the tryptophan catabolic pathway in plasma from 23 healthy men and women before and after a 28-d controlled dietary vitamin B-6 restriction (restriction yielded increased cystathionine (53% pre- and 76% postprandial; P restriction yielded lower kynurenic acid (22% pre- and 20% postprandial; P restriction and multilevel partial least squares-discriminant analysis supported this conclusion. Thus, plasma concentrations of creatine, cystathionine, kynurenic acid, and 3-hydroxykynurenine jointly reveal effects of vitamin B-6 restriction on the profiles of one-carbon and tryptophan metabolites and serve as biomarkers of functional effects of marginal vitamin B-6 deficiency.

Phase relationships in the BaO-Ga2O3-Ta2O5 system and the structure of Ba6Ga21TaO40.

Science.gov (United States)

Cao, Jiang; Yu, Xiaodi; Kuang, Xiaojun; Su, Qiang

2012-07-16

Phase relationships in the BaO-Ga(2)O(3)-Ta(2)O(5) ternary system at 1200 °C were determined. The A(6)B(10)O(30) tetragonal tungsten bronze (TTB) related solution in the BaO-Ta(2)O(5) subsystem dissolved up to ~11 mol % Ga(2)O(3), forming a ternary trapezoid-shaped TTB-related solid solution region defined by the BaTa(2)O(6), Ba(1.1)Ta(5)O(13.6), Ba(1.58)Ga(0.92)Ta(4.08)O(13.16), and Ba(6)GaTa(9)O(30) compositions in the BaO-Ga(2)O(3)-Ta(2)O(5) system. Two ternary phases Ba(6)Ga(21)TaO(40) and eight-layer twinned hexagonal perovskite solid solution Ba(8)Ga(4-x)Ta(4+0.6x)O(24) were confirmed in the BaO-Ga(2)O(3)-Ta(2)O(5) system. Ba(6)Ga(21)TaO(40) crystallized in a monoclinic cell of a = 15.9130(2) Å, b = 11.7309(1) Å, c = 5.13593(6) Å, β = 107.7893(9)°, and Z = 1 in space group C2/m. The structure of Ba(6)Ga(21)TaO(40) was solved by the charge flipping method, and it represents a three-dimensional (3D) mixed GaO(4) tetrahedral and GaO(6)/TaO(6) octahedral framework, forming mixed 1D 5/6-fold tunnels that accommodate the Ba cations along the c axis. The electrical property of Ba(6)Ga(21)TaO(40) was characterized by using ac impedance spectroscopy.

Structural Stability and Electronic Properties of Na2C6O6 for a Rechargeable Sodium-ion Battery

Science.gov (United States)

Yamashita, Tomoki; Fujii, Akihiro; Momida, Hiroyoshi; Oguchi, Tamio

2014-03-01

Sodium-ion batteries have been explored as a promising alternative to lithium-ion batteries owing to a significant advantage of a natural abundance of sodium. Recently, it has been reported that disodium rhodizonate, Na2C6O6, exhibit good electrochemical properties and cycle performance as a minor-metal free organic cathode for sodium-ion batteries. However, its crystal structures during discharge/charge cycle still remain unclear. In this work, we theoretically propose feasible crystal structures of Na2+xC6O6 using first principles calculations. A structural phase transition has been found: Na4C6O6 has a different C6O6 packing arrangement from Na2C6O6. Electronic structures of Na2+xC6O6 during discharge/charge cycle are also discussed. Our predictions could be the key to understanding the discharge/charge process of Na2C6O6. Supported by MEXT program ``Elements Strategy Initiative to Form Core Rersearch Center'' (since 2012), MEXT; Ministry of Education Culture, Sports, Science and Technology, Japan.

Comparative Pharmacokinetics of the Organophosphorus Insecticide Chlorpyrifos and its Major Metabolites Diethylphosphate, Diethylthiophosphate and 3,5,6-Trichloro-2-pyridinol in the Rat

Energy Technology Data Exchange (ETDEWEB)

Timchalk, Chuck; Busby, Andrea L; Campbell, James A; Needham, Larry L; Barr, Dana

2007-07-31

Abstract Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of metabolism and of environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. However, because these same chemicals can result from metabolism or by biodegradation, monitoring total urinary metabolite levels may be reflective of not only an individual’s contact with the parent pesticide, but also exposure with the metabolites, which are present in the environment. The objective of the current study was to compare the pharmacokinetics of orally administered DEP, DETP and TCPy with their kinetics following oral dosing with the parent insecticide CPF in the rat. Groups of rats were orally administered CPF, DEP, TCPy or DETP at doses of 140 μmol/kg body weight, and the time-courses of the metabolites were evaluated in blood and urine. Following oral administration, all three metabolites were well absorbed with peak blood concentrations being attained between 1-3 h post-dosing. In the case of DEP and TCPy virtually all the administered dose was recovered in the urine by 72 h post-dosing, suggesting negligible, if any, metabolism; whereas with DETP, ~50% of the orally administered dose was recovered in the urine. The CPF oral dose was likewise rapidly absorbed and metabolized to DEP, TCPy and DETP, with the distribution of metabolites in the urine followed the order: TCPy (22 ± 3 μmol) > DETP (14 ± 2 μmol) > DEP (1.4 ± 0.7 μmol). Based upon the total amount of TCPy detected in the urine a minimum of 63% of the oral CPF dose was absorbed. These studies support the hypotheses that DEP, DETP and TCPy present in the environment can be readily absorbed and eliminated in the urine of rats and potentially humans.

Secondary Metabolites of Astragalus cruciatus Link. and Their Chemotaxonomic Significance

Directory of Open Access Journals (Sweden)

Wassila Benchadi

2013-03-01

Full Text Available In continuation of our chemical studies on the secondary metabolites of Algerian saharan species, we report on the isolation, from the methanol extract of the whole plant Astragalus cruciatus Link. , of seven known compounds including two saponins named azukisaponin V (1 and astragaloside VIII (2, four flavonoids called narcissin (3, nicotiflorin (4, kaempferol 3-O- α -L-rhamnopyranosyl-(1 ¦ 4- α -L-rhamnopyranosyl-(1 ¦ 6-β-D-glucopyranoside (5 and 5,7,2’-trihydroxyflavone (6 and one phytosterol glycoside, daucosterol (7. All the isolated compounds were characterized by using spectroscopic methods especially 1D and 2D NMR and ESI mass spectrometry and comparison with literature data . The chemotaxonomic and systematic characters of the genus Astragalus are summarized in this study to show its interesting chemodiversity throughout the world, as well as to establish the chemotaxonomical classification of this genus.

Preparation and characterization of Fe3O4/SiO2/Bi2MoO6 composite as magnetically separable photocatalyst

International Nuclear Information System (INIS)

Hou, Xuemei; Tian, Yanlong; Zhang, Xiang; Dou, Shuliang; Pan, Lei; Wang, Wenjia; Li, Yao; Zhao, Jiupeng

2015-01-01

Highlights: • Fe 3 O 4 /SiO 2 /Bi 2 MoO 6 composite was prepared by a hydrothermal method. • The composite has an enhanced visible absorption compared with pure Bi 2 MoO 6 . • The magnetic photocatalyst displayed excellent stability and reusability. • O 2 ·− and · OH play a major role during the photocatalytic process. - Abstract: In this paper, Fe 3 O 4 /SiO 2 /Bi 2 MoO 6 microspheres were prepared by a facile hydrothermal method. The scanning electron microscope (SEM) results revealed that flower-like three dimensional (3D) Bi 2 MoO 6 microspheres were decorated with Fe 3 O 4 /SiO 2 magnetic nanoparticles. The UV–vis diffuse reflection spectra showed extended absorption within the visible light range compared with pure Bi 2 MoO 6 . We evaluated the photocatalytic activities of Fe 3 O 4 /SiO 2 /Bi 2 MoO 6 microspheres on the degradation of Rhodamine B (RhB) under visible light irradiation and found that the obtained composite exhibited higher photocatalytic activity than pure Bi 2 MoO 6 and P25. Moreover, the Fe 3 O 4 /SiO 2 /Bi 2 MoO 6 composite also displayed excellent stability and their photocatalytic activity decreased slightly after reusing 5 cycles. Meanwhile, the composite could be easily separated by applying an external magnetic field. The trapping experiment results suggest that superoxide radical species O 2 ·− and hydroxyl radicals · OH play a major role in Fe 3 O 4 /SiO 2 /Bi 2 MoO 6 system under visible light irradiation. The combination of flower-like three dimensional (3D) Bi 2 MoO 6 microspheres and Fe 3 O 4 /SiO 2 magnetic nanospheres provides a useful strategy for designing multifunctional nanostructure materials with enhanced photocatalytic activities in the potential applications of water purification

Preclinical pharmacokinetic evaluation and metabolites identification of methyl salicylate-2-O-β-d-lactoside in rats using LC-MS/MS and Q-TOF-MS methods.

Science.gov (United States)

Zhang, Dan; Huang, Chao; Xin, Wenyu; Ma, Xiaowei; Zhang, Weiku; Zhang, Tiantai; Du, Guanhua

2015-05-10

Methyl salicylate-2-O-β-d-lactoside (MSL) is a natural salicylate derivative from the traditional Chinese medicine of Gaultheria yunnanensis (Franch.) Rehder (G. yunnanensis). As a non-steroidal anti-inflammatory drug (NSAID), MSL exerts a significant anti-arthritis effect but hardly has any gastrointestinal toxicity. In this paper, the pharmacokinetics, distribution, excretion and identification of MSL and its metabolites are described following rat oral and intravenous administration. The biological samples were quantified by UPLC-MS/MS and the metabolites in urine and feces were identified by using Q-TOF-MS. These results will support future investigations leading to clinical development of this drug. Copyright © 2015 Elsevier B.V. All rights reserved.

Solid-liquid stable phase equilibria of the ternary systems MgCl2 + MgB6O10+ H2O AND MgSO4 + MgB6O10 + H2O at 308.15 K

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Lingzong Meng

2014-03-01

Full Text Available The solubilities and the relevant physicochemical properties of the ternary systems MgCl2 + MgB6O10 + H2O and MgSO4 + MgB6O10 + H2O at 308.15 K were investigated using an isothermal dissolution method. It was found that there is one invariant point, two univariant curves, and two crystallization regions of the systems. The systems belong to a simple co-saturated type, and neither double salts nor solid solutions were found. Based on the extended HW model and its temperature-dependent equations, the single-salt Pitzer parameters β(0, β(1, β(2 and CØ for MgCl2, MgSO4, and Mg(B6O7(OH6, the mixed ion-interaction parameters θCl,B6O10, θSO4,B6O10, ΨMg,Cl,B6O10, ΨMg,SO4,B6O10 of the systems at 308.15 K were fitted, In addition, the average equilibrium constants of the stable equilibrium solids at 308.15 K were obtained by a method using the activity product constant. Then the solubilities of the ternary systems are calculated. The calculated solubilities agree well with the experimental values.

Oxidation kinetics of (B6O) boron oxide

International Nuclear Information System (INIS)

Makarov, V.S.; Solov'ev, N.E.; Ugaj, Ya.A.

1987-01-01

Reactivity of B 6 O to oxygen is investigated. It is shown that the process of B 6 O oxidation in the air in the temperature range 760-1150 K results in the maximum transformation degree equal to 0.35. At the initial stages oxidation proceeds in kinetic regime, at final stages - in diffusion one, and high viscosity of B 2 O 3 probably affects the oxidation process

Mollecarbamates, Molleureas, and Molledihydroisoquinolone, o-Carboxyphenethylamide Metabolites of the Ascidian Didemnum molle Collected in Madagascar.

Science.gov (United States)

Issac, Michal; Aknin, Maurice; Gauvin-Bialecki, Anne; Pond, Christopher D; Barrows, Louis R; Kashman, Yoel; Carmeli, Shmuel

2017-06-23

The extract of a sample of the tunicate Didemnum molle (MAY13-117) collected in Mayotte afforded eight new metabolites, mollecarbamates A-D (1-4) and molleureas B-E (5-8), along with the two known natural products, N,N'-diphenylethyl urea (10) and molleurea A (11). Another sample of D. molle (MAD11-BA065) collected in Baie des Assassins, Madagascar, afforded molledihydroisoquinolone (9). Mollecarbamates 1-4 are a family of compounds that possess repeating o-carboxyphenethylamide units and a carbamate moiety, while the molleureas 5-8 contain tetra- and penta-repeating carboxyphenethylamide units and a urea bridge in different positions. Molledihydroisoquinolone (9) is a cyclic form of o-carboxyphenethylamide. We propose that these unique natural products are most probably produced by an unprecedented biosynthetic pathway that contains a yet unknown chorismate mutase variant. The structures of the compounds were elucidated by interpretation of the data from 1D and 2D NMR, HRESIMS, and MS/MS analyses of the positive ESIMS experiments. Compounds 1-8 were tested against pathogenic bacteria and in a cytoprotective HIV cell based assay but did not show any significant effects in these assays.

Comparison of phosphodiesterase type V inhibitors use in eight European cities through analysis of urban wastewater

DEFF Research Database (Denmark)

Causanilles, Ana; Rojas Cantillano, Daniela; Emke, Erik

2018-01-01

active pharmaceutical ingredients (sildenafil, tadalafil and vardenafil) together with (bio)transformation products and other analogues. Only sildenafil and its two human urinary metabolites desmethyl- and desethylsildenafil were detected in the samples with concentrations reaching 60 ng L−1....... The concentrations were transformed into normalized measured loads and the estimated actual consumption of sildenafil was back-calculated from these loads. In addition, national prescription data from five countries was gathered in the form of the number of prescribed daily doses and transformed into predicted loads...

Human metabolites of brevetoxin PbTx-2: Identification and confirmation of structure

Science.gov (United States)

Guo, Fujiang; An, Tianying; Rein, Kathleen S.

2010-01-01

Four metabolites were identified upon incubation of brevetoxin (PbTx-2) with human liver microsomes. Chemical transformation of PbTx-2 confirmed the structures of three known metabolites BTX-B5, PbTx-9 and 41, 43-dihydro-BTX-B5 and a previously unknown metabolite, 41, 43-dihydro-PbTx-2. These metabolites were also observed upon incubation of PbTx-2 with nine human recombinant cytochrome P450s (1A1, 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5). Cytochrome P450 3A4 produced oxidized metabolites while other CYPs generated the reduced products. PMID:20600229

Thermodynamic characterization of Ni3TeO6, Ni2Te3O8 and NiTe2O5

Science.gov (United States)

Dawar, Rimpi; Babu, R.; Ananthasivan, K.; Anthonysamy, S.

2017-09-01

Measurement of vapour pressure of TeO2(g) over the biphasic mixture Ni3TeO6 (s) + NiO(s) in the temperature range 1143-1272 K was carried out using transpiration-thermogravimetric technique (TTG). Gibbs energy of formation of Ni3TeO6 was obtained from the temperature dependence of vapour pressure of TeO2 (g) generated by the incongruent vapourisation reaction, Ni3TeO6 (s) → NiO(s) + TeO2 (g) + 1/2 O2 in the temperature range 1143-1272 K. An isoperibol type drop calorimeter was used to measure the enthalpy increments of Ni3TeO6, Ni2Te3O8 and NiTe2O5. Thermodynamic functions viz., heat capacity, entropy and Gibbs energy functions of these compounds were derived from the experimentally measured enthalpy increment values. Third-law analysis was carried out to ascertain absence of temperature dependent systematic errors in the measurement of vapour pressure of TeO2 (g). A value of -1265.1 ± 1.5 kJ mol-1 was obtained for Δ Hf,298K o (Ni3TeO6) using third-law analysis.

Development and validation of an ultra-fast and sensitive microflow liquid chromatography-tandem mass spectrometry (MFLC-MS/MS) method for quantification of LSD and its metabolites in plasma and application to a controlled LSD administration study in humans.

Science.gov (United States)

Steuer, Andrea E; Poetzsch, Michael; Stock, Lorena; Eisenbeiss, Lisa; Schmid, Yasmin; Liechti, Matthias E; Kraemer, Thomas

2017-05-01

Lysergic acid diethylamide (LSD) is a semi-synthetic hallucinogen that has gained popularity as a recreational drug and has been investigated as an adjunct to psychotherapy. Analysis of LSD represents a major challenge in forensic toxicology due to its instability, low drug concentrations, and short detection windows in biological samples. A new, fast, and sensitive microflow liquid chromatography (MFLC) tandem mass spectrometry method for the validated quantification of LSD, iso-LSD, 2-oxo 3-hydroxy-LSD (oxo-HO-LSD), and N-desmethyl-LSD (nor-LSD) was developed in plasma and applied to a controlled pharmacokinetic (PK) study in humans to test whether LSD metabolites would offer for longer detection windows. Five hundred microlitres of plasma were extracted by solid phase extraction. Analysis was performed on a Sciex Eksigent MFLC system coupled to a Sciex 5500 QTrap. The method was validated according to (inter)-national guidelines. MFLC allowed for separation of the mentioned analytes within 3 minutes and limits of quantification of 0.01 ng/mL. Validation criteria were fulfilled for all analytes. PK data could be calculated for LSD, iso-LSD, and oxo-HO-LSD in all participants. Additionally, hydroxy-LSD (HO-LSD) and HO-LSD glucuronide could be qualitatively detected and PK determined in 11 and 8 subjects, respectively. Nor-LSD was only sporadically detected. Elimination half-lives of iso-LSD (median 12 h) and LSD metabolites (median 9, 7.4, 12, and 11 h for oxo-HO-LSD, HO-LSD, HO-LSD-gluc, and nor-LSD, respectively) exceeded those of LSD (median 4.2 h). However, screening for metabolites to increase detection windows in plasma seems not to be constructive due to their very low concentrations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

A new aurone and two rare metabolites from the leaves of Diospyros melanoxylon.

Science.gov (United States)

Mallavadhani, Uppuluri V; Mahapatra, Anita

2005-01-01

A new aurone, 4,6-dihydroxy-2-[alpha,alpha-(4-hydroxyphenyl)hydroxy]methylene-3(2H)-benzofuranone (2) and two rare metabolites viz. selin-4(15)-en-1beta,11-diol (5) and 5,7-dihydroxy-3-O-beta-D-glucopyranosyl-l''' --> 6''glucopyranoside-2-{4-hydroxyphenyl}-4H-benzopyran-4-one (6) in addition to the known protocatechuic acid methyl ester (1), quercitin (3) and gallic acid (4) were isolated from the methanol extract of Diospyros melanoxylon leaves. The structures were elucidated by a combination of chemical and spectroscopic analysis. Interestingly, compound 2 was found to exist in both E- and Z-isomeric forms in a 15:85 ratio. The present isolation of compounds 2 and 5 assumes taxonomic significance as aurones and sesquiterpenes have not yet been reported from the Diospyros genus, consisting of more than 350 identified species.

Carbaryl and monocrotophos residues in cottonseed products. Part of a coordinated programme on isotopic tracer-aided studies of chemical residues in cotton seed, feed, oil and related products

International Nuclear Information System (INIS)

Pablo, F.E.

1981-03-01

Cotton plants of Deltapine variety were treated with carbaryl (naphthyl-1- 14 C), (6.7 mg/plant) three times at two week intervals. Seeds were collected at maturity and 14 C-residues were determined in the oil and cake by standard procedures. 14 C-carbaryl and/or metabolite residues were 0.42 and 0.15 mg/kg in the crude oil and cake respectively. Parallel studies were conducted with spectrophotometric techniques using p-nitrobenzene diazonium fluoborate as chromogenic agent. Applications were made three times at a rate of 14 mg/plant. Residues in the crude oil and cake were found to be 0.83 and 0.04 mg/kg respectively. The higher residue level in the oil - compared to the radiometric technique - probably relates to higher application rates. Cotton plants of Deltapine variety were treated with (N-methyl- 14 C) monocrotophos (0.09 mg/plant) three times at two week intervals, as recommended for agricultural practice. Seeds were collected at maturity and standard procedures for extraction, clean-up and paper and thin-layer chromatography were adopted for the ultimate determination of residues in seed, oil and cake. Parallel experiments, using spectrophotometric techniques, were made for comparison. 14 C-residues of monocrotophos and/or metabolites in cottonseed, crude oil and cake were found to be 0.06, 0.12 and 0.05 mg/kg respectively. Corresponding data obtained by non-nuclear techniques were 0.18, 0.42 and 0.15 mg/kg respectively. The discrepancy between the two sets of results may be related to different rates of application: 0.3 mg and 0.09 mg/plant for non-nuclear and radiometric techniques respectively. Among the major metabolites identified in the cottonseed were dimethyl phosphate and O-desmethyl monocrotophos. N-demethylated monocrotophos and sugar conjugates were also identified

Estrogenic activities of diuron metabolites in female Nile tilapia (Oreochromis niloticus).

Science.gov (United States)

Pereira, Thiago Scremin Boscolo; Boscolo, Camila Nomura Pereira; Felício, Andreia Arantes; Batlouni, Sergio Ricardo; Schlenk, Daniel; de Almeida, Eduardo Alves

2016-03-01

Some endocrine disrupting chemicals (EDCs) can alter the estrogenic activities of the organism by directly interacting with estrogen receptors (ER) or indirectly through the hypothalamus-pituitary-gonadal axis. Recent studies in male Nile tilapia (Oreochromis niloticus) indicated that diuron may have anti-androgenic activity augmented by biotransformation. In this study, the effects of diuron and three of its metabolites were evaluated in female tilapia. Sexually mature female fish were exposed for 25 days to diuron, as well as to its metabolites 3,4-dichloroaniline (DCA), 3,4-dichlorophenylurea (DCPU) and 3,4-dichlorophenyl-N-methylurea (DCPMU), at concentrations of 100 ng/L. Diuron metabolites caused increases in E2 plasma levels, gonadosomatic indices and in the percentage of final vitellogenic oocytes. Moreover, diuron and its metabolites caused a decrease in germinative cells. Significant differences in plasma concentrations of the estrogen precursor and gonadal regulator17α-hydroxyprogesterone (17α-OHP) were not observed. These results show that diuron metabolites had estrogenic effects potentially mediated through enhanced estradiol biosynthesis and accelerated the ovarian development of O. niloticus females. Copyright © 2015 Elsevier Ltd. All rights reserved.

Repair of O6-methylguanine adducts in human telomeric G-quadruplex DNA by O6-alkylguanine-DNA alkyltransferase

Science.gov (United States)

Hellman, Lance M.; Spear, Tyler J.; Koontz, Colton J.; Melikishvili, Manana; Fried, Michael G.

2014-01-01

O6-alkylguanine-DNA alkyltransferase (AGT) is a single-cycle DNA repair enzyme that removes pro-mutagenic O6-alkylguanine adducts from DNA. Its functions with short single-stranded and duplex substrates have been characterized, but its ability to act on other DNA structures remains poorly understood. Here, we examine the functions of this enzyme on O6-methylguanine (6mG) adducts in the four-stranded structure of the human telomeric G-quadruplex. On a folded 22-nt G-quadruplex substrate, binding saturated at 2 AGT:DNA, significantly less than the ∼5 AGT:DNA found with linear single-stranded DNAs of similar length, and less than the value found with the telomere sequence under conditions that inhibit quadruplex formation (4 AGT:DNA). Despite these differences, AGT repaired 6mG adducts located within folded G-quadruplexes, at rates that were comparable to those found for a duplex DNA substrate under analogous conditions. Repair was kinetically biphasic with the amplitudes of rapid and slow phases dependent on the position of the adduct within the G-quadruplex: in general, adducts located in the top or bottom tetrads of a quadruplex stack exhibited more rapid-phase repair than did adducts located in the inner tetrad. This distinction may reflect differences in the conformational dynamics of 6mG residues in G-quadruplex DNAs. PMID:25080506

Quantitation of intracellular metabolites of [35S]-6-mercaptopurine in L5178Y cells grown in time-course incubates.

Science.gov (United States)

Breter, H J; Zahn, R K

1979-09-01

6-Mercaptopurine (6MP) metabolism was quantitatively determined in L5178Y murine lymphoma. Cells grown in time-course incubates with [35S]-6MP were extracted with cold perchloric acid, and the buffered extracts were subjected to high-performance liquid cation-exchange chromatography prior to and after hydrolysis with alkaline phosphatase. Free sulfate, 6-thiouric acid, 6-thioxanthosine, 6-thioguanosine, 6-thioinosine, free 6MP, and 6-methylthioinosine were separated from each other; identified in the radiochromatograms by elution volume, UV spectroscopic data, and enzymatic peak-shifting analyses with purine nucleoside phosphorylase; and quantitatively determined by means of 35S radioactivity. Gross intracellular 35S concentrations remained constant at 5 x 10(-5) M after 1 hr of incubation. 6MP metabolism in L5178Y cells was distinguished into an early phase (to 1 hr of incubation) in which 6MP was predominantly catabolized to 6-thiouric acid and free sulfate, into an intermediate phase (to 8 hr) in which substantial amounts of free 6MP and of ribonucleotides of 6-thioxanthosine and 6-thioguanosine were present while the concentrations of nonnucleotide oxidation products sharply decreased, and into a late phase (to 24 hr) in which the ribonucleotides of 6MP, of 6-thioguanosine and, in particular, of 6-methylthioinosine were the most abundant metabolites.

Preparing the key metabolite of Z-ligustilide in vivo by a specific electrochemical reaction.

Science.gov (United States)

Duan, Feipeng; Xu, Wenjuan; Liu, Jie; Jia, Zhixin; Chen, Kuikui; Chen, Yijun; Wang, Mingxia; Ma, Kaiyue; Dong, Jiaojiao; Chen, Lianming; Xiao, Hongbin

2018-04-16

The key in vivo metabolites of a drug play an important role in its efficacy and toxicity. However, due to the low content and instability of these metabolites, they are hard to obtain through in vivo methods. Electrochemical reactions can be an efficient alternative to biotransformation in vivo for the preparation of metabolites. Accordingly, in this study, the metabolism of Z-ligustilide was investigated in vitro by electrochemistry coupled online to mass spectrometry. This work showed that five oxidation products of the electrochemical reaction were detected and that two of the oxidation products (senkyunolide I and senkyunolide H) were identified from liver microsomal incubation as well. Furthermore, after intragastric administration of Z-ligustilide in rats, senkyunolide I and senkyunolide H were detected in the rat plasma and liver, while 6,7-epoxyligustilide, a key intermediate metabolite of Z-ligustilide, was difficult to detect in vivo. By contrast, 6,7-epoxyligustilide was obtained from the electrochemical reaction. In addition, for the first time, 6 mg of 6,7-epoxyligustilide was prepared from 120 mg of Z-ligustilide. Therefore, electrochemical reactions represent an efficient laboratory method for preparing key drug metabolites. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Zinc Oxide Nanoparticles Influence Microflora in Ileal Digesta and Correlate Well with Blood Metabolites

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Yanni Feng

2017-06-01

Full Text Available Zinc oxide nanoparticles (ZnO NPs are used widely in consumer and industrial products, however, their influence on gut microbiota and metabolism and their mutual interactions are not fully understood. In this study, the effects of ZnO NPs on ileal bacterial communities, plasma metabolites, and correlations between them were investigated. Hens were fed with different concentrations of ZnO NPs [based on Zn; 0 mg/kg (control, 25 mg/kg, 50 mg/kg, and 100 mg/kg] for 9 weeks. Subsequently, ileal digesta and blood plasma were collected for analysis of microflora and metabolites, respectively. The V3-V4 region of the 16S rRNA gene of ileal digesta microbiota was sequenced using the Illumina HiSeq 2500 platform. The predominant bacterial community in the ileum belongs to the phylum Firmicutes. The richness of the bacterial community was negatively correlated with increasing amounts of ZnO NPs (r = -0.636, P < 0.01; when ZnO NP levels were at 100 mg/kg, microbiota diversity was significantly decreased (P < 0.05. The community structure determined by LEfSe analysis indicated that Bacilli, Fusobacteria, and Proteobacteria were changed, and Lactobacillus was reduced by ZnO NPs. Moreover, metabolism as analyzed by nuclear magnetic resonance (NMR indicated that glucose, some amino acids, and other metabolites were changed by ZnO NPs. Choline, lactate, and methionine were positively correlated with bacterial richness. In summary, ZnO NPs could influence the levels of microflora in ileal digesta, particularly Lactobacillus. Furthermore, the richness of the microbiota was related to changes in choline, lactate, and methionine metabolism.

Quantitative Rationalization of Gemfibrozil Drug Interactions: Consideration of Transporters-Enzyme Interplay and the Role of Circulating Metabolite Gemfibrozil 1-O-β-Glucuronide.

Science.gov (United States)

Varma, Manthena V S; Lin, Jian; Bi, Yi-an; Kimoto, Emi; Rodrigues, A David

2015-07-01

Gemfibrozil has been suggested as a sensitive cytochrome P450 2C8 (CYP2C8) inhibitor for clinical investigation by the U.S. Food and Drug Administration and the European Medicines Agency. However, gemfibrozil drug-drug interactions (DDIs) are complex; its major circulating metabolite, gemfibrozil 1-O-β-glucuronide (Gem-Glu), exhibits time-dependent inhibition of CYP2C8, and both parent and metabolite also behave as moderate inhibitors of organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. Additionally, parent and metabolite also inhibit renal transport mediated by OAT3. Here, in vitro inhibition data for gemfibrozil and Gem-Glu were used to assess their impact on the pharmacokinetics of several victim drugs (including rosiglitazone, pioglitazone, cerivastatin, and repaglinide) by employing both static mechanistic and dynamic physiologically based pharmacokinetic (PBPK) models. Of the 48 cases evaluated using the static models, about 75% and 98% of the DDIs were predicted within 1.5- and 2-fold of the observed values, respectively, when incorporating the interaction potential of both gemfibrozil and its 1-O-β-glucuronide. Moreover, the PBPK model was able to recover the plasma profiles of rosiglitazone, pioglitazone, cerivastatin, and repaglinide under control and gemfibrozil treatment conditions. Analyses suggest that Gem-Glu is the major contributor to the DDIs, and its exposure needed to bring about complete inactivation of CYP2C8 is only a fraction of that achieved in the clinic after a therapeutic gemfibrozil dose. Overall, the complex interactions of gemfibrozil can be quantitatively rationalized, and the learnings from this analysis can be applied in support of future predictions of gemfibrozil DDIs. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Activation of the Silent Secondary Metabolite Production by Introducing Neomycin-Resistance in a Marine-Derived Penicillium purpurogenum G59

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Chang-Jing Wu

2015-04-01

Full Text Available Introduction of neomycin-resistance into a marine-derived, wild-type Penicillium purpurogenum G59 resulted in activation of silent biosynthetic pathways for the secondary metabolite production. Upon treatment of G59 spores with neomycin and dimethyl sulfoxide (DMSO, a total of 56 mutants were obtained by single colony isolation. The acquired resistance of mutants to neomycin was testified by the resistance test. In contrast to the G59 strain, the EtOAc extracts of 28 mutants inhibited the human cancer K562 cells, indicating that the 28 mutants have acquired the capability to produce bioactive metabolites. HPLC-photodiode array detector (PDAD-UV and HPLC-electron spray ionization (ESI-MS analyses further indicated that diverse secondary metabolites have been newly produced in the bioactive mutant extracts. Followed isolation and characterization demonstrated that five bioactive secondary metabolites, curvularin (1, citrinin (2, penicitrinone A (3, erythro-23-O-methylneocyclocitrinol (4 and 22E-7α-methoxy-5α, 6α-epoxyergosta-8(14,22-dien-3β-ol (5, were newly produced by a mutant, 4-30, compared to the G59 strain. All 1–5 were also not yet found in the secondary metabolites of other wild type P. purpurogenum strains. Compounds 1–5 inhibited human cancer K562, HL-60, HeLa and BGC-823 cells to varying extents. Both present bioassays and chemical investigations demonstrated that the introduction of neomycin-resistance into the marine-derived fungal G59 strain could activate silent secondary metabolite production. The present work not only extended the previous DMSO-mediated method for introducing drug-resistance in fungi both in DMSO concentrations and antibiotics, but also additionally exemplified effectiveness of this method for activating silent fungal secondary metabolites. This method could be applied to other fungal isolates to elicit their metabolic potentials to investigate secondary metabolites from silent biosynthetic pathways.

Metabolite Profile Analysis Reveals Functional Effects of 28-Day Vitamin B-6 Restriction on One-Carbon Metabolism and Tryptophan Catabolic Pathways in Healthy Men and Women123

Science.gov (United States)

da Silva, Vanessa R.; Rios-Avila, Luisa; Lamers, Yvonne; Ralat, Maria A.; Midttun, Øivind; Quinlivan, Eoin P.; Garrett, Timothy J.; Coats, Bonnie; Shankar, Meena N.; Percival, Susan S.; Chi, Yueh-Yun; Muller, Keith E.; Ueland, Per Magne; Stacpoole, Peter W.; Gregory, Jesse F.

2013-01-01

Suboptimal vitamin B-6 status, as reflected by low plasma pyridoxal 5′-phosphate (PLP) concentration, is associated with increased risk of vascular disease. PLP plays many roles, including in one-carbon metabolism for the acquisition and transfer of carbon units and in the transsulfuration pathway. PLP also serves as a coenzyme in the catabolism of tryptophan. We hypothesize that the pattern of these metabolites can provide information reflecting the functional impact of marginal vitamin B-6 deficiency. We report here the concentration of major constituents of one-carbon metabolic processes and the tryptophan catabolic pathway in plasma from 23 healthy men and women before and after a 28-d controlled dietary vitamin B-6 restriction (restriction yielded increased cystathionine (53% pre- and 76% postprandial; P restriction yielded lower kynurenic acid (22% pre- and 20% postprandial; P restriction and multilevel partial least squares-discriminant analysis supported this conclusion. Thus, plasma concentrations of creatine, cystathionine, kynurenic acid, and 3-hydroxykynurenine jointly reveal effects of vitamin B-6 restriction on the profiles of one-carbon and tryptophan metabolites and serve as biomarkers of functional effects of marginal vitamin B-6 deficiency. PMID:23966327

Assessing the associations of blood metabolites with osteoporosis: a Mendelian randomization study.

Science.gov (United States)

Liu, Li; Wen, Yan; Zhang, Lei; Xu, Peng; Liang, Xiao; Du, Yanan; Li, Ping; He, Awen; Fan, QianRui; Hao, Jingcan; Wang, Wenyu; Guo, Xiong; Shen, Hui; Tian, Qing; Zhang, Feng; Deng, Hong-Wen

2018-03-01

Osteoporosis is a metabolic bone disease. The impact of blood metabolites on the development of osteoporosis remains elusive now. To explore the relationship between blood metabolites and osteoporosis. We used 2,286 unrelated Caucasian subjects as discovery samples and 3,143 unrelated Caucasian subjects from the Framingham heart study (FHS) as replication samples. Bone mineral density (BMD) were measured using dual-energy X-ray absorptiometry. Genome-wide SNP genotyping was performed using Affymetrix Human SNP Array 6.0 (for discovery samples) and Affymetrix SNP 500K and 50K array (for FHS replication samples). The SNP sets significantly associated with blood metabolites were obtained from a published whole-genome sequencing study. For each subject, the genetic risk score (GRS) of metabolite was calculated from the genotype data of metabolite associated SNP sets. Pearson correlation analysis was conducted to evaluate the potential impact of blood metabolites on the variations bone phenotypes. 10,000 permutations were conducted to calculate the empirical P value and false discovery rate (FDR). 481 blood metabolites were analyzed in this study. We identified multiple blood metabolites associated with hip BMD, such as 1,5-anhydroglucitol(1,5-AG) (Pdiscovery metabolites on the variations of BMD, and identified several candidate blood metabolites for osteoporosis.

Cytotoxic Cytochalasins and Other Metabolites from Xylariaceae sp. FL0390, a Fungal Endophyte of Spanish Moss.

Science.gov (United States)

Xu, Ya-Ming; Bashyal, Bharat P; Liu, Mangping X; Espinosa-Artiles, Patricia; U'Ren, Jana M; Arnold, A Elizabeth; Gunatilaka, A A Leslie

2015-10-01

Two new metabolites, 6-oxo-12-norcytochalasin D (1) and 4,5-di-isobutyl-2(1H)-pyrimidinone (2), together with seven known metabolites, cytochalasins D (3), Q (4), and N (5), 12-hydroxyzygosporin G (6), heptelidic acid chlorohydrin (7), (+)-heptelidic acid (8), and trichoderonic acid A (9), were isolated from Xylariaceae sp. FL0390, a fungal endophyte inhabiting Spanish moss, Tillandsia usneoides. Metabolite 1 is the first example of a 12-norcytochalasin. All metabolites, except 2 and 9, showed cytotoxic activity in a panel of five human tumor cell lines with IC50S of 0.2-5.0 μM.

Metabolites of alectinib in human: their identification and pharmacological activity

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Mika Sato-Nakai

2017-07-01

Full Text Available Two metabolites (M4 and M1b in plasma and four metabolites (M4, M6, M1a and M1b in faeces were detected through the human ADME study following a single oral administration of [14C]alectinib, a small-molecule anaplastic lymphoma kinase inhibitor, to healthy subjects. In the present study, M1a and M1b, which chemical structures had not been identified prior to the human ADME study, were identified as isomers of a carboxylate metabolite oxidatively cleaved at the morpholine ring. In faeces, M4 and M1b were the main metabolites, which shows that the biotransformation to M4 and M1b represents two main metabolic pathways for alectinib. In plasma, M4 was a major metabolite and M1b was a minor metabolite. The contribution to in vivo pharmacological activity of these circulating metabolites was assessed from their in vitro pharmacological activity and plasma protein binding. M4 had a similar cancer cell growth inhibitory activity and plasma protein binding to that of alectinib, suggesting its contribution to the antitumor activity of alectinib, whereas the pharmacological activity of M1b was insignificant.

Determinants of Organophosphorus Pesticide Urinary Metabolite Levels in Young Children Living in an Agricultural Community

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Brenda Eskenazi

2011-04-01

Full Text Available Organophosphorus (OP pesticides are used in agriculture and several are registered for home use. As young children age they may experience different pesticide exposures due to varying diet, behavior, and other factors. We measured six OP dialkylphosphate (DAP metabolites (three dimethyl alkylphosphates (DMAP and three diethyl alkylphosphates (DEAP in urine samples collected from ~400 children living in an agricultural community when they were 6, 12, and 24 months old. We examined bivariate associations between DAP metabolite levels and determinants such as age, diet, season, and parent occupation. To evaluate independent impacts, we then used generalized linear mixed multivariable models including interaction terms with age. The final models indicated that DMAP metabolite levels increased with age. DMAP levels were also positively associated with daily servings of produce at 6- and 24-months. Among the 6-month olds, DMAP metabolite levels were higher when samples were collected during the summer/spring versus the winter/fall months. Among the 12-month olds, DMAP and DEAP metabolites were higher when children lived ≤60 meters from an agricultural field. Among the 24-month-olds, DEAP metabolite levels were higher during the summer/spring months. Our findings suggest that there are multiple determinants of OP pesticide exposures, notably dietary intake and temporal and spatial proximity to agricultural use. The impact of these determinants varied by age and class of DAP metabolite.

Different Cholinesterase Inhibitor Effects on CSF Cholinesterases in Alzheimer Patients

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Nordberg, Agneta; Darreh-Shori, Taher; Peskind, Elaine; Soininen, Hilkka; Mousavi, Malahat; Eagle, Gina; Lane, Roger

2014-01-01

Background The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients. Methods and Findings AD patients aged 50–85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman’s colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2%increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively. Conclusion The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation. PMID:19199870

Chemopreventive Activities of Sulforaphane and Its Metabolites in Human Hepatoma HepG2 Cells

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Peng Liu

2018-05-01

Full Text Available Sulforaphane (SFN exhibits chemopreventive effects through various mechanisms. However, few studies have focused on the bioactivities of its metabolites. Here, three metabolites derived from SFN were studied, known as sulforaphane glutathione, sulforaphane cysteine and sulforaphane-N-acetylcysteine. Their effects on cell viability, DNA damage, tumorigenicity, cell migration and adhesion were measured in human hepatoma HepG2 cells, and their anti-angiogenetic effects were determined in a 3D co-culture model of human umbilical vein endothelial cells (HUVECs and pericytes. Results indicated that these metabolites at high doses decreased cancer cell viability, induced DNA damage and inhibited motility, and impaired endothelial cell migration and tube formation. Additionally, pre-treatment with low doses of SFN metabolites protected against H2O2 challenge. The activation of the nuclear factor E2-related factor 2 (Nrf2-antioxidant response element (ARE pathway and the induction of intracellular glutathione (GSH played an important role in the cytoprotective effects of SFN metabolites. In conclusion, SFN metabolites exhibited similar cytotoxic and cytoprotective effects to SFN, which proves the necessity to study the mechanisms of action of not only SFN but also of its metabolites. Based on the different tissue distribution profiles of these metabolites, the most relevant chemical forms can be selected for targeted chemoprevention.

Complicating factors in safety testing of drug metabolites: Kinetic differences between generated and preformed metabolites

International Nuclear Information System (INIS)

Prueksaritanont, Thomayant; Lin, Jiunn H.; Baillie, Thomas A.

2006-01-01

This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models

Syntheses, crystal structures, and characterization of two new Tl{sup +}-Cu{sup 2+}-Te{sup 6+} oxides: Tl{sub 4}CuTeO{sub 6} and Tl{sub 6}CuTe{sub 2}O{sub 10}

Energy Technology Data Exchange (ETDEWEB)

Yeon, Jeongho; Kim, Sang-Hwan [Department of Chemistry, University of Houston, 136 Fleming Building, Houston, TX 77204-5003 (United States); Green, Mark A. [Department of Materials Science and Engineering, University of Maryland, College Park, MD, 20742-2115 and NIST Center for Neutron Research, National Institute of Standard and Technology, 100 Bureau Drive, Gaithersburg, MD 20899-6103 (United States); Bhatti, Kanwal Preet; Leighton, C. [Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455-0132 (United States); Shiv Halasyamani, P., E-mail: psh@uh.edu [Department of Chemistry, University of Houston, 136 Fleming Building, Houston, TX 77204-5003 (United States)

2012-12-15

Crystals and polycrystalline powders of two new oxide materials, Tl{sub 4}CuTeO{sub 6} and Tl{sub 6}CuTe{sub 2}O{sub 10}, have been synthesized by hydrothermal and solid-state methods. The materials were structurally characterized by single-crystal X-ray diffraction. Tl{sub 4}CuTeO{sub 6} and Tl{sub 6}CuTe{sub 2}O{sub 10} exhibit one dimensional anionic slabs of [CuTeO{sub 6}]{sup 4-} and [CuTe{sub 2}O{sub 10}]{sup 6-}, respectively. Common to both slabs is the occurrence of Cu{sup 2+}O{sub 4} distorted squares and Te{sup 6+}O{sub 6} octahedra. The slabs are separated by Tl{sup +} cations. For Tl{sub 4}CuTeO{sub 6}, magnetic measurements indicate a maximum at {approx}8 K in the temperature dependence of the susceptibility. Low temperature neutron diffraction data confirm no long-range magnetic ordering occurs and the susceptibility was adequately accounted for by fits to a Heisenberg alternating chain model. For Tl{sub 6}CuTe{sub 2}O{sub 10} on the other hand, magnetic measurements revealed paramagnetism with no evidence of long-range magnetic ordering. Infrared, UV-vis spectra, thermogravimetric, and differential thermal analyses are also reported. Crystal data: Tl{sub 4}CuTeO{sub 6}, Triclinic, space group P-1 (No. 2), a=5.8629(8) A, b=8.7848(11) A, c=9.2572(12) A, {alpha}=66.0460(10), {beta}=74.2010(10), {gamma}=79.254(2), V=417.70(9) A{sup 3}, and Z=2; Tl{sub 6}CuTe{sub 2}O{sub 10}, orthorhombic, space group Pnma (No. 62), a=10.8628(6) A, b=11.4962(7) A, c=10.7238(6) A, V=1339.20(13) A{sup 3}, and Z=4. - Graphical Abstract: Two new oxide materials, Tl{sub 4}CuTeO{sub 6} and Tl{sub 6}CuTe{sub 2}O{sub 10}, have been synthesized and characterized. The materials exhibit one dimensional crystal structures consisting of CuO{sub 4} and TeO{sub 6} polyhedra. Highlights: Black-Right-Pointing-Pointer Two New Tl-Te-Cu-oxides have been synthesized and structurally characterized. Black-Right-Pointing-Pointer For Tl{sub 4}CuTeO{sub 6}, magnetic measurements indicate a

Ge 3P 6Si 2O 25: A cage structure closely related to the intersecting tunnel structure KMo 3P 6Si 2O 25

Science.gov (United States)

Leclaire, A.; Raveau, B.

1988-08-01

A germanosilicophosphate Ge 3P 6Si 2O 25 has been isolated. Its structure was solved from a single-crystal study in the space group P overline31c . Its cell parameters are a = b = 7.994(1) Å, c = 16.513(2) Å, Z = 2. The refinement by full-matrix least-squares calculations leads to R = 0.043 with 686 independent reflections. The structure of this oxide is built up from corner-sharing PO 4 and SiO 4 tetrahedra and GeO 6 octahedra. One observes a feature common to several silicophosphates: the presence of the structural unit P 6Si 2O 25 built up from a disilicate group sharing its corners with six PO 4 tetrahedra. The structural relationships between this oxide and the silicophosphates AMo 3P 6Si 2O 25 and Si 3P 6Si 2O 25 (or Ge 3P 6 Ge 2O 25) are described.

Metabolites in Blood for Prediction of Bacteremic Sepsis in the Emergency Room.

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Anna M Kauppi

Full Text Available A metabolomics approach for prediction of bacteremic sepsis in patients in the emergency room (ER was investigated. In a prospective study, whole blood samples from 65 patients with bacteremic sepsis and 49 ER controls were compared. The blood samples were analyzed using gas chromatography coupled to time-of-flight mass spectrometry. Multivariate and logistic regression modeling using metabolites identified by chromatography or using conventional laboratory parameters and clinical scores of infection were employed. A predictive model of bacteremic sepsis with 107 metabolites was developed and validated. The number of metabolites was reduced stepwise until identifying a set of 6 predictive metabolites. A 6-metabolite predictive logistic regression model showed a sensitivity of 0.91(95% CI 0.69-0.99 and a specificity 0.84 (95% CI 0.58-0.94 with an AUC of 0.93 (95% CI 0.89-1.01. Myristic acid was the single most predictive metabolite, with a sensitivity of 1.00 (95% CI 0.85-1.00 and specificity of 0.95 (95% CI 0.74-0.99, and performed better than various combinations of conventional laboratory and clinical parameters. We found that a metabolomics approach for analysis of acute blood samples was useful for identification of patients with bacteremic sepsis. Metabolomics should be further evaluated as a new tool for infection diagnostics.

Electronic structures and properties of the rhenium alkoxy derivatives Re2O3(OMe)6, Re4O6(OMe)12, and ReMoO2(OMe)7

International Nuclear Information System (INIS)

Ermakov, A.I.; Belousov, V.V.; Drobot, D.V.; Shcheglov, P.A.

2006-01-01

The geometrical structures, charge distributions, dipole moments, frequencies of normal vibrations, NMR spectra, and total energies of the chemical bonds for the rhenium alkoxy derivatives Re 2 O 3 (OMe) 6 , Re 4 O 6 (OMe) 12 , and ReMoO 2 (OMe) 7 were calculated by the DFT-B3LYP and Hartree-Fock ab initio methods based on the effective core potential theory (LANL2DZ approximation) and the semiempirical PM3(tm) method. Two optimized structures of Re 2 O 3 (OMe) 6 with close energies were found to substantially differ in geometry, 1 H, 13 C, and 17 O NMR spectra, and dipole moment. Various characteristics of the electronic structures and the trans-effect of the ligands in the compounds under consideration were discussed [ru

The significance of sampling time in therapeutic drug monitoring of clozapine

DEFF Research Database (Denmark)

Jakobsen, M I; Larsen, J R; Svensson, C K

2017-01-01

OBJECTIVE: Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite...... N-desmethyl-clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose. METHOD: Forty-six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10-14 h postdose. RESULTS: Minor changes in median percentage values were...

Vibrational spectra of Cs2Cu(SO4)2·6H2O and Cs2Cu(SeO4)2·nH2O (n = 4, 6) with a crystal structure determination of the Tutton salt Cs2Cu(SeO4)2·6H2O

Science.gov (United States)

Wildner, M.; Marinova, D.; Stoilova, D.

2016-02-01

The solubility in the three-component systems Cs2SO4-CuSO4-H2O and Cs2SeO4-CuSeO4-H2O have been studied at 25 °C. The experimental results show that double salts, Cs2Cu(SO4)2·6H2O and Cs2Cu(SeO4)2·4H2O, crystallize from the ternary solutions within large concentration ranges. Crystals of Cs2Cu(SeO4)2·6H2O were synthesized at somewhat lower temperatures (7-8 °C). The thermal dehydration of the title compounds was studied by TG, DTA and DSC methods and the respective dehydration schemes are proposed. The calculated enthalpies of dehydration (ΔHdeh) have values of: 434.2 kJ mol-1 (Cs2Cu(SeO4)2·6H2O), 280.9 kJ mol-1 (Cs2Cu(SeO4)2·4H2O), and 420.2 kJ mol-1 (the phase transition of Cs2Cu(SO4)2·6H2O into Cs2Cu(SO4)2·H2O). The crystal structure of Cs2Cu(SeO4)2ṡ6H2O was determined from single crystal X-ray diffraction data. It belongs to the group of Tutton salts, crystallizing isotypic to the respective sulfate in a monoclinic structure which is characterized by isolated Cu(H2O)6 octahedra and SeO4 tetrahedra, interlinked by hydrogen bonds and [9]-coordinated Cs+ cations. Infrared spectra of the cesium copper compounds are presented and discussed with respect to both the normal modes of the tetrahedral ions and the water molecules. The analysis of the infrared spectra of the double compounds reveals that the distortion of the selenate tetrahedra in Cs2Cu(SeO4)2·4H2O is stronger than those in Cs2Cu(SeO4)2·6H2O in agreement with the structural data. Matrix-infrared spectroscopy was applied to confirm this claim - Δν3 for SO4 2 - ions matrix-isolated in Cs2Cu(SeO4)2·6H2O has a value of 35 cm-1 and that of the same ions included in Cs2Cu(SeO4)2·4H2O - 84 cm-1. This spectroscopic finding is due to the formation of strong covalent bands Cu-OSO3 on one hand, and on the other to the stronger deformation of the host SeO4 2 - tetrahedra in Cs2Cu(SeO4)2·4H2O as compared to those in Cs2Cu(SeO4)2·6H2O. The strength of the hydrogen bonds as deduced from the

Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation.

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Więckowska, Anna; Kołaczkowski, Marcin; Bucki, Adam; Godyń, Justyna; Marcinkowska, Monika; Więckowski, Krzysztof; Zaręba, Paula; Siwek, Agata; Kazek, Grzegorz; Głuch-Lutwin, Monika; Mierzejewski, Paweł; Bienkowski, Przemysław; Sienkiewicz-Jarosz, Halina; Knez, Damijan; Wichur, Tomasz; Gobec, Stanislav; Malawska, Barbara

2016-11-29

As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT 6 receptor antagonist) over monotherapy with donepezil. Here, we present the first report on the design, synthesis and biological evaluation of a novel class of multifunctional ligands that combines a 5-HT 6 receptor antagonist with a cholinesterase inhibitor. Novel multi-target-directed ligands (MTDLs) were designed by combining pharmacophores directed against the 5-HT 6 receptor (1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-indole) and cholinesterases (tacrine or N-benzylpiperidine analogues). In vitro evaluation led to the identification of tacrine derivative 12 with well-balanced potencies against the 5-HT 6 receptor (K b  = 27 nM), acetylcholinesterase and butyrylcholinesterase (IC 50 hAChE  = 12 nM, IC 50 hBuChE  = 29 nM). The compound also showed good in vitro blood-brain-barrier permeability (PAMPA-BBB assay), which was confirmed in vivo (open field study). Central cholinomimetic activity was confirmed in vivo in rats using a scopolamine-induced hyperlocomotion model. A novel class of multifunctional ligands with compound 12 as the best derivative in a series represents an excellent starting point for the further development of an effective treatment for AD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Porritoxins, metabolites of Alternaria porri, as anti-tumor-promoting active compounds.

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Horiuchi, Masayuki; Tokuda, Harukuni; Ohnishi, Keiichiro; Yamashita, Masakazu; Nishino, Hoyoku; Maoka, Takashi

2006-02-01

To search for possible cancer chemopreventive agents from natural sources, we performed primary screening of metabolites of Alternaria porri by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The ethyl acetate extract of A. porri showed the inhibitory effect on EBV-EA activation. Three porritoxins (1-3) were obtained as inhibitory active compounds for EBV-EA from ethyl acetate extract. 6-(3',3'-Dimethylallyloxy)-4-methoxy-5-methylphthalide (2) showed the strongest activity among them. Inhibitory effect of porritoxin (1) and (2) was superior to that of beta-carotene, a well-known anti-tumor promoter. Furthermore, the structure-activity correlation of porritoxins and their related compounds were discussed.

Identification of metabolites during biodegradation of pendimethalin in bioslurry reactor

International Nuclear Information System (INIS)

Ramakrishna, M.; Venkata Mohan, S.; Shailaja, S.; Narashima, R.; Sarma, P.N.

2008-01-01

Bioslurry phase reactor was used for the degradation of pendimethalin, a pre-emergence herbicide in the contaminated soil under aerobic environment. More than 91% degradation of pendimethalin was observed for 5 days of reactor operation augmented with sewage from effluent treatment plant (ETP). The performance of the reactor was monitored regularly by measuring pH and colony forming units (CFU). The metabolites of pendimethalin formed during degradation were identified using various analytical techniques, viz., thin layer chromatography (TLC), high performance liquid chromatography (HPLC) and liquid chromatography-mass spectroscopy (LC-MS/MS). Four metabolites were formed and identified as N-(1-ethylpropyl)-3,4-dicarboxy 2,6-dinitrobenzenamine-N-oxide, N-(1-ethylpropyl)-3,4-dimethoxy-2,6-dinitrobenzenamine and benezimadazole-7-carboxyaldehyde. The reactions involved were monohydrolysis of 2-methyl groups followed by dihydrolysis. Further oxidation of amine groups and hydroxylation of propyl groups produced the above said metabolites. Degradation pathway of pendimethalin has been proposed in the bioslurry phase reactor

Abscisic Acid Induced Changes in Production of Primary and Secondary Metabolites, Photosynthetic Capacity, Antioxidant Capability, Antioxidant Enzymes and Lipoxygenase Inhibitory Activity of Orthosiphon stamineus Benth.

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Mohd Hafiz Ibrahim

2013-07-01

Full Text Available An experiment was conducted to investigate and distinguish the relationships in the production of total phenolics, total flavonoids, soluble sugars, H2O2, O2−, phenylalanine ammonia lyase (PAL activity, leaf gas exchange, antioxidant activity, antioxidant enzyme activity [ascorbate peroxidase (APX, catalase (CAT, superoxide dismutase (SOD and Lipoxygenase inhibitory activity (LOX] under four levels of foliar abscisic acid (ABA application (0, 2, 4, 6 µM for 15 weeks in Orthosiphon stamineus Benth. It was found that the production of plant secondary metabolites, soluble sugars, antioxidant activity, PAL activity and LOX inhibitory activity was influenced by foliar application of ABA. As the concentration of ABA was increased from 0 to 6 µM the production of total phenolics, flavonoids, sucrose, H2O2, O2−, PAL activity and LOX inhibitory activity was enhanced. It was also observed that the antioxidant capabilities (DPPH and ORAC were increased. This was followed by increases in production of antioxidant enzymes APX, CAT and SOD. Under high application rates of ABA the net photosynthesis and stomatal conductance was found to be reduced. The production of primary and secondary metabolites displayed a significant positive relationship with H2O2 (total phenolics, r2 = 0.877; total flavonoids, r2 = 0.812; p ≤ 0.05 and O2− (total phenolics, r2 = 0.778; total flavonoids, r2 = 0.912; p ≤ 0.05. This indicated that increased oxidative stress at high application rates of ABA, improved the production of phytochemicals.

Determination of the Nicotine Metabolites Cotinine and Trans-3′-Hydroxycotinine in Biologic fluids of Smokers and Non-Smokers using Liquid Chromatography - Tandem Mass Spectrometry: Biomarkers for Tobacco Smoke Exposure and for Phenotyping Cytochrome P450 2A6 Activity

Science.gov (United States)

Jacob, Peyton; Yu, Lisa; Duan, Minjiang; Ramos, Lita; Yturralde, Olivia; Benowitz, Neal L.

2011-01-01

The nicotine metabolite cotinine is widely used to assess the extent of tobacco use in smokers, and secondhand smoke exposure in non-smokers. The ratio of another nicotine metabolite, trans-3′-hydroxycotinine, to cotinine in biofluids is highly correlated with the rate of nicotine metabolism, which is catalyzed mainly by Cytochrome P450 2A6 (CYP2A6). Consequently, this nicotine metabolite ratio is being used to phenotype individuals for CYP2A6 activity and to individualize pharmacotherapies for tobacco addiction. In this paper we describe a highly sensitive liquid chromatography – tandem mass spectrometry method for determination of the nicotine metabolites cotinine and trans-3′-hydroxycotinine in human plasma, urine, and saliva. Lower limits of quantitation range from 0.02 to 0.1 ng/ mL. The extraction procedure is straightforward and suitable for large-scale studies. The method has been applied to several thousand biofluid samples for pharmacogenetic studies and for studies of exposure to low levels of secondhand smoke. Concentrations of both metabolites in urine of non-smokers with different levels of secondhand smoke exposure are presented. PMID:21208832

Stable isotope N-phosphoryl amino acids labeling for quantitative profiling of amine-containing metabolites using liquid chromatography mass spectrometry.

Science.gov (United States)

Zhang, Shanshan; Shi, Jinwen; Shan, Changkai; Huang, Chengting; Wu, Yile; Ding, Rong; Xue, Yuhua; Liu, Wen; Zhou, Qiang; Zhao, Yufen; Xu, Pengxiang; Gao, Xiang

2017-07-25

Stable isotope chemical labeling liquid chromatography-mass spectrometry (LC-MS) is a powerful strategy for comprehensive metabolomics profiling, which can improve metabolites coverage and quantitative information for exploration of metabolic regulation in complex biological systems. In the current work, a novel stable isotope N-phosphoryl amino acids labeling strategy (SIPAL) has been successful developed for quantitative profiling of amine-containing metabolites in urine based on organic phosphorus chemistry. Two isotopic reagents, 16 O 2 - and 18 O 2 -N-diisopropyl phosphoryl l-alanine N-hydroxysuccinimide esters ( 16 O/ 18 O-DIPP-L-Ala-NHS), were firstly synthesized in high yields for labeling the amine-containing metabolites. The performance of SIPAL strategy was tested by analyzing standard samples including 20 l-amino acids, 10 d-amino acids and small peptides by using LC-MS. We observed highly efficient and selective labeling for SIPAL strategy within 15 min in a one-pot derivatization reaction under aqueous reaction conditions. The introduction of a neutral phosphate group at N-terminus can increase the proton affinity and overall hydrophobicity of targeted metabolites, leading to the better ionization efficiency in electrospray ionization processes and chromatographic separations of hydrophilic metabolites on reversed-phase column. Furthermore, the chiral metabolites, such as d-amino acids, could be converted to diastereomers after SIPAL and successfully separated on regular reversed-phase column. The chirality of labeled enantiomers can be determined by using different detection methods such as 31 P NMR, UV, and MS, demonstrating the potential application of SIPAL strategy. In addition, absolute quantification of chiral metabolites in biological samples can be easily achieved by using SIPAL strategy. For this purpose, urine samples collected from a healthy volunteer were analyzed by using LC-ESI-Orbitrap MS. Over 300 pairs of different amine

Modular Synthesis of Heparin-Related Tetra-, Hexa- and Octasaccharides with Differential O-6 Protections: Programming for Regiodefined 6-O-Modifications

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Marek Baráth

2015-04-01

Full Text Available Heparin and heparan sulphate (H/HS are important members of the glycosaminoglycan family of sugars that regulate a substantial number of biological processes. Such biological promiscuity is underpinned by hetereogeneity in their molecular structure. The degree of O-sulfation, particularly at the 6-position of constituent D-GlcN units, is believed to play a role in modulating the effects of such sequences. Synthetic chemistry is essential to be able to extend the diversity of HS-like fragments with defined molecular structure, and particularly to deconvolute the biological significance of modifications at O6. Here we report a synthetic approach to a small matrix of protected heparin-type oligosaccharides, containing orthogonal D-GlcN O-6 protecting groups at programmed positions along the chain, facilitating access towards programmed modifications at specific sites, relevant to sulfation or future mimetics.

Tocopherol metabolites 2, 5, 7, 8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2, 7, 8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC) in human serum after a single dose of natural vitamin E.

Science.gov (United States)

Radosavac, Dragan; Graf, Peter; Polidori, M Cristina; Sies, Helmut; Stahl, Wilhelm

2002-06-01

alpha- and gamma-Tocopherol are vitamin E compounds in human blood and tissues. alpha-CEHC (2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman) and gamma-CEHC (2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman) have been identified as water-soluble metabolites which are excreted with the urine in humans. To assess over-time changes of serum levels of alpha- and gamma-CEHC in humans after a single dose of vitamin E from a natural source. Twenty-one healthy subjects ingested a single dose of vitamin E (306 mg of RRR-alpha-tocopherol and 1.77 mg of gamma-tocopherol). Blood was collected before (baseline) and 2, 6, 12, 24, 35, 50, and 74 h after ingestion. Serum was separated and levels of alpha- and gamma-tocopherol and alpha- and gamma-CEHC were determined by HPLC. After vitamin E ingestion, a statistically significant increase was observed for alpha-tocopherol and alpha-CEHC. Maximum serum levels for both compounds were measured 12 h after application (33.3 +/- 11.1 micromol alpha-toco-pherol /L and 42.4 +/- 18.3 nmol alpha-CEHC /L); baseline values were reached again after 72 h. While gamma-tocopherol levels decreased during the study period, an increase in the metabolite gamma-CEHC was observed. The optical isomer formed in the metabolism of RRR-alpha-tocopherol was assigned as S-alpha-CEHC. alpha-CEHC levels increase after administration of a single dose of natural vitamin E in humans. The appearance of the metabolite in blood parallels that of the parent compound. The gamma-tocopherol analog appears to be metabolized more efficiently than alpha-tocopherol.

Propane-1,3-diammonium bis[aquachlorido(4-hydroxypyridine-2,6-dicarboxylato-κ3O2,N,O6mercurate(II] tetrahydrate

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Hossein Aghabozorg

2008-08-01

Full Text Available The reaction of mercury(II chloride dihydrate, propane-1,3-diamine and 4-hydroxypyridine-2,6-dicarboxylic acid in a 1:1:1 molar ratio in aqueous solution, resulted in the formation of the title compound, (C3H12N2[Hg(C7H3NO5Cl(H2O]2·4H2O or (pnH2[Hg(hypydcCl(H2O]2·4H2O (where pn is propane-1,3-diamine and hypydcH2 is 4-hydroxypyridine-2,6-dicarboxylic acid. The metal atom is coordinated by one chloride group, one water molecule cis to the chloride ligand and one (hypydc2− ligand. The coordinated water molecule is almost perpendicular to the plane of the aromatic ring of (hypydc2−. The geometry of the resulting HgClNO3 coordination can be described as distorted square-pyramidal. This structure also contains propane-1,3-diammonium (site symmetry 2 as a counter-ion and four uncoordinated water molecules. There is a wide range of non-covalent interactions consisting of hydrogen bonding [of the types O—H...O, N—H...O and C—H...O, with D...A ranging from 2.548 (5 to 3.393 (6 Å] and ion pairing.

Spin 1/2 Delafossite Honeycomb Compound Cu5SbO6

DEFF Research Database (Denmark)

Climent-Pascual, E.; Norby, Poul; Andersen, Niels Hessel

2012-01-01

Cu5SbO6 is found to have a monoclinic, Delafossite-derived structure consisting of alternating layers of O–Cu(I)–O sticks and magnetic layers of Jahn–Teller distorted Cu(II)O6 octahedra in an edge sharing honeycomb arrangement with Sb(V)O6 octahedra. This yields the structural formula Cu(I)3Cu(II...

Pharmacokinetic study of isocorynoxeine metabolites mediated by cytochrome P450 enzymes in rat and human liver microsomes.

Science.gov (United States)

Zhao, Lizhu; Zang, Bin; Qi, Wen; Chen, Fangfang; Wang, Haibo; Kano, Yoshihiro; Yuan, Dan

2016-06-01

Isocorynoxeine (ICN) is one of the major bioactive tetracyclic oxindole alkaloids found in Uncaria rhynchophylla (Miq.) Jacks. that is widely used for the treatment of hypertension, vascular dementia, and stroke. The present study was undertaken to assess the plasma pharmacokinetic characteristics of major ICN metabolites, and the role of simulated gastric and intestinal fluid (SGF and SIF), human and rat liver microsomes (HLMs and RLMs), and seven recombinant human CYP enzymes in the major metabolic pathway of ICN. A rapid, sensitive and accurate UHPLC/Q-TOF MS method was validated for the simultaneous determination of ICN and its seven metabolites in rat plasma after oral administration of ICN at 40mg/kg. It was found that 18.19-dehydrocorynoxinic acid (DCA) and 5-oxoisocorynoxeinic acid (5-O-ICA) were both key and predominant metabolites, rather than ICN itself, due to the rapid and extensive metabolism of ICN in vivo. The further study indicated that ICN was mainly metabolized in human or rat liver, and CYPs 2C19, 3A4 and 2D6 were the major enzymes responsible for the biotransformation of ICN to DCA and 5-O-ICA in human. These findings are of significance in understanding of the pharmacokinetic nature of tetracyclic oxindole alkaloids, and provide helpful information for the clinical co-administration of the herbal preparations containing U. rhynchophylla with antihypertensive drugs that are mainly metabolized by CYP3A4 and CYP2C19. Copyright © 2016 Elsevier B.V. All rights reserved.

Profiling of primary metabolites and flavonols in leaves of two table grape varieties collected from semiarid and temperate regions.

Science.gov (United States)

Harb, Jamil; Alseekh, Saleh; Tohge, Takayuki; Fernie, Alisdair R

2015-09-01

Cultivation of grapes in West Bank - Palestine is very old and a large number of grape varieties exist as a result of continuous domestication over thousands of years. This rich biodiversity has highly influenced the consumer behavior of local people, who consume both grape berries and leaves. However, studies that address the contents of health-promoting metabolites in leaves are scarce. Accordingly the aim of this study is to assess metabolite levels in leaves of two grape varieties that were collected from semiarid and temperate regions. Metabolic profiling was conducted using GC-MS and LC-MS. The obtained results show that abiotic stresses in the semiarid region led to clear changes in primary metabolites, in particular in amino acids, which exist at very high levels. By contrast, qualitative and genotype-dependent differences in secondary metabolites were observed, whereas abiotic stresses appear to have negligible effect on the content of these metabolites. The qualitative difference in the flavonol profiles between the two genotypes is most probably related to differential expression of specific genes, in particular flavonol 3-O-rhamnosyltransferase, flavonol-3-O-glycoside pentosyltransferases and flavonol-3-O-d-glucosidel-rhamnosyltransferase by 'Beituni' grape leaves, which led to much higher levels of flavonols with rutinoside, pentoside, and rhamnoside moieties with this genotype. Copyright © 2015 Elsevier Ltd. All rights reserved.

Analytical method for urinary metabolites of the fluorine-containing pyrethroids metofluthrin, profluthrin and transfluthrin by gas chromatography/mass spectrometry.

Science.gov (United States)

Yoshida, Toshiaki

2013-01-15

An analytical method was developed for measurement of the major urinary metabolites in rats administered fluorine-containing pyrethroids (metofluthrin, profluthrin and transfluthrin) which are widely used recently as mosquito repellents or mothproof repellents. Eight metabolites, 2,3,5,6-tetrafluorobenzoic acid, 4-methyl-2,3,5,6-tetrafluorobenzoic acid, 2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylic acid, 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (carboxylic metabolites), 2,3,5,6-tetrafluorobenzyl alcohol, 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol, 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol and 4-hydroxymethyl-2,3,5,6-tetrafluorobenzyl alcohol (alcoholic metabolites), were extracted from enzymatic hydrolyzed urine using toluene and then concentrated. After transformation to their tert-butyldimethylsilyl derivatives for carboxylic metabolites or their trimethylsilyl derivatives for alcoholic metabolites, analysis was conducted by gas chromatography/mass spectrometry in the electron impact ionization mode. The calibration curves for each metabolite were linear over the concentration range of 0-20μg/ml in urine, and the quantification limits were between 0.009 and 0.03μg/ml. The relative errors and the relative standard deviations on replicate assays were less than 6% and 5%, respectively, for all concentrations studied. The measurements were accurate and precise. The collected urine samples could be stored for up to 1 month at -20°C in a freezer. The proposed method was applied to the analysis of several urine samples collected from rats treated with these pyrethroids. Copyright © 2012 Elsevier B.V. All rights reserved.

Structural elucidation of in vitro and in vivo metabolites of emodin in rats by LC -ESI-MS/MS

International Nuclear Information System (INIS)

Wang, D.; Zhu, Q.; Chen, G.; Liu, B.; Chen, L.

2013-01-01

Emodin is a widely occurring natural product and has been studied extensively for its varieties of pharmacological activity. In attempt to know more deeply about its metabolism, this paper investigated the metabolites of emodin in rats, including its in vitro conversion product by intestinal microflora and urinary metabolites. The detection of emodin metabolites was performed by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) with negative ion mode. By comparing the changes of metabolites in molecular masses (delta M), product ions and retention times with those of the parent drug, six metabolites (8-O-methylemodin, omega-hydroxyemodin, x-hydroxyemodin, emodin glucuronide, hydroxyemodin glucuronide and emodin sulfate) were observed,and what is more, the metabolite hydroxyemodin glucuronide was first reported in this article. For some metabolites, identification of their precise structure needs to be confirmed by other techniques such as the 1H and 13C NMR. (author)

Enantioselective pharmacokinetics of sibutramine in rat.

Science.gov (United States)

Noh, Keumhan; Bae, Kyoungjin; Min, Bokyoung; Kim, Eunyoung; Kwon, Kwang-il; Jeong, Taecheon; Kang, Wonku

2010-02-01

Racemic sibutramine is widely used to treat obesity owing to its inhibition of serotonin and noradrenaline reuptake in synapses. Although the enantioselective effects of sibutramine and its two active desmethyl-metabolites, monodesmethylsibutramine (MDS) and didesmethylsibutramine (DDS), on anorexia and energy expenditure have been elucidated, the enantioselective pharmacokinetics of sibutramine are still unclear. Therefore, we aimed to characterize the enantioselective pharmacokinetics of sibutramine and its metabolites in plasma and urine following an intravenous and a single oral administration of sibutramine in rats. The absolute bioavailability of sibutramine was only about 7%. The pharmacologically less effective S-isomer of DDS was predominant in the plasma: the C ( max ) and the AUC ( inf ) were 28 and 30 times higher than those of the R-isomer, respectively (psibutramine metabolites MDS and DDS were present at lower concentrations, owing to their rapid biotransformation to hydroxylated and/or carbamoylglucuronized forms and their faster excretion in the urine. The present study is the first to elucidate the enantioselective pharmacokinetics of sibutramine in rats.

Isolation and Characterization of a Human Intestinal Bacterium Eggerthella sp. AUH-JLD49s for the Conversion of (-)-3'-Desmethylarctigenin.

Science.gov (United States)

Wang, Ye; Yu, Fei; Liu, Ming-Yue; Zhao, Yi-Kai; Wang, Dong-Ming; Hao, Qing-Hong; Wang, Xiu-Ling

2017-05-24

Arctiin is the most abundant bioactive compound contained in the Arctium lappa plant. In our previous study, we isolated one single bacterium capable of bioconverting arctigenin, an aglycone of arctiin, to 3'-desmethylarctigenin (3'-DMAG) solely. However, to date, a specific bacterium capable of producing other arctiin metabolites has not been reported. In this study, we isolated one single bacterium, which we named Eggerthella sp. AUH-JLD49s, capable of bioconverting 3'-DMAG under anaerobic conditions. The metabolite of 3'-DMAG by strain AUH-JLD49s was identified as 3'-desmethyl-4'-dehydroxyarctigenin (DMDH-AG) based on electrospray ionization mass spectrometry (ESI-MS) and 1 H and 13 C nuclear magnetic resonance spectroscopy. The bioconversion kinetics and bioconversion capacity of strain AUH-JLD49s were investigated. In addition, the metabolite DMDH-AG showed an inhibitory effect on cell growth of human colon cancer cell line HCT116 and human breast cancer cell line MDA-MB-231.

Immune regulation by microbiome metabolites.

Science.gov (United States)

Kim, Chang H

2018-03-22

Commensal microbes and the host immune system have been co-evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite-specific receptors such as P2X 7 , GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets. Microbial metabolites and their receptors form an extensive array of signals to respond to changes in nutrition, health and immunological status. As a consequence, microbial metabolite signals contribute to nutrient harvest from diet, and regulate host metabolism and the immune system. Importantly, microbial metabolites bidirectionally function to promote both tolerance and immunity to effectively fight infection without developing inflammatory diseases. In pathogenic conditions, adverse effects of microbial metabolites have been observed as well. Key immune-regulatory functions of the metabolites, generated from carbohydrates, proteins and bile acids, are reviewed in this article. © 2018 John Wiley & Sons Ltd.

New Methodology for Known Metabolite Identification in Metabonomics/Metabolomics: Topological Metabolite Identification Carbon Efficiency (tMICE).

Science.gov (United States)

Sanchon-Lopez, Beatriz; Everett, Jeremy R

2016-09-02

A new, simple-to-implement and quantitative approach to assessing the confidence in NMR-based identification of known metabolites is introduced. The approach is based on a topological analysis of metabolite identification information available from NMR spectroscopy studies and is a development of the metabolite identification carbon efficiency (MICE) method. New topological metabolite identification indices are introduced, analyzed, and proposed for general use, including topological metabolite identification carbon efficiency (tMICE). Because known metabolite identification is one of the key bottlenecks in either NMR-spectroscopy- or mass spectrometry-based metabonomics/metabolomics studies, and given the fact that there is no current consensus on how to assess metabolite identification confidence, it is hoped that these new approaches and the topological indices will find utility.

Phase selection in the containerless solidification of undercooled CaO · 6Al2O3 melts

International Nuclear Information System (INIS)

Li Mingjun; Kuribayashi, Kazuhiko

2004-01-01

The CaO · 6Al 2 O 3 melts were solidified on an aero-acoustic levitator under a containerless processing condition at various undercoolings. A high-speed video was operated to monitor the recalescence behavior, from which the growth velocity as a function of melt undercooling was determined. The microstructures were observed and the crystalline phases were identified using the X-ray diffraction technique, indicting that the Al 2 O 3 was solidified when the melt temperature was higher than the peritectic temperature, T p . When the melt was undercooled below T p , the CaO · 6Al 2 O 3 (CA 6 ) peritectic phase was crystallized directly from the undercooled melts. With respect to the direct formation of the peritectic phase, further analysis from the viewpoints of competitive nucleation indicated that the minimum free energy principle may be applied to elucidate the nucleation of CA 6 phase. In terms of the competitive growth behavior, the interface attachment kinetics for Al 2 O 3 and CA 6 phases are calculated by using the classical BCT model indicating that although the Al 2 O 3 phase doped by CaO has about four times larger interface kinetic coefficient than that of the CA 6 peritectic phase, the growth kinetics of Al 2 O 3 in the melt with the CaO · 6Al 2 O 3 chemical composition is not sufficiently high to replace the CA 6 phase as the primary phase. Therefore, once CA 6 is nucleated, it can develop into a macro crystal as the primary phase. The competitive nucleation and growth behavior in the CA 6 system is different from those in other well-studied peritectic alloys and the present investigation on the phase formation will be an essential supplement to the phase selection theory

Combined Mass Spectrometry-Based Metabolite Profiling of Different Pigmented Rice (Oryza sativa L. Seeds and Correlation with Antioxidant Activities

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Ga Ryun Kim

2014-09-01

Full Text Available Nine varieties of pigmented rice (Oryza sativa L. seeds that were black, red, or white were used to perform metabolite profiling by using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS and gas chromatography (GC TOF-MS, to measure antioxidant activities. Clear grouping patterns determined by the color of the rice seeds were identified in principle component analysis (PCA derived from UPLC-Q-TOF-MS. Cyanidin-3-glucoside, peonidin-3-glucoside, proanthocyanidin dimer, proanthocyanidin trimer, apigenin-6-C-glugosyl-8-C-arabiboside, tricin-O-rhamnoside-O-hexoside, and lipids were identified as significantly different secondary metabolites. In PCA score plots derived from GC-TOF-MS, Jakwangdo (JKD and Ilpoom (IP species were discriminated from the other rice seeds by PC1 and PC2. Valine, phenylalanine, adenosine, pyruvate, nicotinic acid, succinic acid, maleic acid, malonic acid, gluconic acid, xylose, fructose, glucose, maltose, and myo-inositol were significantly different primary metabolites in JKD species, while GABA, asparagine, xylitol, and sucrose were significantly distributed in IP species. Analysis of antioxidant activities revealed that black and red rice seeds had higher activity than white rice seeds. Cyanidin-3-glucoside, peonidin-3-glucoside, proanthocyanidin dimers, proanthocyanidin trimers, and catechin were highly correlated with antioxidant activities, and were more plentiful in black and red rice seeds. These results are expected to provide valuable information that could help improve and develop rice-breeding techniques.

Identification of a new metabolite of GHB

DEFF Research Database (Denmark)

Petersen, Ida Nymann; Tortzen, Christian; Kristensen, Jesper Langgaard

2013-01-01

Gamma-hydroxybutyric acid (GHB) is an important analyte in clinical and forensic toxicology with a narrow detection window of 3-6 h. In the search of improved detection methods, the existence in vivo of a glucuronated GHB metabolite (GHB-GLUC) was hypothesized. Chemically pure standards of GHB...

Metabolite coupling in genome-scale metabolic networks

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Palsson Bernhard Ø

2006-03-01

Full Text Available Abstract Background Biochemically detailed stoichiometric matrices have now been reconstructed for various bacteria, yeast, and for the human cardiac mitochondrion based on genomic and proteomic data. These networks have been manually curated based on legacy data and elementally and charge balanced. Comparative analysis of these well curated networks is now possible. Pairs of metabolites often appear together in several network reactions, linking them topologically. This co-occurrence of pairs of metabolites in metabolic reactions is termed herein "metabolite coupling." These metabolite pairs can be directly computed from the stoichiometric matrix, S. Metabolite coupling is derived from the matrix ŜŜT, whose off-diagonal elements indicate the number of reactions in which any two metabolites participate together, where Ŝ is the binary form of S. Results Metabolite coupling in the studied networks was found to be dominated by a relatively small group of highly interacting pairs of metabolites. As would be expected, metabolites with high individual metabolite connectivity also tended to be those with the highest metabolite coupling, as the most connected metabolites couple more often. For metabolite pairs that are not highly coupled, we show that the number of reactions a pair of metabolites shares across a metabolic network closely approximates a line on a log-log scale. We also show that the preferential coupling of two metabolites with each other is spread across the spectrum of metabolites and is not unique to the most connected metabolites. We provide a measure for determining which metabolite pairs couple more often than would be expected based on their individual connectivity in the network and show that these metabolites often derive their principal biological functions from existing in pairs. Thus, analysis of metabolite coupling provides information beyond that which is found from studying the individual connectivity of individual

The crystal structures of 3-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-6-O-triphenylmethyl-α-d-glucofuranose and its azide displacement product

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Zane Clarke

2018-06-01

Full Text Available The effect of different leaving groups on the substitution versus elimination outcomes with C-5 d-glucose derivatives was investigated. The stereochemical configurations of 3-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-6-O-triphenylmethyl-α-d-glucofuranose, C36H38O8S (3 [systematic name: 1-[(3aR,5R,6S,6aR-6-benzyloxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl-2-(trityloxyethyl methanesulfonate], a stable intermediate, and 5-azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-6-O-triphenylmethyl-β-l-idofuranose, C35H35N3O5 (4 [systematic name: (3aR,5S,6S,6aR-5-[1-azido-2-(trityloxyethyl]-6-benzyloxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole], a substitution product, were examined and the inversion of configuration for the azido group on C-5 in 4 was confirmed. The absolute structures of the molecules in the crystals of both compounds were confirmed by resonant scattering. In the crystal of 3, neighbouring molecules are linked by C—H...O hydrogen bonds, forming chains along the b-axis direction. The chains are linked by C—H...π interactions, forming layers parallel to the ab plane. In the crystal of 4, molecules are also linked by C—H...O hydrogen bonds, forming this time helices along the a-axis direction. The helices are linked by a number of C—H...π interactions, forming a supramolecular framework.

Enhanced 77 K vortex-pinning in Y Ba2Cu3O7−x films with Ba2Y TaO6 and mixed Ba2Y TaO6 + Ba2Y NbO6 nano-columnar inclusions with irreversibility field to 11 T

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F. Rizzo

2016-06-01

Full Text Available Pulsed laser deposited thin Y Ba2Cu3O7−x (YBCO films with pinning additions of 5 at. % Ba2Y TaO6 (BYTO were compared to films with 2.5 at. % Ba2Y TaO6 + 2.5 at. % Ba2Y NbO6 (BYNTO additions. Excellent magnetic flux-pinning at 77 K was obtained with remarkably high irreversibility fields greater than 10 T (YBCO-BYTO and 11 T (YBCO-BYNTO, representing the highest ever achieved values in YBCO films.

Engineering Microbial Metabolite Dynamics and Heterogeneity.

Science.gov (United States)

Schmitz, Alexander C; Hartline, Christopher J; Zhang, Fuzhong

2017-10-01

As yields for biological chemical production in microorganisms approach their theoretical maximum, metabolic engineering requires new tools, and approaches for improvements beyond what traditional strategies can achieve. Engineering metabolite dynamics and metabolite heterogeneity is necessary to achieve further improvements in product titers, productivities, and yields. Metabolite dynamics, the ensemble change in metabolite concentration over time, arise from the need for microbes to adapt their metabolism in response to the extracellular environment and are important for controlling growth and productivity in industrial fermentations. Metabolite heterogeneity, the cell-to-cell variation in a metabolite concentration in an isoclonal population, has a significant impact on ensemble productivity. Recent advances in single cell analysis enable a more complete understanding of the processes driving metabolite heterogeneity and reveal metabolic engineering targets. The authors present an overview of the mechanistic origins of metabolite dynamics and heterogeneity, why they are important, their potential effects in chemical production processes, and tools and strategies for engineering metabolite dynamics and heterogeneity. The authors emphasize that the ability to control metabolite dynamics and heterogeneity will bring new avenues of engineering to increase productivity of microbial strains. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Desenvolvimento e avaliação das propriedades psicométricas da versão brasileira do Addiction Severity Index 6 (ASI-6 Light

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Lídia Reis Fernandes

2015-06-01

Full Text Available Objetivo Desenvolver e avaliar as propriedades psicométricas de uma versão brasileira reduzida do Addiction Severity Index 6 Light (ASI-6 Light previamente proposta com base em um estudo de validação dos construtos do instrumento e desenvolver os novos escores de cada área do instrumento baseados na Teoria de Resposta ao Item (TRI. Métodos Foram entrevistados 200 sujeitos, 100 com uso problemático de álcool e outras drogas e 100 sem uso problemático. Foram calculados os escores dos indivíduos com base na TRI. As propriedades psicométricas foram avaliadas pela correlação entre os escores do ASI-6 Light e do Alcohol, Smoking and Substance Involvement Screening Test (ASSIST, padrão-ouro do estudo. Foram avaliados os índices de sensibilidade e especificidade. Resultados Foi encontrada alta correlação entre os escores da área “álcool” do ASI-6 Light e os escores do ASSIST em relação ao álcool (r = 0,79, correlações moderadas em relação ao tabaco (r = 0,47 e cocaína/crack (r = 0,44 e baixa (r = 0,39 em relação à maconha. Ao correlacionarem-se os escores do ASSIST e os escores da área “drogas” do ASI-6 Light, obteve-se alta correlação em relação à cocaína/crack (r = 0,85, correlações moderadas em relação ao tabaco (r = 0,57 e maconha (r = 0,68 e baixa (r = 0,29 em relação ao álcool. A área sob a curva ROC da área “álcool” foi de 0,93 e a da área “drogas” foi de 0,88. Conclusão Boas evidências de validade das áreas “álcool” e “drogas” foram apresentadas. Essa nova versão tornou-se um instrumento de fácil manejo e de rápida aplicação, contendo os itens que melhor avaliam a gravidade de problemas.

Linking fungal secondary metabolites and pathways to their genes in Aspergillus

DEFF Research Database (Denmark)

Petersen, Lene Maj

. oryzae metabolites, however, revealed the chemical link between the two species. In two parallel projects, involving A. niger and A. aculeatus respectively, the polyketide 6-methyl salicylic acid (6-MSA), and corresponding biosynthetic pathways, were investigated. In A. niger, 6-MSA was converted...

Crop-ecology and nutritional variability influence growth and secondary metabolites of Stevia rebaudiana Bertoni.

Science.gov (United States)

Pal, Probir Kumar; Kumar, Rajender; Guleria, Vipan; Mahajan, Mitali; Prasad, Ramdeen; Pathania, Vijaylata; Gill, Baljinder Singh; Singh, Devinder; Chand, Gopi; Singh, Bikram; Singh, Rakesh Deosharan; Ahuja, Paramvir Singh

2015-02-27

Plant nutrition and climatic conditions play important roles on the growth and secondary metabolites of stevia (Stevia rebaudiana Bertoni); however, the nutritional dose is strongly governed by the soil properties and climatic conditions of the growing region. In northern India, the interactive effects of crop ecology and plant nutrition on yield and secondary metabolites of stevia are not yet properly understood. Thus, a field experiment comprising three levels of nitrogen, two levels of phosphorus and three levels of potassium was conducted at three locations to ascertain whether the spatial and nutritional variability would dominate the leaf yield and secondary metabolites profile of stevia. Principal component analysis (PCA) indicates that the applications of 90 kg N, 40 kg P2O5 and 40 kg K2O ha-1 are the best nutritional conditions in terms of dry leaf yield for CSIR-IHBT (Council of Scientific and Industrial Research- Institute Himalayan Bioresource Technology) and RHRS (Regional Horticultural Research Station) conditions. The spatial variability also exerted considerable effect on the leaf yield and stevioside content in leaves. Among the three locations, CSIR-IHBT was found most suitable in case of dry leaf yield and secondary metabolites accumulation in leaves. The results suggest that dry leaf yield and accumulation of stevioside are controlled by the environmental factors and agronomic management; however, the accumulation of rebaudioside-A (Reb-A) is not much influenced by these two factors. Thus, leaf yield and secondary metabolite profiles of stevia can be improved through the selection of appropriate growing locations and proper nutrient management.

Direct detection of glucuronide metabolites of lidocaine in sheep urine.

Science.gov (United States)

Doran, Gregory S; Smith, Alistair K; Rothwell, Jim T; Edwards, Scott H

2018-02-15

The anaesthetic lidocaine is metabolised quickly to produce a series of metabolites, including several hydroxylated metabolites, which are further metabolised by addition of a glucuronic acid moiety. Analysis of these glucuronide metabolites in urine is performed indirectly by cleaving the glucuronic acid group using β-glucuronidase. However, direct analysis of intact glucuronide conjugates is a more straightforward approach as it negates the need for long hydrolysis incubations, and minimises the oxidation of sensitive hydrolysis products, while also distinguishing between the two forms of hydroxylated metabolites. A method was developed to identify three intact glucuronides of lidocaine in sheep urine using LC-MS/MS, which was further confirmed by the synthesis of glucuronide derivatives of 3OH-MEGX and 4OH-LIDO. Direct analysis of urine allowed the detection of the glucuronide metabolites of hydroxylidocaine (OH-LIDO), hydroxyl-monoethylglycinexylidide (OH-MEGX), and hydroxy-2,6-xylidine (OH-XYL). Analysis of urine before and after β-glucuronidase digestion showed that the efficiency of hydrolysis of these glucuronide metabolites may be underestimated in some studies. Analysis of urine in the current study from three different sheep with similar glucuronide metabolite concentrations resulted in different hydrolysis efficiencies, which may have been a result of different levels of substrate binding by matrix components, preventing enzyme cleavage. The use of direct analysis of intact glucuronides has the benefit of being less influenced by these matrix effects, while also allowing analysis of unstable metabolites like 4OH-XYL, which rapidly oxidises after hydrolysis. Additionally, direct analysis is less expensive and less time consuming, while providing more information about the status of hydroxylated metabolites in urine. Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.

Synthesis and crystal structure of Bi6.4Pb0.6P2O15.2

International Nuclear Information System (INIS)

Arumugam, N.; Lynch, V.; Steinfink, H.

2007-01-01

Bi 6.4 Pb 0.6 P 2 O 15.2 is a polymorph of structures with the general stoichiometry Bi 6+x M 1-x P 2 O 15+y . However, unlike previously published structures that consist of layers formed by edge sharing OBi 4 tetrahedra bridged by PO 4 and TO 6 (T=transition metal) tetrahedra and octahedra the title compound's structure is more complex. It is monoclinic, C2, a=19.4698(4) A, b=11.3692(3) A, c=16.3809(5) A, β=101.167(1) o , Z=10. Single-crystal X-ray diffraction data were refined by least squares on F 2 converging to R 1 =0.0387, wR 2 =0.0836 for 7023 intensities. The crystal twins by mirror reflection across (001) as the twin plane and twin component 1 equals 0.74(1). Oxygen ions are in tetrahedral coordination to four metal ions and the O(BiPb) 4 units share corners to form layers that are part of the three-dimensional framework. Eight oxygen ions form a cube around the two crystallographically independent Pb ions. Pb-O bond lengths vary from 2.265(14) to 2.869(14) A. Pairs of such cubes share an edge to form a Pb 3 O 20 unit. The two oxygen ions from the unshared edges are part of irregular Bi polyhedra. Other oxygen ions of Bi polyhedra are part only of O(BiPb) 4 units, and some oxygen ions of the polyhedra are also part of PO 4 tetrahedra. One, two, three and or four PO 4 moieties are connected to the Bi polyhedra. Bi-O bond lengths ≤3.1 A vary from 2.090(12) to 3.07(3) A. The articulations of Pb cubes, Bi polyhedra and PO 4 tetrahedra link into the three-dimensional structure. - Graphical abstract: View of the structure of Bi 6.4 Pb 0.6 P 2 O 15.2 parallel to the b-axis

Ammonia Sensing Behaviors of TiO2-PANI/PA6 Composite Nanofibers

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Fenglin Huang

2012-12-01

Full Text Available Titanium dioxide-polyaniline/polyamide 6 (TiO2-PANI/PA6 composite nanofibers were prepared by in situ polymerization of aniline in the presence of PA6 nanofibers and a sputtering-deposition process with a high purity titanium sputtering target. TiO2-PANI/PA6 composite nanofibers and PANI/PA6 composite nanofibers were fabricated for ammonia gas sensing. The ammonia sensing behaviors of the sensors were examined at room temperature. All the results indicated that the ammonia sensing property of TiO2-PANI/PA6 composite nanofibers was superior to that of PANI/PA6 composite nanofibers. TiO2-PANI/PA6 composite nanofibers had good selectivity to ammonia. It was also found that the content of TiO2 had a great influence on both the morphology and the sensing property of TiO2-PANI/PA6 composite nanofibers.

Magnetocaloric effect in gadolinium-oxalate framework Gd2(C2O4)3(H2O)6⋅(0⋅6H2O)

International Nuclear Information System (INIS)

Sibille, Romain; Didelot, Emilie; Mazet, Thomas; Malaman, Bernard; François, Michel

2014-01-01

Magnetic refrigerants incorporating Gd 3+ ions and light organic ligands offer a good balance between isolation of the magnetic centers and their density. We synthesized the framework material Gd 2 (C 2 O 4 ) 3 (H 2 O) 6 ⋅0.6H 2 O by a hydrothermal route and characterized its structure. The honeycomb lattice of Gd 3+ ions interlinked by oxalate ligands in the (a,c) plane ensures their decoupling in terms of magnetic exchange interactions. This is corroborated by magnetic measurements indicating negligible interactions between the Gd 3+ ions in this material. The magnetocaloric effect was evaluated from isothermal magnetization measurements. The maximum entropy change −ΔS M max reaches 75.9 mJ cm −3 K −1 (around 2 K) for a moderate field change (2 T)

Biotransformation of cannabidiol in mice. Identification of new acid metabolites.

Science.gov (United States)

Martin, B R; Harvey, D J; Paton, W D

1977-01-01

The in vivo metabolism of cannabidiol (CBD) was investigated in mice. Following the ip administration of CBD to mice, livers were removed and metabolites were extracted with ethyl acetate prior to partial purification on Sephadex LH-20 columns. Fractions from the columns were converted into trimethylsilyl, d9-trimethylsilyl, and methylester-trimethylsilyl derivatives for analysis by gas-liquid chromatography-mass spectrometry. In addition, metabolites containing carboxylic acid and ketone functional groups were reduced to alcohols with lithium aluminum deuteride before trimethylsilation. A total of 22 metabolites were characterized, 14 of which had not been reported previously. The metabolites could be categorized as follows: monohydroxylated (N=2), dihydroxylated (N=3), CBD-7-oic acid, side chain hydroxy-GBD-7-oic acids (N=3), side-chain acids (N=3), 7-hydroxy-side-chain acids (N=4), 6-oxo-side-chain acids (N=3) and glucuronide conjugates (N=3). The most significant biotransformations were glucuronide conjugation and, to a lesser extent, formation of CBD-7-oic acid.

Seasonal variation of the major secondary metabolites present in the extract of Eremanthus mattogrossensis Less (Asteraceae: Vernonieae leaves

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Dayana Rubio Gouvea

2012-01-01

Full Text Available The species Eremanthus mattogrossensis, known as "veludo do cerrado" (cerrado velvet, is native to the Brazilian Cerrado. Because the amount of metabolites present in plants may be influenced by biological and environmental factors, here we conducted an HPLC-DAD-MS/MS investigation of the metabolite concentrations found in the MeOH/H2O extract of the leaves of this species. The main compounds were identified and quantified, and the metabolites were grouped by chemical class (caffeoylquinic acids, flavonoids, and sesquiterpene lactone. Statistical analysis indicated a straight correlation between the quantity of metabolites and seasonality, suggesting that environmental properties elicit important metabolic responses.

Circulating Metabolite Predictors of Glycemia in Middle-Aged Men and Women

OpenAIRE

W?rtz, Peter; Tiainen, Mika; M?kinen, Ville-Petteri; Kangas, Antti J.; Soininen, Pasi; Saltevo, Juha; Kein?nen-Kiukaanniemi, Sirkka; M?ntyselk?, Pekka; Lehtim?ki, Terho; Laakso, Markku; Jula, Antti; K?h?nen, Mika; Vanhala, Mauno; Ala-Korpela, Mika

2012-01-01

OBJECTIVE Metabolite predictors of deteriorating glucose tolerance may elucidate the pathogenesis of type 2 diabetes. We investigated associations of circulating metabolites from high-throughput profiling with fasting and postload glycemia cross-sectionally and prospectively on the population level. RESEARCH DESIGN AND METHODS Oral glucose tolerance was assessed in two Finnish, population-based studies consisting of 1,873 individuals (mean age 52 years, 58% women) and reexamined after 6.5 yea...

Formation reactions and thermal stability of Ca/sub 2/NbCoO/sub 6/ and Ca/sub 2/TaCoO/sub 6/

Energy Technology Data Exchange (ETDEWEB)

Kuleshova, T B; Razumovskaya, O N; Belyaev, I N; Salei, V S [Rostovskij-na-Donu Gosudarstvennyj Univ. (USSR)

1979-11-01

Ca/sub 2/M/sup 5/CoO/sub 6/ compounds and reactions of their formation from oxides were investigated by thermogravimetric and X-ray phase analysis methods. Optimum conditions for synthesizing the above compounds have been found, and the degree of oxidation of Co therein, determined. The thermal stability of the compounds was also studied. It was shown, that the stability of Co (3) in Ca/sub 2/NbCaO/sub 6/ Ca/sub 2/TaCoO/sub 6/ is higher than that in similar compounds containing Pb. The resultant compounds are pure perovskites. Presented are the calculated and the experimental values of perovskite cell parameters.

Secondary metabolites of Antarctic fungi antagonistic to aquatic pathogenic bacteria

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Zhao Huibin

2018-03-01

Full Text Available Polar microbial derived antibiotics have potential as alternatives to traditional antibiotics in treating fish against pathogenic bacteria. In this paper, 23 strains of polar fungi were fermented to detect bacteriostatic products on three aquatic pathogenic bacteria, subsequently the active fungus was identified. It was indicated that secondary metabolites of 23 strains weredistinct; of these, the extract of strain B-7 (belonging to Bjerkandera according to molecular identification demonstrated a strong antibacterial activity to Streptococcus agalactiae, Vibrio anguillarum and Aeromonas hydrophila ATCC7966 by Kirby-Bauerpaper strip method. During one fermentation cycle, the pH curve of the fermentation liquor became lowest (4.0 on the 4th day and rose back to 7.6 finally after 5 days, The residual sugar curve was decreased before stablising on the 6th day. It is presumed that a large amount of alkaline secondary metabolites might have been produced during fermentation. This study focuses on antagonism between aquatic pathogenic bacteria and fermentation metabolites from Antarctic fungi for the first time, which may provide data on research of antibiotics against aquatic pathogenic bacteria.

Facile fabrication of core-shell Pr6O11-ZnO modified silane coatings for anti-corrosion applications

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Jeeva Jothi, K.; Palanivelu, K.

2014-01-01

In this work, we have developed a facile and inexpensive method to fabricate anti-corrosive and hydrophobic surface with hierarchical micro and nano structures. We demonstrate for the first time the use of praseodymium oxide doped zinc oxide (Pr6O11-ZnO) nanocomposites loaded in a hybrid sol-gel (SiOx/ZrOx) layer, to effectively protect the underlying steel substrate from corrosion attack. The influence of Pr6O11-ZnO gives the surprising aspects based on active anti-corrosion and hydrophobic coatings. The spherical SiO2 particles have been successfully coated with Pr6O11-ZnO layer through sol-gel process. The resulted SiO2@Pr6O11-ZnO core-shell was characterized by Transmission Electron Microscopy (TEM), X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and X-ray Photoelectron Spectroscopy (XPS). The barrier properties of the intact coatings were assessed by Electrochemical Impedance Spectroscopy (EIS). The fabrication of SiO2@Pr6O11-ZnO shows dual properties of hydrophobic and anti-corrosion micro/nanostructured sol-gel coatings follows a single/simple step coating procedure. This study has led to a better understanding factor influencing the anti-corrosion performance with embedded nanocomposites. These developments are particularly for silane network@ Pr6O11-ZnO for self-healing and self-cleaning behavior which can be designed for new protective coating system.

The Partial Molar Volume and Compressibility of the FeO Component in Model Basalts (Mixed CaAl2Si2O8-CaMgSi2O6-CaFeSi2O6 Liquids) at 0 GPa: evidence of Fe2+ in 6-fold coordination

Science.gov (United States)

Guo, X.; Lange, R. A.; Ai, Y.

2010-12-01

FeO is an important component in magmatic liquids and yet its partial molar volume at one bar is not as well known as that for Fe2O3 because of the difficulty of performing double-bob density measurements under reducing conditions. Moreover, there is growing evidence from spectroscopic studies that Fe2+ occurs in 4, 5, and 6-fold coordination in silicate melts, and it is expected that the partial molar volume and compressibility of the FeO component will vary accordingly. We have conducted both density and relaxed sound speed measurements on four liquids in the An-Di-Hd (CaAl2Si2O8-CaMgSi2O6-CaFeSi2O6) system: (1) Di-Hd (50:50), (2) An-Hd (50:50), (3) An-Di-Hd (33:33:33) and (4) Hd (100). Densities were measured between 1573 and 1838 K at one bar with the double-bob Archimedean method using molybdenum bobs and crucibles in a reducing gas (1%CO-99%Ar) environment. The sound speeds were measured under similar conditions with a frequency-sweep acoustic interferometer, and used to calculate isothermal compressibility. All the density data for the three multi-component (model basalt) liquids were combined with density data on SiO2-Al2O3-CaO-MgO-K2O-Na2O liquids (Lange, 1997) in a fit to a linear volume equation; the results lead to a partial molar volume (±1σ) for FeO =11.7 ± 0.3(±1σ) cm3/mol at 1723 K. This value is similar to that for crystalline FeO at 298 K (halite structure; 12.06 cm3/mol), which suggests an average Fe2+ coordination of ~6 in these model basalt compositions. In contrast, the fitted partial molar volume of FeO in pure hedenbergite liquid is 14.6 ± 0.3 at 1723 K, which is consistent with an average Fe2+ coordination of 4.3 derived from EXAFS spectroscopy (Rossano, 2000). Similarly, all the compressibility data for the three multi-component liquids were combined with compressibility data on SiO2-Al2O3-CaO-MgO liquids (Ai and Lange, 2008) in a fit to an ideal mixing model for melt compressibility; the results lead to a partial molar

Design, synthesis and luminescence properties of Ba2 YB2 O6 Cl- and Ba2 YB2 O6 F-based phosphors.

Science.gov (United States)

Chen, Wanping; Yang, Xin; Liu, Yan; Dai, Xiaoyan

2015-05-01

Using a high-temperature solid-state reaction, the chlorine in Ba2 YB2 O6 Cl is gradually replaced by F, and a new compound with the nominal chemical formula Ba2 YB2 O6 F and two phosphors doped with Ce(3+) and Eu(3+) , respectively, are obtained. X-Ray diffraction and photoluminescence spectroscopy are used to characterize the as-synthesized samples. The as-synthesized Ba2 YB2 O6 Cl exhibits bright blue emission in the spectral range ~ 330-410 nm with a maximum around 363 nm under X-ray or UV excitation. Ba2 YB2 O6 F:0.01Ce(3+) exhibits blue emission in the range ~ 340-570 nm with a maximum around 383 nm. Ba2 YB2 O6 F:0.01Eu(3+) exhibits a predominantly (5) D0 -(7)  F2 emission (~610 nm) and the relative intensities of the (5) D0 -(7)  F0,1,2 emissions are tunable under different wavelength UV excitation. The luminescence behaviors of the two phosphors are explained simply in terms of the host composition and site occupancy probability of Ce(3+) and Eu(3+) , respectively. The results indicate that these phosphors have potential application as a blue phosphor or as a red phosphor. Copyright © 2014 John Wiley & Sons, Ltd.

Protection of hematopoietic cells from O(6)-alkylation damage by O(6)-methylguanine DNA methyltransferase gene transfer: studies with different O(6)-alkylating agents and retroviral backbones.

Science.gov (United States)

Jansen, M; Bardenheuer, W; Sorg, U R; Seeber, S; Flasshove, M; Moritz, T

2001-07-01

Overexpression of O(6)-methylguanine DNA methyltransferase (MGMT) can protect hematopoietic cells from O(6)-alkylation damage. To identify possible clinical applications of this technology we compared the effect of MGMT gene transfer on the hematotoxicity induced by different O(6)-alkylating agents in clinical use: the chloroethylnitrosoureas ACNU, BCNU, CCNU and the tetrazine derivative temozolomide. In addition, various retroviral vectors expressing the MGMT-cDNA were investigated to identify optimal viral backbones for hematoprotection by MGMT expression. Protection from ACNU, BCNU, CCNU or temozolomide toxicity was evaluated utilizing a Moloney murine leukemia virus-based retroviral vector (N2/Zip-PGK-MGMT) to transduce primary murine bone marrow cells. Increased resistance in murine colony-forming units (CFU) was demonstrated for all four drugs. In comparison to mock-transduced controls, after transduction with N2/Zip-PGK-MGMT the IC50 for CFU increased on average 4.7-fold for ACNU, 2.5-fold for BCNU, 6.3-fold for CCNU and 1.5-fold for temozolomide. To study the effect of the retroviral backbone on hematoprotection various vectors expressing the human MGMT-cDNA from a murine embryonic sarcoma virus LTR (MSCV-MGMT) or a hybrid spleen focus-forming/murine embryonic sarcoma virus LTR (SF1-MGMT) were compared with the N2/Zip-PGK-MGMT vector. While all vectors increased resistance of transduced human CFU to ACNU, the SF1-MGMT construct was most efficient especially at high ACNU concentrations (8-12 microg/ml). Similar results were obtained for protection of murine high-proliferative-potential colony-forming cells. These data may help to optimize treatment design and retroviral constructs in future clinical studies aiming at hematoprotection by MGMT gene transfer.

Synthesis and characterization of the lead borate Pb{sub 6}B{sub 12}O{sub 21}(OH){sub 6}

Energy Technology Data Exchange (ETDEWEB)

Schoenegger, Sandra; Ortner, Teresa S.; Wurst, Klaus; Heymann, Gunter; Huppertz, Hubert [Innsbruck Univ. (Austria). Inst. fuer Allgemeine, Anorganische und Theoretische Chemie

2016-11-01

A lead borate with the composition Pb{sub 6}B{sub 12}O{sub 21}(OH){sub 6} was synthesized through a hydrothermal synthesis, using lead metaborate in combination with sodium nitrate and potassium nitrate. The compound crystallizes in the trigonal, non-centrosymmetric space group P3{sub 2} (no. 145) with the lattice parameters a = 1176.0(4), c = 1333.0(4) pm, and V = 0.1596(2) nm{sup 3}. Interestingly, the data of Pb{sub 6}B{sub 12}O{sub 21}(OH){sub 6} correct the structure of a literature known lead borate with the composition ''Pb{sub 6}B{sub 11}O{sub 18}(OH){sub 9}''. For the latter compound, nearly identical lattice parameters of a = 1176.91(7) and c = 1333.62(12) pm were reported, possessing a crystal structure, in which the localization and refinement of one boron atom was obviously overlooked. The structure of Pb{sub 6}B{sub 12}O{sub 21}(OH){sub 6} is built up from trigonal planar BO{sub 3} and tetrahedral BO{sub 4} groups forming complex chains. The Pb{sup 2+} cations are located between neighboring polyborate chains. The here reported compound Pb{sub 6}B{sub 12}O{sub 21}(OH){sub 6} and ''Pb{sub 6}B{sub 11}O{sub 18}(OH){sub 9}'' were, however, produced under different synthesis conditions. While ''Pb{sub 6}B{sub 11}O{sub 18}(OH){sub 9}'' was synthesized via a hydrothermal synthesis including ethylenediamine and acetic acid, the here reported lead borate Pb{sub 6}B{sub 12}O{sub 21}(OH){sub 6} could be obtained under moderate hydrothermal conditions (240 C) without the addition of organic reagents.

The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes.

Science.gov (United States)

Johänning, Janina; Kröner, Patrick; Thomas, Maria; Zanger, Ulrich M; Nörenberg, Astrid; Eichelbaum, Michel; Schwab, Matthias; Brauch, Hiltrud; Schroth, Werner; Mürdter, Thomas E

2018-03-01

Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte® hepatocytes. The influence of 5 µM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug-drug-interactions.

NMR-based metabolite profiling of human milk: A pilot study of methods for investigating compositional changes during lactation

International Nuclear Information System (INIS)

Wu, Junfang; Domellöf, Magnus; Zivkovic, Angela M.; Larsson, Göran; Öhman, Anders; Nording, Malin L.

2016-01-01

Low-molecular-weight metabolites in human milk are gaining increasing interest in studies of infant nutrition. In the present study, the milk metabolome from a single mother was explored at different stages of lactation. Metabolites were extracted from sample aliquots using either methanol/water (MeOH/H_2O) extraction or ultrafiltration. Nuclear magnetic resonance (NMR) spectroscopy was used for metabolite identification and quantification, and multi- and univariate statistical data analyses were used to detect changes over time of lactation. Compared to MeOH/H_2O extraction, ultrafiltration more efficiently reduced the interference from lipid and protein resonances, thereby enabling the identification and quantification of 36 metabolites. The human milk metabolomes at the early (9–24 days after delivery) and late (31–87 days after delivery) stages of lactation were distinctly different according to multi- and univariate statistics. The late lactation stage was characterized by significantly elevated concentrations of lactose, choline, alanine, glutamate, and glutamine, as well as by reduced levels of citrate, phosphocholine, glycerophosphocholine, and N-acetylglucosamine. Our results indicate that there are significant compositional changes of the human milk metabolome also in different phases of the matured lactation stage. These findings complement temporal studies on the colostrum and transitional metabolome in providing a better understanding of the nutritional variations received by an infant. - Highlights: • 36 metabolites were simultaneously quantified in human milk by NMR. • Ultrafiltration more efficiently reduces interferences than MeOH/H_2O extraction. • Compositional changes of the human milk exist during the matured lactation stage.

NMR-based metabolite profiling of human milk: A pilot study of methods for investigating compositional changes during lactation

Energy Technology Data Exchange (ETDEWEB)

Wu, Junfang [Department of Chemistry, Umeå University (Sweden); Domellöf, Magnus [Department of Clinical Sciences, Pediatrics, Umeå University (Sweden); Zivkovic, Angela M. [Foods for Health Institute, University of California, Davis, CA (United States); Department of Nutrition, University of California, Davis, CA (United States); Larsson, Göran [Department of Medical Biochemistry and Biophysics, Unit of Research, Education and Development-Östersund, Umeå University (Sweden); Öhman, Anders, E-mail: anders.ohman01@umu.se [Department of Pharmacology and Clinical Neuroscience, Umeå University (Sweden); Nording, Malin L., E-mail: malin.nording@umu.se [Department of Chemistry, Umeå University (Sweden)

2016-01-15

Low-molecular-weight metabolites in human milk are gaining increasing interest in studies of infant nutrition. In the present study, the milk metabolome from a single mother was explored at different stages of lactation. Metabolites were extracted from sample aliquots using either methanol/water (MeOH/H{sub 2}O) extraction or ultrafiltration. Nuclear magnetic resonance (NMR) spectroscopy was used for metabolite identification and quantification, and multi- and univariate statistical data analyses were used to detect changes over time of lactation. Compared to MeOH/H{sub 2}O extraction, ultrafiltration more efficiently reduced the interference from lipid and protein resonances, thereby enabling the identification and quantification of 36 metabolites. The human milk metabolomes at the early (9–24 days after delivery) and late (31–87 days after delivery) stages of lactation were distinctly different according to multi- and univariate statistics. The late lactation stage was characterized by significantly elevated concentrations of lactose, choline, alanine, glutamate, and glutamine, as well as by reduced levels of citrate, phosphocholine, glycerophosphocholine, and N-acetylglucosamine. Our results indicate that there are significant compositional changes of the human milk metabolome also in different phases of the matured lactation stage. These findings complement temporal studies on the colostrum and transitional metabolome in providing a better understanding of the nutritional variations received by an infant. - Highlights: • 36 metabolites were simultaneously quantified in human milk by NMR. • Ultrafiltration more efficiently reduces interferences than MeOH/H{sub 2}O extraction. • Compositional changes of the human milk exist during the matured lactation stage.

Tangeretin and its metabolite 4'-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K.

Science.gov (United States)

Cheng, Z; Surichan, S; Ruparelia, K; Arroo, R; Boarder, M R

2011-04-01

The mechanisms by which the dietary compound tangeretin has anticancer effects may include acting as a prodrug, forming an antiproliferative product in cancer cells. Here we show that tangeretin also inhibits cell cycle progression in hepatocytes and investigate the role of its primary metabolite 4'-hydroxy-5,6,7,8-tetramethoxyflavone (4'-OH-TMF) in this effect. We used epidermal growth factor (EGF)-stimulated rat hepatocytes, with [(3)H]-thymidine incorporation into DNA as an index of progression to S-phase of the cell cycle, and Western blots for phospho-proteins involved in the cell signalling cascade. Incubation of tangeretin with microsomes expressing CYP1A, or with hepatocytes, generated a primary product we identified as 4'-OH-TMF. Low micromolar concentrations of tangeretin or 4'-OH-TMF gave a concentration-dependent inhibition of EGF-stimulated progression to S-phase while having little effect on cell viability. To determine whether time for conversion of tangeretin to an active metabolite would enhance the inhibitory effect we used long pre-incubations; this reduced the inhibitory effect, in parallel with a reduction in the concentration of tangeretin. The EGF-stimulation of hepatocyte cell cycle progression requires signalling through Akt/mTOR/p70S6K kinase cascades. The tangeretin metabolite 4'-OH-TMF selectively inhibited S6K phosphorylation in the absence of significant inhibition of upstream Akt activity, suggesting an effect at the level of mTOR. Tangeretin and 4'-OH-TMF both inhibit cell cycle progression in primary hepatocytes. The inhibition of p70S6K phosphorylation by 4'-OH-TMF raises the possibility that inhibition of the mTOR pathway may contribute to the anticancer influence of a flavonoid-rich diet. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemometrics-assisted spectrophotometric green method for correcting interferences in biowaiver studies: Application to assay and dissolution profiling study of donepezil hydrochloride tablets

Science.gov (United States)

Korany, Mohamed A.; Mahgoub, Hoda; Haggag, Rim S.; Ragab, Marwa A. A.; Elmallah, Osama A.

2018-06-01

A green, simple and cost effective chemometric UV-Vis spectrophotometric method has been developed and validated for correcting interferences that arise during conducting biowaiver studies. Chemometric manipulation has been done for enhancing the results of direct absorbance, resulting from very low concentrations (high incidence of background noise interference) of earlier points in the dissolution timing in case of dissolution profile using first and second derivative (D1 & D2) methods and their corresponding Fourier function convoluted methods (D1/FF& D2/FF). The method applied for biowaiver study of Donepezil Hydrochloride (DH) as a representative model was done by comparing two different dosage forms containing 5 mg DH per tablet as an application of a developed chemometric method for correcting interferences as well as for the assay and dissolution testing in its tablet dosage form. The results showed that first derivative technique can be used for enhancement of the data in case of low concentration range of DH (1-8 μg mL-1) in the three different pH dissolution media which were used to estimate the low drug concentrations dissolved at the early points in the biowaiver study. Furthermore, the results showed similarity in phosphate buffer pH 6.8 and dissimilarity in the other 2 pH media. The method was validated according to ICH guidelines and USP monograph for both assays (HCl of pH 1.2) and dissolution study in 3 pH media (HCl of pH 1.2, acetate buffer of pH 4.5 and phosphate buffer of pH 6.8). Finally, the assessment of the method greenness was done using two different assessment techniques: National Environmental Method Index label and Eco scale methods. Both techniques ascertained the greenness of the proposed method.

3D organic Na4C6O6/graphene architecture for fast sodium storage with ultralong cycle life.

Science.gov (United States)

Gu, Jianan; Gu, Yue; Yang, Shubin

2017-11-23

Sodium-ion batteries (SIBs) have aroused increasing interest as one of the most promising replacements for lithium-ion batteries (LIBs). Here, a novel organic-inorganic 3D Na 4 C 6 O 6 -graphene architecture was successfully fabricated from commercial Na 2 C 6 O 6 and for the first time applied for sodium storage. Hence, the 3D Na 4 C 6 O 6 -graphene architecture exhibits a high reversible capacity, good cyclic performance and high-rate capability for sodium storage.

Identification of di- and tri-substituted hydroxy and ketone metabolites of delta1-tetrahydrocannabinol in mouse liver.

Science.gov (United States)

Harvey, D J; Martin, B R; Paton, W D

1977-08-01

In vivo liver metabolites of delta1-tetrahydrocannabinol (delta1-THC) were examined with a gas chromatograph--mass spectrometer--computer system as trimethylsilyl (TMS), [2H9]TMS and methyloxime-TMS derivatives. In addition to the reported monohydroxy, acid, and hydroxyacid metabolites, the following multiply substituted metabolites were identified: 2'',7-, 3'', 7-, and 6beta,7-dihydroxy-delta1-THC; 2'',6alpha,7-, and 3'',6alpha,7-trihydroxy-delta1-THC; 2''-, 3''-, and 7-hydroxy-6-oxo-delta1-THC, and 2'',7- and 3'',7-dihydroxy-6-oxo-delta1-THC. The ketones and hydroxyacids were reduced to common alcohols with lithium aluminium deuteride and the number of deuterium atoms in the product was used to distinguish the metabolic alcohols from those produced by reduction.

Rivastigmine Improves Appetite by Increasing the Plasma Acyl/Des-Acyl Ghrelin Ratio and Cortisol in Alzheimer Disease

Directory of Open Access Journals (Sweden)

Yoshiko Furiya

2018-03-01

Full Text Available Background: Weight loss accelerates cognitive decline and increases mortality in patients with dementia. While acetylcholinesterase (AChE inhibitors are known to cause appetite loss, we sometimes encounter patients in whom switching from donepezil (AChE inhibitor to rivastigmine (AChE and butyrylcholinesterase [BuChE] inhibitor improves appetite. Since BuChE inactivates ghrelin, a potent orexigenic hormone, we speculated that rivastigmine improves appetite by inhibiting BuChE-mediated ghrelin inactivation. Methods: The subjects were patients with mild to moderate Alzheimer disease treated with either rivastigmine patch (n = 11 or donepezil (n = 11 for 6 months. Before and after treatment, we evaluated appetite (0, decreased; 1, slightly decreased; 2, normal; 3, slightly increased; 4, increased, cognitive function, and blood biochemical variables, including various hormones. Results: Rivastigmine treatment significantly improved appetite (from 1.6 ± 0.5 to 2.6 ± 0.7, whereas donepezil treatment did not (from 2.0 ± 0.0 to 1.8 ± 0.4. Simultaneously, rivastigmine, but not donepezil, significantly decreased the serum cholinesterase activity (from 304.3 ± 60.5 to 246.8 ± 78.5 IU/L and increased the cortisol level (from 11.86 ± 3.12 to 14.61 ± 3.29 μg/dL and the acyl/des-acyl ghrelin ratio (from 4.03 ± 2.96 to 5.28 ± 2.72. The levels of leptin, insulin, total ghrel­in, and cognitive function were not significantly affected by either treatment. Conclusions: Our results suggest that compared with donepezil, rivastigmine has the advantage of improving appetite by increasing the acyl/des-acyl ghrelin ratio and cortisol level, thereby preventing weight loss.

Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease.

Science.gov (United States)

Bautista-Aguilera, Oscar M; Esteban, Gerard; Bolea, Irene; Nikolic, Katarina; Agbaba, Danica; Moraleda, Ignacio; Iriepa, Isabel; Samadi, Abdelouahid; Soriano, Elena; Unzeta, Mercedes; Marco-Contelles, José

2014-03-21

The design, synthesis, and pharmacological evaluation of donepezil-indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure-Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13 versus 7 and 8) or equipotent (see compounds 14, 15 versus 9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 ± 1.4 nM) and moderately potent hMAO B (IC50 = 150 ± 31 nM), EeAChE (IC50 = 190 ± 10 nM), and eqBuChE (IC50 = 830 ± 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil-indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Rationalization and prediction of in vivo metabolite exposures: The role of metabolite kinetics, clearance predictions and in vitro parameters

Science.gov (United States)

Lutz, Justin D.; Fujioka, Yasushi; Isoherranen, Nina

2010-01-01

Importance of the field Due to growing concerns over toxic or active metabolites, significant efforts have been focused on qualitative identification of potential in vivo metabolites from in vitro data. However, limited tools are available to quantitatively predict their human exposures. Areas covered in this review Theory of clearance predictions and metabolite kinetics is reviewed together with supporting experimental data. In vitro and in vivo data of known circulating metabolites and their parent drugs was collected and the predictions of in vivo exposures of the metabolites were evaluated. What the reader will gain The theory and data reviewed will be useful in early identification of human metabolites that will circulate at significant levels in vivo and help in designing in vivo studies that focus on characterization of metabolites. It will also assist in rationalization of metabolite-to-parent ratios used as markers of specific enzyme activity. Take home message The relative importance of a metabolite in comparison to the parent compound as well as other metabolites in vivo can only be predicted using the metabolites in vitro formation and elimination clearances, and the in vivo disposition of a metabolite can only be rationalized when the elimination pathways of that metabolite are known. PMID:20557268

Low-temperature sintering and microwave dielectric properties of Al2TeO6–TeO2 ceramics

International Nuclear Information System (INIS)

Kagomiya, Isao; Kodama, Yuichiro; Shimizu, Yukihiro; Kakimoto, Ken-ichi; Ohsato, Hitoshi; Miyauchi, Yasuharu

2015-01-01

Highlights: • This is the first study of dielectric properties of Al 2 TeO 6 –TeO 2 sintered at 900 °C. • The sintering at 900 °C contributed to densification, but it causes TeO 2 evaporation. • The annealing at 750 °C was effective for the further densification. • The both ε r and Q · f in the Al 2 TeO 6 –TeO 2 were improved with the annealing. - Abstract: We propose Al 2 TeO 6 –TeO 2 ceramics as a candidate for use as low-temperature co-fired ceramics (LTCC). We investigated microwave dielectric properties and low-temperature sintering conditions for Al 2 TeO 6 –TeO 2 ceramics. The calcined Al 2 TeO 6 powders were sintered at 900 °C for 2–10 h with 30–50 wt% additive TeO 2 . X-ray powder diffraction patterns showed that the sintered samples were Al 2 TeO 6 –TeO 2 composite with no other phase. The apparent density was improved with the additive TeO 2 content of up to 45 wt%. The dielectric constant (ε r ) increased by adding TeO 2 content from 35 to 45 wt%, although the quality factor (Q · f) decreased. During sintering at 900 °C, the ε r of the Al 2 TeO 6 –TeO 2 decreased slightly, whereas the Q · f increased gradually. The observed microstructures showed that the longer sintering time makes fewer pores in Al 2 TeO 6 –TeO 2 ceramics. Sintering at 900 °C for a long time contributes to densification, but it simultaneously causes TeO 2 evaporation. To prevent TeO 2 evaporation, we investigated the effects of annealing at 750 °C after sintering at 900 °C. Apparent densities or ε r for the annealed samples were higher than those of the non-annealed samples. The Q · f improved with increasing annealing duration time, suggesting that sintering proceeded well during annealing with slower TeO 2 evaporation at 750 °C. The results show that annealing at 750 °C is effective to facilitate sintering and to control TeO 2 evaporation

Metabolite Profiling of Red Sea Corals

KAUST Repository

Ortega, Jovhana Alejandra

2016-12-01

Looking at the metabolite profile of an organism provides insights into the metabolomic state of a cell and hence also into pathways employed. Little is known about the metabolites produced by corals and their algal symbionts. In particular, corals from the central Red Sea are understudied, but interesting study objects, as they live in one of the warmest and most saline environments and can provide clues as to the adjustment of corals to environmental change. In this study, we applied gas chromatography – mass spectrometry (GC–MS) metabolite profiling to analyze the metabolic profile of four coral species and their associated symbionts: Fungia granulosa, Acropora hemprichii, Porites lutea, and Pocillopora verrucosa. We identified and quantified 102 compounds among primary and secondary metabolites across all samples. F. granulosa and its symbiont showed a total of 59 metabolites which were similar to the 51 displayed by P. verrucosa. P. lutea and A. hemprichii both harbored 40 compounds in conjunction with their respective isolated algae. Comparing across species, 28 metabolites were exclusively present in algae, while 38 were exclusive to corals. A principal component and cluster analyses revealed that metabolite profiles clustered between corals and algae, but each species harbored a distinct catalog of metabolites. The major classes of compounds were carbohydrates and amino acids. Taken together, this study provides a first description of metabolites of Red Sea corals and their associated symbionts. As expected, the metabolites of coral hosts differ from their algal symbionts, but each host and algal species harbor a unique set of metabolites. This corroborates that host-symbiont species pairs display a fine-tuned complementary metabolism that provide insights into the specific nature of the symbiosis. Our analysis also revealed aquatic pollutants, which suggests that metabolite profiling might be used for monitoring pollution levels and assessing

Metabolitos secundários como fontes de bioherbicidas: situação actual e perspectivas Secondary metabolites as sources of bioherbicides: present situation and perspectives

Directory of Open Access Journals (Sweden)

L.S. Dias

2007-01-01

Full Text Available Metabolitos secundários produzidos e libertados por plantas, bactérias e fungos estão envolvidos numa variedade de processos ecológicos, nomeadamente como semioquímicos e alelopatinos. Adicionalmente, e para além das suas possíveis funções ecológicas, muitos dos metabolitos secundários são fitotóxicos, constituindo uma fonte relativamente inexplorada de novos herbicidas. Solanum nigrum (erva-moira é uma infestante importante e muito bem sucedida num grande número de culturas, nomeadamente hortícolas e será usada como exemplo principal das utilizações actuais de aleloquímicos vegetais bem como das perspectivas de utilização deste tipo de compostos como bioherbicidas. Nesse âmbito revêem-se as principais estratégias de pesquisa de bioherbicidas e apresenta-se o estado da arte dos modos de acção de aleloquímicos já comercializados como herbicidas (Bialaphos e PPT, patenteados (AAL-toxina e em investigação, quer produzidos por plantas superiores (sorgoleona e derivados do cineol quer de origem bacteriana (hidantocidina e fúngica (fumonisinas, coletotriquina.Secondary metabolites produced and released by plants, bacteria, and fungi are involved in a number of ecological processes, namely as semiochemicals and allelopathins. In addition, and beside their possible ecological roles, a greater number of secondary metabolites are phytotoxic and represent a relatively unexplored source of new herbicides. Solanum nigrum (black nightshade is an important and successful weed in many crops, namely in horticulture, and will be used as a major example of actual and prospective uses of phytoallelochemicals as bioherbicides. Therefore, the main strategies for bioherbicides search are reviewed and the state of art of the modes of action of allelochemicals is presented, including those already in use as herbicides (Bialaphos and PPT, patented (AAL-toxin, and under investigation, whether produced by plants (sorgoleone and cineol

Secondary metabolites from marine microorganisms.

Science.gov (United States)

Kelecom, Alphonse

2002-03-01

After 40 years of intensive research, chemistry of marine natural products has become a mature field. Since 1995, there are signals of decreased interest in the search of new metabolites from traditional sources such as macroalgae and octocorals, and the number of annual reports on marine sponges stabilized. On the contrary, metabolites from microorganisms is a rapidly growing field, due, at least in part, to the suspicion that a number of metabolites obtained from algae and invertebrates may be produced by associated microorganisms. Studies are concerned with bacteria and fungi, isolated from seawater, sediments, algae, fish and mainly from marine invertebrates such as sponges, mollusks, tunicates, coelenterates and crustaceans. Although it is still to early to define tendencies, it may be stated that the metabolites from microorganisms are in most cases quite different from those produced by the invertebrate hosts. Nitrogenated metabolites predominate over acetate derivatives, and terpenes are uncommon. Among the latter, sesquiterpenes, diterpenes and carotenes have been isolated; among nitrogenated metabolites, amides, cyclic peptides and indole alkaloids predominate.

Secondary metabolites from marine microorganisms

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KELECOM ALPHONSE

2002-01-01

Full Text Available After 40 years of intensive research, chemistry of marine natural products has become a mature field. Since 1995, there are signals of decreased interest in the search of new metabolites from traditional sources such as macroalgae and octocorals, and the number of annual reports on marine sponges stabilized. On the contrary, metabolites from microorganisms is a rapidly growing field, due, at least in part, to the suspicion that a number of metabolites obtained from algae and invertebrates may be produced by associated microorganisms. Studies are concerned with bacteria and fungi, isolated from seawater, sediments, algae, fish and mainly from marine invertebrates such as sponges, mollusks, tunicates, coelenterates and crustaceans. Although it is still to early to define tendencies, it may be stated that the metabolites from microorganisms are in most cases quite different from those produced by the invertebrate hosts. Nitrogenated metabolites predominate over acetate derivatives, and terpenes are uncommon. Among the latter, sesquiterpenes, diterpenes and carotenes have been isolated; among nitrogenated metabolites, amides, cyclic peptides and indole alkaloids predominate.

Oxidative metabolites of diethylstilbestrol in the fetal Syrian golden hamster

International Nuclear Information System (INIS)

Maydl, R.; Metzler, M.

1984-01-01

14 C-Diethylstilbestrol was administered orally, intraperitoneally, and intrafetally to 15-day pregnant hamsters at a dose of 20 mg/kg body weight, and the radioactivity was determined in the fetus, placenta, and maternal liver after 6 hours. Significant amounts of radioactivity were found in these tissues in every case, indicating maternal-fetal and fetal-maternal transfer of diethylstilbestrol. Part of the radioactivity found in the tissues could not be extracted even after excessive washing. This implied the presence of reactive metabolites. In the fetal and placental extracts, eight oxidative metabolites of diethylstilbestrol were identified by mass fragmentography as hydroxy- and methoxy-derivatives of diethylstilbestrol, pseudodiethylstilbestrol, and dienestrol. The presence of oxidative metabolites in the hamster fetus and the covalent binding to tissue macromolecules are possibly associated with the fetotoxic effects of diethylstilbestrol

Characterization of metabolites of leonurine (SCM-198) in rats after oral administration by liquid chromatography/tandem mass spectrometry and NMR spectrometry.

Science.gov (United States)

Zhu, Qing; Zhang, Jinlian; Yang, Ping; Tan, Bo; Liu, Xinhua; Zheng, Yuanting; Cai, Weimin; Zhu, Yizhun

2014-01-01

Leonurine, a major bioactive component from Herba Leonuri, shows therapeutic potential for cardiovascular disease and stroke prevention in some preclinical experiments. The aim of this study is to characterize metabolites of leonurine in rats using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS). The chromatographic separation was performed on an Agilent ZORBAX SB-C18 column using a gradient elution with acetonitrile/ammonium acetate buffer (10 mM, pH 4.0) solvent system. An information dependent acquisition (IDA) method was developed for screening and identifying metabolites of leonurine under positive ion mode. Compared with control, the interesting compound in the extracted ion chromatogram (XIC) of the in vivo samples was chosen and further identified by analyzing their retention times, changes in observed mass (Δm/z), and spectral patterns of product ion utilizing advanced software tool. For the first time, a total of three metabolites were identified, including two phase II metabolites generated by glucuronidation (M1) and sulfation (M2) and one phase I metabolite formed by O-demethylation (M3). Finally, the lead metabolite M1 was isolated from urine and its structure was characterized as leonurine-10-O- β-D-glucuronide by NMR spectroscopy (¹H, ¹³C, HMBC, and HSQC).

Butane-1,4-diammonium bis(pyridine-2,6-dicarboxylato-κ3O2,N,O6cadmate(II dihydrate

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Najmeh Firoozi

2008-10-01

Full Text Available In the title compound, (C4H14N2[Cd(C7H3NO42]·2H2O, the CdII ion is coordinated by four O atoms [Cd—O = 2.2399 (17–2.2493 (17 Å] and two N atoms [Cd—N = 2.3113 (15 and 2.3917 (15 Å] from two tridentate pyridine-2,6-dicarboxylato ligands in a distorted octahedral geometry. The uncoordinated water molecules are involved in O—H...O and N—H...O hydrogen bonds, which contribute to the formation of a three-dimensional supramolecular structure, along with π–π stacking interactions [centroid–centroid distances of 3.5313 (13 and 3.6028 (11 Å between the pyridine rings of neighbouring dianions].

Effect of Pr6O11 doping in electrical and microstructural properties of SnO2-based varistors

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Hervê Stangler Irion

2014-04-01

Full Text Available The influence of the dopant Pr6O11 was investigated with regard to the electrical and microstructural properties of the system (98.95-x%SnO2.1.0%CoO.0.05%Ta2O5.x%Pr6O11, where x = 0.05%, 0.10%, 0.30% and 0.50% in mol. Pr6O11 doping modifies the electrical behavior of the ceramics. The electrical parameters were: α = 8.0, EB = 319 V cm-1 and Vb = 0.66 V barrier-1 for the system without Pr6O11 and α = 17.0, EB = 853 V cm-1 and Vb = 1.15 V barrier-1 with the addition of 0.10% in mol Pr6O11. The system with 0.05% in mol Pr6O11 had the same non-linearity coefficient α as the system with 0.10% in mol. However, breakdown electrical field and voltage per barrier rates were lower (EB = 708 V cm-1 and Vb = 0.98 V barrier-1. The low rates in the breakdown electrical field enabled the varistor systems under study to be used in protection systems for low-voltage energy grids. In the case of Pr6O11 concentrations above 0.10% in mol, the presence of the dopant became deleterious to the varistor’s electrical characteristics. This effect was due to an increase in praseodymium stannate (Pr2Sn2O7 secondary phase. The crystalline phase coupled to the cassiterite (SnO2 phase was found with XRD and SEM/EDS and quantified by Rietveld’s refining method.

Diaqua{6,6′-dimethoxy-2,2′-[ethane-1,2-diylbis(nitrilomethylidyne]diphenolato-κ2O,N,N′,O′}manganese(III perchlorate 18-crown-6 hemisolvate monohydrate

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Ming-Ming Yu

2009-02-01

Full Text Available In the cation of the title compound, [Mn(C18H18N2O4(H2O2]ClO4·0.5C12H24O6·H2O, the MnIII ion is coordinated by two water O atoms, and two O atoms and two N atoms from the tetradentate 6,6′-dimethoxy-2,2′-[ethane-1,2-diylbis(nitrilomethylidyne]diphenolate ligand, completing a distorted octahedral geometry. One O atom of the 18-crown-6-ether is disordered over two positions with occupancies of 0.70 (2 and 0.30 (2.

Experimental studies on cycling stable characteristics of inorganic phase change material CaCl2·6H2O-MgCl2·6H2O modified with SrCl2·6H2O and CMC

Science.gov (United States)

He, Meizhi; Yang, Luwei; Zhang, Zhentao

2018-01-01

By means of mass ratio method, binary eutectic hydrated salts inorganic phase change thermal energy storage system CaCl2·6H2O-20wt% MgCl2·6H2O was prepared, and through adding nucleating agent 1wt% SrCl2·6H2O and thickening agent 0.5wt% carboxy methyl cellulose (CMC), inoganic phase change material (PCM) modified was obtained. With recording cooling-melting curves simultaneously, this PCM was frozen and melted for 100 cycles under programmable temperature control. After per 10 cycles, the PCM was charaterized by differential scanning calorimeter (DSC), X-ray diffraction (XRD) and density meter, then analysing variation characteristics of phase change temperature, supercooling degree, superheat degree, latent heat, crystal structure and density with the increase of cycle index. The results showed that the average values of average phase change temperature for cooling and heating process were 25.70°C and 27.39°C respectively with small changes. The average values of average supercooling and superheat degree were 0.59°C and 0.49°C respectively, and the maximum value was 1.10°C. The average value and standard deviation of latent heat of fusion were 120.62 J/g and 1.90 J/g respectively. Non-molten white solid sediments resulted from phase separation were tachyhydrite (CaMg2Cl6·12H2O), which was characterized by XRD. Measuring density of the PCM after per 10 cycles, and the results suggested that the total mass of tachyhydrite was limited. In summary, such modified inoganic PCM CaCl2·6H2O-20wt% MgCl2·6H2O-1wt% SrCl2·6H2O-0.5wt% CMC could stay excellent circulation stability within 100 cycles, and providing reference value in practical use.

Metabolites of hirsuteine and hirsutine, the major indole alkaloids of Uncaria rhynchophylla, in rats.

Science.gov (United States)

Nakazawa, Takahiro; Banba, Koh-ichi; Hata, Kazumasa; Nihei, Yutaka; Hoshikawa, Ayumi; Ohsawa, Keisuke

2006-08-01

The metabolic fate of hirsuteine (HT) and hirsutine (HS), the major indole alkaloids of Uncaria rhynchophylla, was investigated using rats. On HPLC analysis, urine from rats orally administered HT were found to contain two metabolites (HT1 and HT2) together with unchanged HT. Similarly HS also was metabolized to two compounds (HS1 and HS2). Metabolite structures were determined to be 11-hydroxyhirsuteine-11-O-beta-D-glucuronide (HT1), 11-hydroxyhirsuteine (HT2), 11-hydroxyhirsutine-11-O-beta-D-glucuronide (HS1) and 11-hydroxyhirsutine (HS2), based on spectroscopic and chemical data. HT1 and HS1 were also detected in bile from rats administered HT and HS, respectively. Total cumulative urinary excretion within 72 h of oral administration was approximately 14% and 26% of the HT and HS doses, respectively, while total cumulative biliary excretion was 35% and 46%, respectively. HT and HS 11-hydroxylation were catalyzed by rat liver microsomes. This 11-hydroxylation activity was inhibited by addition of SKF-525A (a nonselective CYP inhibitor) or cimetidine (a CYP2C inhibitor). These results indicate that orally administered HT and HS are converted to 11-hydroxy metabolites in rats, and that the metabolites are predominantly excreted in bile rather than urine following glucuronidation. Furthermore, the results suggest that CYP2C enzymes are involved, at least in part, in the specific 11-hydroxylation of HT and HS.

Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?

Science.gov (United States)

Vikingsson, Svante; Carlsson, Björn; Almer, Sven H C; Peterson, Curt

2009-06-01

Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of me

Kinetic method for determination of molybdenum(6) and tungsten(6) from oxidaton of O-aminophenol with hydrogen peroxide

International Nuclear Information System (INIS)

Krejngol'ts, S.U.; Vasnev, A.N.

1978-01-01

A new method for determination of Mo(6) and W(6), based on the oxidation of O-aminophenol with hydrogen peroxide, catalysed by Mo and W(6) ions, is suggested. The reaction takes place in the neutral medium at a rather high substrate concentrations. The 1.5 M acetate buffer solution, 0.2N EDTA and 0.1M solution of O-aminophenol in 0.1M HCl were suggested for determination of Mo (0.2N EDTA was used for Fe(3) camouflage). The 1.5M acetate buffer solution with 0.3M K 2 C 2 O 4 xH 2 O additions, for Fe(3) and Mo(6) camouflage, and 0.1M O-aminophenol solution in 0.1M solution of H 2 C 2 O 4 xH 2 O were used for tungsten determination. The range for Mo and W determination is 3x10 -3 and 1x10 -2 mkg/ml respectively. The range of Mo and W concentrations under determination is from 3x10 -3 -10 -2 to 2 mkg/ml. The techniques for the analysis of highly pure substances is developed

Determination of venlafaxine and O-desmethylvenlafaxine in dried blood spots using LC-MS/MS

NARCIS (Netherlands)

Berm, E.J.J.; Brummel-Mulder, E.; Paardekooper, J.; Hak, E.; Wilffert, B.; Maring, J.G.

2013-01-01

Background: Venlafaxine (VEN) is an antidepressant which exerts both serotonin and norepinephrine reuptake inhibition. The drug is mainly metabolized by CYP2D6 to its active metabolite O-desmetylvenlafaxine (ODMV). Due to large interindividual differences in clearance in which genetic variance in

Quasielastic neutron scattering and infra-red band contour study of H2O reorientations in [Ni(H2O)6] (ClO4)2

International Nuclear Information System (INIS)

Janik, J.A.; Janik, J.M.; Otnes, K.; Stanek, T.

1980-01-01

IR band contour measurements carried out for [Ni(H 2 O) 6 ] (ClO 4 ) 2 revealed an existence of fast H 2 O 180 deg flips around Ni-O axes at room temperatures. These flips were subjected to a more accurate study by the quasielastic neutron scattering method. Correlation times of the order of picosecond were obtained for room temperatures and the barrier to rotation of ca. 7 kcal/mole. The results are compared to those previously obtained for [Mg(H 2 O) 6 ] (ClO 4 ) 2 and also to those for [Ni(NH 3 ) 6 ] (ClO 4 ) 2 and [Mg(NH 3 ) 6 ] (ClO 4 ) 2 . (author)

A novel organic–inorganic hybrid with Anderson type polyanions as building blocks: (C{sub 6}H{sub 10}N{sub 3}O{sub 2}){sub 2}Na(H{sub 2}O){sub 2}[Al(OH){sub 6}Mo{sub 6}O{sub 18}]·6H{sub 2}O

Energy Technology Data Exchange (ETDEWEB)

Thabet, Safa, E-mail: safathabet@hotmail.fr [Laboratoire de matériaux et cristallochimie, Département de chimie, Institut Supérieur des Sciences Appliquées et Technologier, Avenue El Mourouj, 5111 Mahdia (Tunisia); Ayed, Brahim, E-mail: brahimayed@yahoo.fr [Laboratoire de matériaux et cristallochimie, Département de chimie, Institut Supérieur des Sciences Appliquées et Technologier, Avenue El Mourouj, 5111 Mahdia (Tunisia); Haddad, Amor [Laboratoire de matériaux et cristallochimie, Département de chimie, Institut Supérieur des Sciences Appliquées et Technologier, Avenue El Mourouj, 5111 Mahdia (Tunisia)

2012-11-15

Graphical abstract: Display Omitted Highlights: ► Synthesis of a novel inorganic–organic hybrid compound based on Anderson polyoxomolybdates. ► Characterization by X-ray diffraction, IR and UV–Vis spectroscopies of the new compound. ► Potential applications in catalysis, biochemical analysis and electrical conductivity of the organic–inorganic compound. -- Abstract: A new organic–inorganic hybrid compound based on Anderson polyoxomolybdates, (C{sub 6}H{sub 10}N{sub 3}O{sub 2}){sub 2}Na(H{sub 2}O){sub 2}[Al(OH){sub 6}Mo{sub 6}O{sub 18}]·6H{sub 2}O (1) have been isolated by the conventional solution method and characterized by single-crystal X-ray diffraction, infrared, ultraviolet spectroscopy and Thermogravimetric Analysis (TGA). This compound crystallized in the triclinic system, space group P−1, with a = 94.635(1) Å, b = 10.958(1) Å, c = 11.602(1) Å, α = 67.525(1)°, β = 71.049(1)°, γ = 70.124(1)° and Z = 1. The crystal structures of the compounds exhibit three-dimensional supramolecular assembly based on the extensive hydrogen bonding interactions between organic cations, sodium cations, water molecules and Anderson polyoxoanions. The infrared spectrum fully confirms the X-ray crystal structure and the UV spectrum of the title compound exhibits an absorption peak at 210 nm.

Tangeretin and its metabolite 4′-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K

Science.gov (United States)

Cheng, Z; Surichan, S; Ruparelia, K; Arroo, R; Boarder, MR

2011-01-01

BACKGROUND AND PURPOSE The mechanisms by which the dietary compound tangeretin has anticancer effects may include acting as a prodrug, forming an antiproliferative product in cancer cells. Here we show that tangeretin also inhibits cell cycle progression in hepatocytes and investigate the role of its primary metabolite 4′-hydroxy-5,6,7,8-tetramethoxyflavone (4′-OH-TMF) in this effect. EXPERIMENTAL APPROACH We used epidermal growth factor (EGF)-stimulated rat hepatocytes, with [3H]-thymidine incorporation into DNA as an index of progression to S-phase of the cell cycle, and Western blots for phospho-proteins involved in the cell signalling cascade. KEY RESULTS Incubation of tangeretin with microsomes expressing CYP1A, or with hepatocytes, generated a primary product we identified as 4′-OH-TMF. Low micromolar concentrations of tangeretin or 4′-OH-TMF gave a concentration-dependent inhibition of EGF-stimulated progression to S-phase while having little effect on cell viability. To determine whether time for conversion of tangeretin to an active metabolite would enhance the inhibitory effect we used long pre-incubations; this reduced the inhibitory effect, in parallel with a reduction in the concentration of tangeretin. The EGF-stimulation of hepatocyte cell cycle progression requires signalling through Akt/mTOR/p70S6K kinase cascades. The tangeretin metabolite 4′-OH-TMF selectively inhibited S6K phosphorylation in the absence of significant inhibition of upstream Akt activity, suggesting an effect at the level of mTOR. CONCLUSIONS AND IMPLICATIONS Tangeretin and 4′-OH-TMF both inhibit cell cycle progression in primary hepatocytes. The inhibition of p70S6K phosphorylation by 4′-OH-TMF raises the possibility that inhibition of the mTOR pathway may contribute to the anticancer influence of a flavonoid-rich diet. PMID:21198542

Aquachlorido{6,6′-dimethoxy-2,2′-[ethane-1,2-diylbis(nitrilodimethylidyne]diphenolato-κ2O1,N,N′,O1′}cobalt(III monohydrate

Directory of Open Access Journals (Sweden)

Jianxin Xing

2009-04-01

Full Text Available The title compound, [Co(C18H18N2O4Cl(H2O]·H2O, contains a distorted octahedral cobalt(III complex with a 6,6′-dimethoxy-2,2′-[ethane-1,2-diylbis(nitrilodimethylidyne]diphenolate ligand, a chloride and an aqua ligand, and also a disordered water solvent molecule (half-occupancy. The CoIII ion is coordinated in an N2O3Cl manner. Weak O—H...O hydrogen bonds may help to stabilize the crystal packing.

Depletion of mammalian O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine provides a means to evaluate the role of this protein in protection against carcinogenic and therapeutic alkylating agents

International Nuclear Information System (INIS)

Dolan, M.E.; Pegg, A.E.; Moschel, R.

1990-01-01

O 6 -Alkylguanine-DNA alkyltransferase was rapidly and irreversibly inactivated by exposure to O 6 -benzylguanine or the p-chlorobenzyl and p-methylbenzyl analogues. This inactivation was much more rapid than with O 6 -methylguanine: incubation with 2.5 μM O 6 -benzylguanine led to more than a 90% loss of activity within 10 min, whereas 0.2 mM O 6 -methylguanine for 60 min was required for the same reduction. O 6 -Benzylguanine was highly effective in depleting the alkyltransferase activity of cultured human colon tumor (HT29) cells. Complete loss of activity was produced within 15 min after addition of O 6 -benzylguanine to the culture medium and a maximal effect was obtained with 5 μM. In contrast, at least 100 μM O 6 -methylguanine for 4 hr was needed to get a maximal effect, and this reduced the alkyltransferase by only 80%. Pretreatment of HT29 cells with 10 μM O 6 -benzylguanine for 2 hr led to a dramatic increase in the cytotoxicity produced by the chemotherapeutic agents 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) or 2-chloroethyl(methylsulfonyl)methanesulfonate (Clomesone). Administration of O 6 -benzylguanine to mice at a dose of 10 mg/kg reduced alkyltransferase levels by more than 95% in both liver and kidney. These results indicate that depletion of the alkyltransferase by O 6 -benzylguanine may be used to investigate the role of the DNA repair protein in carcinogenesis and mutagensis and that this treatment may be valuable to increase the chemotherapeutic effectiveness of chloroethylating agents

Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model

Science.gov (United States)

Patil, Avinash S.; Swamy, Geeta K.; Murtha, Amy P.; Heine, R. Phillips; Zheng, Xiaomei; Grotegut, Chad A.

2015-01-01

Objective: We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility. Study Design: Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2α-hydroxyprogesterone, 6β-hydroxyprogesterone (6β-OHP), 16α-hydroxyprogesterone (16α-OHP), or 17-hydroxyprogesterone caproate (17-OHPC) at 10−9 to 10−6 mol/L. Uterine horns were exposed to progestins (10−6 mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites. Results: Oxytocin-induced contractile frequency was decreased by 16α-OHP (P = .03) and increased by 6β-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin-induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16α-OHP and 6β-OHP metabolites were confirmed in all CYP3A isoforms tested. Conclusion: Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility. PMID:26037300

Anisotropic magnetic properties of the KMo4O6

Science.gov (United States)

Andrade, M.; Maffei, M. L.; Dos Santos, C. A. M.; Ferreira, B.; Sartori, A. F.

2012-02-01

Electrical resistivity measurements in the tetragonal KMo4O6 single crystals show a metal-insulator transition (MIT) near 100K. Magnetization measurements as a function of temperature show no evidence of magnetic ordering at this MIT [1]. Single crystals of KMo4O6 were obtained by electrolysis of a melt with a molar ratio of K2MoO4:MoO3 = 6:1. The process were carried out at 930 C with a current of 20-25mA for 52h in argon atmosphere. After that, electrodes were removed from the melt alloying the crystals to cool down to room temperature rapidly. Scanning Electron Microscopy (SEM) showed that the black single crystals were grown on the platinum cathode. Typical dimensions of the single crystals are 1x0.2x0.2mm^3. X-ray diffractometry confirmed that the single crystals have KMo4O6 tetragonal crystalline structure with space group P4. Magnetization measurements were performed parallel and perpendicular to the c-axis from 2 to 300K. The results show anisotropic behavior between both directions. Furthermore, the temperature independence of the magnetization at high temperature and the upturn at low temperature are observed in agreement with previous results [1]. MxH curves measured at several temperatures show nonlinear behavior and a small magnetic ordering. The magnetic ordering seems to be related to the MIT near 100K. This material is based upon support by FAPESP (2009/14524-6 and 2009/54001-6) and CNPq/NSF (490182/2009-7). M. Andrade is CAPES fellow and C.A.M. dos Santos is CNPq fellow. [4pt] [1] K. V. Ramanujachary et al., J. Sol. State Chem.102 (1993) 69.

Multiphonon structure of γ-unstable or O(6) nuclei

International Nuclear Information System (INIS)

Otsuka, T.; Kim, K.H.

1995-01-01

The multiphonon structure is shown for the O(6) limit of the Interacting Boson Model. The phonon states are created by the O(6) quadrupole operator with proper symmetrization. All the σ = N states can be described in this scheme in terms of phonon quanta and two-phonon anharmonicity, while the ground state is γ unstable. This structure is carried over into higher-lying σ < N states. (author)

3-D MnNb{sub 2}O{sub 6} nanogears from 1-D Nb{sub 2}O{sub 5} nanorods

Energy Technology Data Exchange (ETDEWEB)

Hu Weibing, E-mail: w.hu@tom.com [School of Chemical and Environmental Engineering, Hubei Institute for Nationalities, Enshi 445000 (China); Cui Zhicai [School of Chemical and Environmental Engineering, Hubei Institute for Nationalities, Enshi 445000 (China); Mi Yuanzhu [School of Chemistry and Environmental Engineering, Yangtze University, Nanhuan Road 1, Jingzhou 434023 (China)

2012-04-16

Graphical abstract: The geometry morphology of Nb-based nanomaterial evolved from long Nb{sub 2}O{sub 5} nanorods to a mixture of short Nb{sub 2}O{sub 5} nanorods and MnNb{sub 2}O{sub 6} 6-teeth nanogears, and eventually to fully developed pure 3-D nanogears. Highlights: Black-Right-Pointing-Pointer MnNb{sub 2}O{sub 6} nanogears have been generated by a simple solvothermal process when the Mn: Nb ratio was 1:1. Black-Right-Pointing-Pointer MnNb{sub 2}O{sub 6} 6-teeth nanogears accompanied with MnNb{sub 2}O{sub 6} 5-teeth nanogears are got when the Mn:Nb ratio reached 1:2. Black-Right-Pointing-Pointer The nanomaterial consists of nanorods and 6-teeth nanogears at low Mn:Nb molar ratio(1:4). Black-Right-Pointing-Pointer Pure long Nb{sub 2}O{sub 5} nanorods are achieved by only using NbCl{sub 5} - Abstract: MnNb{sub 2}O{sub 6} nanogears have been generated by using mixed NbCl{sub 5} and MnCl{sub 2} at an optimized ratio of 1:1 in a cyclohexanol solvent in a simple solvothermal process. It has shown that the Mn:Nb ratio determines the shape of the products. Detailed characterization by electron microscopy has shown that increasing the Mn{sup +2} concentration during the solvo-thermal synthesis promotes a morphological evolution from relatively long Nb{sub 2}O{sub 5} nanorods to a mixture of short Nb{sub 2}O{sub 5} nanorods and MnNb{sub 2}O{sub 6} 6-teeth nanogears, then to a mixture of short Nb{sub 2}O{sub 5} nanorods and more MnNb{sub 2}O{sub 6} 6-teeth nanogears, then to more and more MnNb{sub 2}O{sub 6} 6-teeth nanogears that are occasionally accompanied with under-developed MnNb{sub 2}O{sub 6} 5-teeth nanogears, and eventually to fully developed pure 3-D nanogears. The driving force for such interesting geometry transformations is attributed to the inclusion of Mn{sup 2+} into the Nb{sub 2}O{sub 5} template at low Mn{sup 2+} concentrations, which introduces internal stresses to the Nb{sub 2}O{sub 5} nanorods. At high Mn{sup 2+} concentrations, close to the

Transportable hyperpolarized metabolites

Science.gov (United States)

Ji, Xiao; Bornet, Aurélien; Vuichoud, Basile; Milani, Jonas; Gajan, David; Rossini, Aaron J.; Emsley, Lyndon; Bodenhausen, Geoffrey; Jannin, Sami

2017-01-01

Nuclear spin hyperpolarization of 13C-labelled metabolites by dissolution dynamic nuclear polarization can enhance the NMR signals of metabolites by several orders of magnitude, which has enabled in vivo metabolic imaging by MRI. However, because of the short lifetime of the hyperpolarized magnetization (typically <1 min), the polarization process must be carried out close to the point of use. Here we introduce a concept that markedly extends hyperpolarization lifetimes and enables the transportation of hyperpolarized metabolites. The hyperpolarized sample can thus be removed from the polarizer and stored or transported for use at remote MRI or NMR sites. We show that hyperpolarization in alanine and glycine survives 16 h storage and transport, maintaining overall polarization enhancements of up to three orders of magnitude. PMID:28072398

Microsomal metabolism of trenbolone acetate metabolites ...

Science.gov (United States)

Trenbolone acetate (TBA) is a synthetic growth promoter widely used in animal agriculture, and its metabolites are suspected endocrine disrupting compounds in agriculturally impacted receiving waters. However, beyond the three widely recognized TBA metabolites (17-trenbolone, 17-trenbolone and trendione), little is known about other metabolites formed in vivo and subsequently discharged into the environment, with some evidence suggesting these unknown metabolites comprise a majority of the TBA mass dosed to the animal. Here, we explored the metabolism of the three known TBA metabolites using rat liver microsome studies. All TBA metabolites are transformed into a complex mixture of monohydroxylated products. Based on product characterization, the majority are more polar than the parent metabolites but maintain their characteristic trienone backbone. A minor degree of interconversion between known metabolites was also observed, as were higher order hydroxylated products with a greater extent of reaction. Notably, the distribution and yield of products were generally comparable across a series of variably induced rat liver microsomes, as well as during additional studies with human and bovine liver microsomes. Bioassays conducted with mixtures of these transformation products suggest that androgen receptor (AR) binding activity is diminished as a result of the microsomal treatment, suggesting that the transformation products are generally less potent than

Synthesis and photocatalytic properties of MgBi2O6 with Ag additions

Science.gov (United States)

Zhong, Liansheng; Hu, Chaohao; Zhu, Binqing; Zhong, Yan; Zhou, Huaiying

2018-02-01

Ag-doped MgBi2O6 photocatalysts were synthesized by the low temperature hydrothermal method in combination with heat treatment reaction using NaBiO3·2H2O, MgCl2·6H2O, and AgNO3 as raw materials. The products were characterized by using power X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), Energy dispersive X-ray detector (EDS), and UV-Vis diffusion reflectance spectra. The photocatalytic activity of MgBi2O6 with Ag additions was evaluated by degrading MB (10 mg/L) under visible light irradiation (λ > 420 nm). The results showed that in comparison with pure MgBi2O6, the photocatalytic activity of MgBi2O6 with about 5% Ag concentration is increased by about 24% after 120 min reaction. The enhancement of catalytic activity of Ag-doped MgBi2O6 photocatalysts should be related to the band structure, morphology and larger specific surface area.

Metabolomic effects of CeO2, SiO2 and CuO metal oxide nanomaterials on HepG2 cells

Data.gov (United States)

U.S. Environmental Protection Agency — The data set is a matrix of cellular biochemical (metabolites) in HepG2 cells treated with various metal oxide nanomaterials composed of CeO2, SiO2 and CuO. This...

Identifying diseases-related metabolites using random walk.

Science.gov (United States)

Hu, Yang; Zhao, Tianyi; Zhang, Ningyi; Zang, Tianyi; Zhang, Jun; Cheng, Liang

2018-04-11

Metabolites disrupted by abnormal state of human body are deemed as the effect of diseases. In comparison with the cause of diseases like genes, these markers are easier to be captured for the prevention and diagnosis of metabolic diseases. Currently, a large number of metabolic markers of diseases need to be explored, which drive us to do this work. The existing metabolite-disease associations were extracted from Human Metabolome Database (HMDB) using a text mining tool NCBO annotator as priori knowledge. Next we calculated the similarity of a pair-wise metabolites based on the similarity of disease sets of them. Then, all the similarities of metabolite pairs were utilized for constructing a weighted metabolite association network (WMAN). Subsequently, the network was utilized for predicting novel metabolic markers of diseases using random walk. Totally, 604 metabolites and 228 diseases were extracted from HMDB. From 604 metabolites, 453 metabolites are selected to construct the WMAN, where each metabolite is deemed as a node, and the similarity of two metabolites as the weight of the edge linking them. The performance of the network is validated using the leave one out method. As a result, the high area under the receiver operating characteristic curve (AUC) (0.7048) is achieved. The further case studies for identifying novel metabolites of diabetes mellitus were validated in the recent studies. In this paper, we presented a novel method for prioritizing metabolite-disease pairs. The superior performance validates its reliability for exploring novel metabolic markers of diseases.

A new triclinic modification of the pyrochlore-type KOs2O6 superconductor

International Nuclear Information System (INIS)

Katrych, S.; Gu, Q.F.; Bukowski, Z.; Zhigadlo, N.D.; Krauss, G.; Karpinski, J.

2009-01-01

A new modification of KOs 2 O 6 , the representative of a new structural type (Pearson symbol aP18, a=5.5668(1) A, b=6.4519(2) A, c=7.2356(2) A, α=65.377(3) o , β=70.572(3) o , γ=75.613(2) o space group P-1, no. 2 was synthesized employing high pressure technique. Its structure was determined by single-crystal X-ray diffraction. The structure can be described as two OsO 6 octahedral chains relating to each other through inversion and forming big voids with K atoms inside. Quantum chemical calculations were performed on the novel compound and structurally related cubic compound. High-pressure X-ray study showed that cubic KOs 2 O 6 phase was stable up to 32.5(2) GPa at room temperature. - Graphical abstract: A new modification of KOs 2 O 6 , the representative of a new structural type (Pearson symbol aP18, a=5.5668(1) A, b=6.4519(2) A, c=7.2356(2) A, α=65.377(3) o , β=70.572(3) o , γ=75.613(2) o space group P-1, no. 2 was synthesized employing high pressure technique. The structure can be described as two OsO 6 octahedral chains relating to each other through inversion and forming big voids with K atoms inside

The synthesis of 8-β-[(methylsulfinyl-[18O])-methyl]-6-propylergoline