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Sample records for acetylcholinesterase inhibitor treatment

  1. Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

    PubMed Central

    Čolović, Mirjana B; Krstić, Danijela Z; Lazarević-Pašti, Tamara D; Bondžić, Aleksandra M; Vasić, Vesna M

    2013-01-01

    Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases. PMID:24179466

  2. Acetylcholinesterase inhibitor treatment delays recovery from axotomy in cultured dorsal root ganglion neurons.

    PubMed

    Dupree, J L; Bigbee, J W

    1996-08-01

    We have previously reported that dorsal root ganglion neurons cultured in the presence of the highly specific, reversible acetylcholinesterase inhibitor 1,5-bis-(4-allyldimethylammoniumphenyl) pentan-3-one dibromide (BW284c51), showed significantly reduced neurite outgrowth and contained massive perikaryal inclusions of neurofilaments. In the present report we have more closely examined these changes in a time course study over a 21-day culture period using a combined morphological, immunocytochemical and enzymatic approach and additionally, describe, the effects of acetylcholinesterase inhibitor treatment on the state of neurofilament phosphorylation. Finally, we have examined the effects of co-administration of N6,2'-0-dibutyryladenosine 3':5'-cyclic monophosphate (dbcAMP) with BW284c51. At 1 day in culture, both control and treated cells displayed eccentrically located nuclei, numerous polysomes and perikaryal accumulations of neurofilaments which were immunoreactive with both phosphorylation- and nonphosphorylation-dependent neurofilament antibodies. These cytological changes, which are common features of the chromatolytic reaction following axotomy in vivo, rapidly resolved in the control neurons, where by 7 days in culture, the neurofilament accumulations had completely disappeared and neurite outgrowth was robust. In contrast, inhibitor-treated neurons retained the post-axotomy features up to 21 days and had significantly reduced neurite outgrowth. In addition, we have investigated a possible role of cyclic adenosine monophosphate (cAMP) in the recovery process since it has been shown to enhance neuritic outgrowth in cultured neurons. Our results demonstrate that the addition of dbcAMP, a membrane permeable analog of cAMP, significantly enhanced neuritic outgrowth and accelerated the recovery of BW284c51-treated dorsal root ganglion cells, as gauged by the disappearance of the axotomy-related cytological changes. Treatment with dbcAMP also increased

  3. Musical Hallucinations Treated with Acetylcholinesterase Inhibitors

    PubMed Central

    Blom, Jan Dirk; Coebergh, Jan Adriaan F.; Lauw, René; Sommer, Iris E. C.

    2015-01-01

    Musical hallucinations are relatively rare auditory percepts which, due to their intrusive nature and the accompanying fear of impending mental decline, tend to cause significant distress and impairment. Although their etiology and pathophysiology appear to be heterogeneous and no evidence-based treatment methods are available, case reports indicate that acetylcholinesterase inhibitors may yield positive results in patients with comorbid hearing loss. We present two female patients (aged 76 and 78 years) both of whom suffered from hearing impairment and practically incessant musical hallucinations. Both patients were successfully treated with the acetylcholinesterase inhibitor rivastigmine. Based on these two case descriptions and an overview of studies describing the use of acetylcholinesterase inhibitors in similar patients, we discuss possible mechanisms and propose further research on the use of acetylcholinesterase inhibitors for musical hallucinations experienced in concordance with hearing loss. PMID:25904872

  4. An overview of phenserine tartrate, a novel acetylcholinesterase inhibitor for the treatment of Alzheimer's disease.

    PubMed

    Greig, Nigel H; Sambamurti, Kumar; Yu, Qian-sheng; Brossi, Arnold; Bruinsma, Gosse B; Lahiri, Debomoy K

    2005-07-01

    Existing cholinesterase (ChE) inhibitor therapies for Alzheimer's disease (AD), while effective in improving cognitive, behavioral and functional impairments, do not alter disease progression. Novel drug design studies have focused on the classical ChE inhibitor, (-)-physostigmine, producing alterations in chemical composition and three-dimensional structure, which may offer an improved therapeutic index. The phenylcarbamate derivative, (-)-phenserine, is a selective, non-competitive inhibitor of acetylcholinesterase (AChE). In vivo, (-)-phenserine produces rapid, potent, and long-lasting AChE inhibition. As a possible result of its preferential brain selectivity, (-)-phenserine is significantly less toxic than (-)-physostigmine. In studies using the Stone maze paradigm, (-)-phenserine has been shown to improve cognitive performance in both young learning-impaired and elderly rats. In addition to reducing inactivation of acetylcholine in the brain, (-)-phenserine appears to have a second mode of action. Reduced secretion of beta-amyloid (Abeta) has been observed in cell lines exposed to (-)-phenserine, occurring through translational regulation of beta-amyloid precursor protein (beta-APP) mRNA via a non-cholinergic mechanism. These in vitro findings appear to translate in vivo into animal models and humans. In a small study of patients with AD, (-)-phenserine treatment tended to reduce beta-APP and Abeta levels in plasma samples. Clinical studies also reveal that (-)-phenserine (5-10 mg b.i.d.) had a favorable safety and pharmacological profile, produced significant improvements in cognitive function and was well tolerated in patients with AD treated for 12 weeks. Further randomized, double-blind, placebo-controlled Phase III studies assessing the efficacy, safety/tolerability and potential disease-modifying effects of (-)-phenserine in patients with AD are currently ongoing.

  5. Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

    PubMed

    Wang, Zhi-Min; Cai, Pei; Liu, Qiao-Hong; Xu, Ding-Qiao; Yang, Xue-Lian; Wu, Jia-Jia; Kong, Ling-Yi; Wang, Xiao-Bing

    2016-11-10

    A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aβ interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu(2+)-induced Aβ1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 μM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aβ1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy. PMID:27484514

  6. Isolation and characterisation of acetylcholinesterase inhibitors from Aquilaria subintegra for the treatment of Alzheimer's disease (AD).

    PubMed

    Bahrani, Hirbod; Mohamad, Jamaludin; Paydar, Mohammad Javad; Rothan, Hussin A

    2014-02-01

    Aquilaria subintegra, locally known as "Gaharu", belongs to the Thymelaeceae family. This plant's leaves have been claimed to be effective for the treatment of Alzheimer's disease (AD) by Malay traditional practitioner in Malaysia. In this research, the chloroform extracts of the leaves and stem of A. subintegra were tested for acetylcholinesterase (AChE) inhibitory activity. The Thin Layer Chromatography (TLC) results indicated the presence of phenols, flavonoids, terpenoids, and alkaloids compounds in the extracts. Analysis of the stem chloroform extracts with LCMS/MS displayed that it contains kaempferol 3,4,7-trimethyl ether. The AChE inhibitory activity of leaves and stem chloroform extracts and kaempferol were 80%, 93% and 85.8%, respectively. The Brine Shrimp Lethality Assay (BSLA) exhibited low to moderate toxicity of the chloroform extract from leaves (LC50=531.18 ± 49.53 μg/ml), the stem chloroform extract (LC50=407.34 ± 68.05 μg/ml) and kaempferol (LC50=762.41 ± 45.09 μg/ml). The extracts and kaempferol were not cytotoxic to human umbilical vein endothelial cells (HUVEC), human normal gastric epithelial cell line (GES-1) and human normal hepatic cell line (WRL-68). The effect of leaf and stem chloroform extracts and kaempferol were determined in the Radial Arm Maze (RAM) after administration by oral gavage to ICR male and female mice with valium-impaired memory. Administration of kaempferol to the mice significantly reduced the number of repeated entries into the arms of maze in males and females. In conclusion, the inhibition of AChE by leaf and stem chloroform extracts of A. subintegra could be due to the presence of kaempferol. This extract is safe for use as a natural AChE inhibitor as an alternative to berberine for the treatment of AD. PMID:24479629

  7. Isolation and characterisation of acetylcholinesterase inhibitors from Aquilaria subintegra for the treatment of Alzheimer's disease (AD).

    PubMed

    Bahrani, Hirbod; Mohamad, Jamaludin; Paydar, Mohammad Javad; Rothan, Hussin A

    2014-02-01

    Aquilaria subintegra, locally known as "Gaharu", belongs to the Thymelaeceae family. This plant's leaves have been claimed to be effective for the treatment of Alzheimer's disease (AD) by Malay traditional practitioner in Malaysia. In this research, the chloroform extracts of the leaves and stem of A. subintegra were tested for acetylcholinesterase (AChE) inhibitory activity. The Thin Layer Chromatography (TLC) results indicated the presence of phenols, flavonoids, terpenoids, and alkaloids compounds in the extracts. Analysis of the stem chloroform extracts with LCMS/MS displayed that it contains kaempferol 3,4,7-trimethyl ether. The AChE inhibitory activity of leaves and stem chloroform extracts and kaempferol were 80%, 93% and 85.8%, respectively. The Brine Shrimp Lethality Assay (BSLA) exhibited low to moderate toxicity of the chloroform extract from leaves (LC50=531.18 ± 49.53 μg/ml), the stem chloroform extract (LC50=407.34 ± 68.05 μg/ml) and kaempferol (LC50=762.41 ± 45.09 μg/ml). The extracts and kaempferol were not cytotoxic to human umbilical vein endothelial cells (HUVEC), human normal gastric epithelial cell line (GES-1) and human normal hepatic cell line (WRL-68). The effect of leaf and stem chloroform extracts and kaempferol were determined in the Radial Arm Maze (RAM) after administration by oral gavage to ICR male and female mice with valium-impaired memory. Administration of kaempferol to the mice significantly reduced the number of repeated entries into the arms of maze in males and females. In conclusion, the inhibition of AChE by leaf and stem chloroform extracts of A. subintegra could be due to the presence of kaempferol. This extract is safe for use as a natural AChE inhibitor as an alternative to berberine for the treatment of AD.

  8. Flavanone glycosides as acetylcholinesterase inhibitors: computational and experimental evidence.

    PubMed

    Remya, C; Dileep, K V; Tintu, I; Variyar, E J; Sadasivan, C

    2014-01-01

    Acetylcholinesterase hydrolyzes the neurotransmitter called acetylcholine and is crucially involved in the regulation of neurotransmission. One of the observable facts in the neurodegenerative disorders like Alzheimer's disease is the decrease in the level of acetylcholine. Available drugs that are used for the treatment of Alzheimer's disease are primarily acetylcholinesterase inhibitors with multiple activities. They maintain the level of acetylcholine in the brain by inhibiting the acetylcholinesterase function. Hence acetylcholinesterase inhibitors can be used as lead compounds for the development of drugs against AD. In the present study, the binding potential of four flavanone glycosides such as naringin, hesperidin, poncirin and sakuranin against acetylcholinesterase was analysed by using the method of molecular modeling and docking. The activity of the top scored compound, naringin was further investigated by enzyme inhibition studies and its inhibitory concentration (IC50) towards acetylcholinesterase was also determined. PMID:25593395

  9. 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

    PubMed

    Semenov, Vyacheslav E; Zueva, Irina V; Mukhamedyarov, Marat A; Lushchekina, Sofya V; Kharlamova, Alexandra D; Petukhova, Elena O; Mikhailov, Anatoly S; Podyachev, Sergey N; Saifina, Lilya F; Petrov, Konstantin A; Minnekhanova, Oksana A; Zobov, Vladimir V; Nikolsky, Evgeny E; Masson, Patrick; Reznik, Vladimir S

    2015-11-01

    Novel 6-methyluracil derivatives with ω-(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron-withdrawing substituents on the benzyl rings. The compounds are mixed-type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10,000-fold higher than that for human butyrylcholinesterase (hBuChE). Molecular modeling studies indicate that these compounds are bifunctional AChE inhibitors, spanning the enzyme active site gorge and binding to its peripheral anionic site (PAS). In vivo experiments show that the 6-methyluracil derivatives are able to penetrate the blood-brain barrier (BBB), inhibiting brain-tissue AChE. The most potent AChE inhibitor, 3 d (1,3-bis[5-(o-nitrobenzylethylamino)pentyl]-6-methyluracil), was found to improve working memory in scopolamine and transgenic APP/PS1 murine models of Alzheimer's disease, and to significantly decrease the number and area of β-amyloid peptide plaques in the brain. PMID:26412714

  10. Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity.

    PubMed

    Pohanka, Miroslav

    2014-06-02

    Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer's disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a "cholinergic anti-inflammatory pathway" which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system.

  11. Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

    PubMed Central

    Pohanka, Miroslav

    2014-01-01

    Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system. PMID:24893223

  12. Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity.

    PubMed

    Pohanka, Miroslav

    2014-01-01

    Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer's disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a "cholinergic anti-inflammatory pathway" which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system. PMID:24893223

  13. Safety and Preliminary Efficacy of the Acetylcholinesterase Inhibitor Huperzine A as a Treatment for Cocaine Use Disorder

    PubMed Central

    Verrico, Christopher D.; Newton, Thomas F.; Mahoney, James J.; Thompson-Lake, Daisy G. Y.

    2016-01-01

    Background: Cholinergic transmission is altered by drugs of abuse and contributes to psychostimulant reinforcement. In particular, acetylcholinesterase inhibitors, like huperzine A, may be effective as treatments for cocaine use disorder. Methods: The current report describes results from a double-blind, placebo-controlled study in which participants (n=14–17/group) were randomized to huperzine A (0.4 or 0.8mg) or placebo. Participants received randomized infusions of cocaine (0 and 40mg, IV) on days 1 and 9. On day 10, participants received noncontingent, randomized infusions of cocaine (0 and 20mg, IV) before making 5 choices to receive additional infusions. Results: Huperzine A was safe and well-tolerated and compared with placebo, treatment with huperzine A did not cause significant changes in any cocaine pharmacokinetic parameters (all P>.05). Time-course and peak effects analyses show that treatment with 0.4mg of huperzine A significantly attenuated cocaine-induced increases of “Any Drug Effect,” “High,” “Stimulated,” “Willing to Pay,” and “Bad Effects” (all P>.05). Conclusions: The current study represents a significant contribution to the addiction field since it serves as the first published report on the safety and potential efficacy of huperzine A as a treatment for cocaine use disorder. PMID:26364275

  14. Theoretical study of classical acetylcholinesterase inhibitors

    NASA Astrophysics Data System (ADS)

    Nascimento, Érica C. M.; Martins, João B. L.; dos Santos, Maria L.; Gargano, R.

    2008-06-01

    Semi-empirical, RHF and DFT calculations were carried out to study well known acetylcholinesterase inhibitors, i.e., tacrine, donepezil, galantamine, physostigmine, and tacrine dimer (bis-tacrine). Electronic and structural parameters were used in order to correlate the acetylcholinesterase inhibition activity with their molecular structure. The optimized geometries of these drugs were analyzed by multivariate PCA statistical method. Frontier orbital energies (HOMO and LUMO), the (HOMO-LUMO) gap and the distance between more acidic hydrogen species were used to determine principal components. The PCA results indicated that these drugs were ordered into three groups according to the first principal component: galantamine/physostigmine, donepezil/tacrine dimer and tacrine.

  15. Molecular evaluation of herbal compounds as potent inhibitors of acetylcholinesterase for the treatment of Alzheimer's disease.

    PubMed

    Chen, Yan-Xiu; Li, Guan-Zeng; Zhang, Bin; Xia, Zhang-Yong; Zhang, Mei

    2016-07-01

    Alzheimer's disease (AD) is a progressive disease and the predominant cause of dementia. Common symptoms include short-term memory loss, and confusion with time and place. Individuals with AD depend on their caregivers for assistance, and may pose a burden to them. The acetylcholinesterase (AChE) enzyme is a key target in AD and inhibition of this enzyme may be a promising strategy in the drug discovery process. In the present study, an inhibitory assay was carried out against AChE using total alkaloidal plants and herbal extracts commonly available in vegetable markets. Subsequently, molecular docking simulation analyses of the bioactive compounds present in the plants were conducted, as well as a protein‑ligand interaction analysis. The stability of the docked protein‑ligand complex was assessed by 20 ns molecular dynamics simulation. The inhibitory assay demonstrated that Uncaria rhynchophylla and Portulaca oleracea were able to inhibit AChE. In addition, molecular docking simulation analyses indicated that catechin present in Uncaria rhynchophylla, and dopamine and norepinephrine present in Portulaca oleracea, had the best docking scores and interaction energy. In conclusion, catechin in Uncaria rhynchophylla, and dopamine and norepinephrine in Portulaca oleracea may be used to treat AD.

  16. Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

    PubMed Central

    Lecoutey, Cédric; Hedou, Damien; Freret, Thomas; Giannoni, Patrizia; Gaven, Florence; Since, Marc; Bouet, Valentine; Ballandonne, Céline; Corvaisier, Sophie; Malzert Fréon, Aurélie; Mignani, Serge; Cresteil, Thierry; Boulouard, Michel; Claeysen, Sylvie; Rochais, Christophe; Dallemagne, Patrick

    2014-01-01

    RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer’s disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPα release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment. PMID:25157130

  17. Possibility of Acetylcholinesterase Overexpression in Alzheimer Disease Patients after Therapy with Acetylcholinesterase Inhibitors.

    PubMed

    Kračmarová, Alžběta; Drtinová, Lucie; Pohanka, Miroslav

    2015-01-01

    Acetylcholinesterase is an enzyme responsible for termination of excitatory transmission at cholinergic synapses by the hydrolyzing of a neurotransmitter acetylcholine. Nowadays, other functions of acetylcholinesterase in the organism are considered, for example its role in regulation of apoptosis. Cholinergic nervous system as well as acetylcholinesterase activity is closely related to pathogenesis of Alzheimer disease. The mostly used therapy of Alzheimer disease is based on enhancing cholinergic function using inhibitors of acetylcholinesterase like rivastigmine, donepezil or galantamine. These drugs can influence not only the acetylcholinesterase activity but also other processes in treated organism. The paper is aimed mainly on possibility of increased expression and protein level of acetylcholinesterase caused by the therapy with acetylcholinesterase inhibitors.

  18. Possibility of Acetylcholinesterase Overexpression in Alzheimer Disease Patients after Therapy with Acetylcholinesterase Inhibitors.

    PubMed

    Kračmarová, Alžběta; Drtinová, Lucie; Pohanka, Miroslav

    2015-01-01

    Acetylcholinesterase is an enzyme responsible for termination of excitatory transmission at cholinergic synapses by the hydrolyzing of a neurotransmitter acetylcholine. Nowadays, other functions of acetylcholinesterase in the organism are considered, for example its role in regulation of apoptosis. Cholinergic nervous system as well as acetylcholinesterase activity is closely related to pathogenesis of Alzheimer disease. The mostly used therapy of Alzheimer disease is based on enhancing cholinergic function using inhibitors of acetylcholinesterase like rivastigmine, donepezil or galantamine. These drugs can influence not only the acetylcholinesterase activity but also other processes in treated organism. The paper is aimed mainly on possibility of increased expression and protein level of acetylcholinesterase caused by the therapy with acetylcholinesterase inhibitors. PMID:26455564

  19. KLHL40-related nemaline myopathy with a sustained, positive response to treatment with acetylcholinesterase inhibitors.

    PubMed

    Natera-de Benito, D; Nascimento, A; Abicht, A; Ortez, C; Jou, C; Müller, J S; Evangelista, T; Töpf, A; Thompson, R; Jimenez-Mallebrera, C; Colomer, J; Lochmüller, H

    2016-03-01

    Congenital myopathies are a group of inherited muscle disorders characterized by hypotonia, weakness and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. Neuromuscular transmission defects have recently been reported in several patients with congenital myopathies (CM). Mutations in KLHL40 are among the most common causes of severe forms of nemaline myopathy. Clinical features of affected individuals include fetal akinesia or hypokinesia, respiratory failure, and swallowing difficulties at birth. Muscle weakness is usually severe and nearly half of the individuals have no spontaneous antigravity movement. The average age of death has been reported to be 5 months in a recent case series. Herein we present a case of a patient with a nemaline myopathy due to KLHL40 mutations (c.604delG, p.Ala202Argfs*56 and c.1513G>C, p.Ala505Pro) with an impressive and prolonged beneficial response to treatment with high-dose pyridostigmine. Myasthenic features or response to ACEI have not previously been reported as a characteristic of nemaline myopathy or KLHL40-related myopathy.

  20. KLHL40-related nemaline myopathy with a sustained, positive response to treatment with acetylcholinesterase inhibitors.

    PubMed

    Natera-de Benito, D; Nascimento, A; Abicht, A; Ortez, C; Jou, C; Müller, J S; Evangelista, T; Töpf, A; Thompson, R; Jimenez-Mallebrera, C; Colomer, J; Lochmüller, H

    2016-03-01

    Congenital myopathies are a group of inherited muscle disorders characterized by hypotonia, weakness and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. Neuromuscular transmission defects have recently been reported in several patients with congenital myopathies (CM). Mutations in KLHL40 are among the most common causes of severe forms of nemaline myopathy. Clinical features of affected individuals include fetal akinesia or hypokinesia, respiratory failure, and swallowing difficulties at birth. Muscle weakness is usually severe and nearly half of the individuals have no spontaneous antigravity movement. The average age of death has been reported to be 5 months in a recent case series. Herein we present a case of a patient with a nemaline myopathy due to KLHL40 mutations (c.604delG, p.Ala202Argfs*56 and c.1513G>C, p.Ala505Pro) with an impressive and prolonged beneficial response to treatment with high-dose pyridostigmine. Myasthenic features or response to ACEI have not previously been reported as a characteristic of nemaline myopathy or KLHL40-related myopathy. PMID:26754003

  1. Synthetic conversion of ACAT inhibitor to acetylcholinesterase inhibitor.

    PubMed

    Obata, R; Sunazuka, T; Otoguro, K; Tomoda, H; Harigaya, Y; Omura, S

    2000-06-19

    Natural product acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor pyripyropene A was synthetically converted to acetylcholinesterase (AChE) inhibitor via heterolitic cleavage of the 2-pyrone ring, followed by gamma-acylation/cyclization with several aroyl chlorides. The 4-pyridyl analogue selectively showed AChE inhibitory activity (IC50 7.9 microM) and no ACAT inhibitory activity IC50 = >1000 microM. PMID:10890154

  2. Acetylcholinesterase inhibitors and Gulf War illnesses

    PubMed Central

    Golomb, Beatrice Alexandra

    2008-01-01

    Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents. Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms in GWV. The link is buttressed by a dose–response relation of PB pill number to chronic symptoms in GWV and by a relation between avidity of AChEi clearance and illness, based on genotypes, concentrations, and activity levels of enzymes that detoxify AChEis. Triangulating evidence derives from studies linking occupational exposure to AChEis to chronic health symptoms that mirror those of ill GWV. Illness is again linked to lower activity of AChEi detoxifying enzymes and genotypes conferring less-avid AChEi detoxification. AChEi exposure satisfies Hill's presumptive criteria for causality, suggesting this exposure may be causally linked to excess health problems in GWV. PMID:18332428

  3. Pharmacological treatments of behavioral and psychological symptoms of dementia in Alzheimer's disease: role of acetylcholinesterase inhibitors and memantine.

    PubMed

    Desmidt, Thomas; Hommet, Caroline; Camus, Vincent

    2016-09-01

    Behavioral and psychological symptoms of dementia (BPSD) are frequent in Alzheimer's disease (AD). They are associated with disability and suffering for both the patients and their caregivers. Even if BPSD are now well diagnosed and characterized by standardized tools, their treatment remains often challenging in clinical setting because of the frequent and severe side effects of the psychotropic drugs when used in this indication. Evidence-based data confirm that antipsychotics and antidepressants are efficient for the treatment of BPSD but have a poor tolerance profile and their use is problematic. Use of cholinesterase inhibitors and memantine, whom French authorities have questioned the relevance in 2008, also have a significant efficacy on non-cognitive symptoms of AD. Therefore, and although their tolerance profile is considered unsatisfying, they keep an indication in patients with AD and BPSD. PMID:27651011

  4. Differential efficacy of treatment with acetylcholinesterase inhibitors in patients with mild and moderate Alzheimer's disease over a 6-month period.

    PubMed

    López-Pousa, S; Turon-Estrada, A; Garre-Olmo, J; Pericot-Nierga, I; Lozano-Gallego, M; Vilalta-Franch, M; Hernández-Ferràndiz, M; Morante-Muñoz, V; Isern-Vila, A; Gelada-Batlle, E; Majó-Llopart, J

    2005-01-01

    There are various anticholinesterase inhibitors (AChEIs) for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). All AChEIs have shown greater efficacy than placebo in randomized, double-blind, parallel-group clinical trials. No differential studies have yet been made of the efficacy between all AChEIs. The study aims to determine the differential efficacy of the AChEIs with respect to a historical sample of patients with AD that were not treated with AChEIs. An open-label, prospective, observational study with a retrospective control group was undertaken to examine the evolution of the cognitive function over a 6-month period. The patients were assessed with the Mini-Mental State Examination (MMSE) at study entry and at 6 months. A general linear model was applied for repeated measurements with the MMSE score as the dependent variable, treatment type as an independent variable and the severity of the deterioration, age and the MMSE baseline score as covariables. Of the sample of 147 patients, 40 initiated treatment with donepezil, 32 with galantamine, 30 with rivastigmine and 45 were part of a historical sample of the memory clinic patients between 1991 and 1996 that had not been treated with AChEIs. The average age was 73.7 years (SD = 6.9; range = 52-86), 67.3% were women, 78.2% of the cases were mild and the MMSE baseline score was 18.1 points (range = 11-27). No significant intergroup differences were observed in these variables. The average doses of donepezil, galantamine and rivastigmine were 5.87 mg/day (SD = 1.92), 14.81 mg/day (SD = 6.25) and 6.41 mg/day (SD = 1.82), respectively. At 6 months, the difference in the MMSE score with respect to the untreated group was 1.6 points for donepezil (95% CI 0.79-2.37; p < 0.001), 0.99 points for galantamine (95% CI 0.14-1.85; p = 0.01) and 0.90 points for rivastigmine (95% CI 0.05-1.74; p = 0.03). No significant differences were observed in the efficacy among the groups treated with AChEIs (p

  5. Vesicular acetylcholine transporter (VAChT) in the brain of spontaneously hypertensive rats (SHR): effect of treatment with an acetylcholinesterase inhibitor.

    PubMed

    Tayebati, S K; Di Tullio, M A; Amenta, F

    2008-11-01

    The cholinergic marker vesicular acetylcholine transporter (VAChT) was investigated in different cerebral areas of spontaneously hypertensive rats (SHR) by immunochemistry (Western blot analysis) and by immunohistochemistry. SHR were used as an animal model of hypertensive brain damage. The sensitivity of manipulation of cholinergic system on VAChT was assessed in rats treated for four weeks with the acetylcholinesterase (AChE) inhibitor galantamine (3 mg/Kg/day). VAChT concentrations were increased in the brain of control SHR compared to age-matched normotensive Wistar-Kyoto rats. This increase probably represents an up-regulation of VAChT to oppose cholinergic deficits reported in SHR and is countered by galantamine administration. The possibility that cholinergic neurotransmission enhancement may represent a therapeutic strategy in cerebrovascular disease is discussed.

  6. Pharmacokinetics and pharmacodynamics of a novel Acetylcholinesterase Inhibitor, DMNG-3.

    PubMed

    Xin-Guo, Zhang; Kou, Fei; Guo-Di, Ma; Tang, Peng; Zhong-Duo, Yang

    2016-01-01

    DMNG-3(3β-Methyl-[2-(4-nitrophenoxy)ethyl]-amino]con-5-enine), is a new and the potentially most potent acetylcholinesterase inhibitor recently obtained from conessine by N-demethylation and nucleophilic substitution reaction. In the present study, a step-down passive avoidance test was used to investigate whether DMNG-3 could modulate impairment of learning and memory induced by scopolamine, and a high performance liquid chromatography(HPLC) method for the determination of DMNG-3 in biological samples was applied to study its pharmacokinetics and tissues distribution. Separation was achieved on C18 column using a mobile phase consisting methanol-water (70:30, v/v) at a flow rate of 1.0ml/min. The intra- and inter-day precisions were good and the RSD was all lower than 1.30%. The mean absolute recovery of DMNG-3 in plasma ranged from 88.55 to 96.45 %. Our results showed oral administration of DMNG-3(10,25,50 mg/kg/day) can significantly improve the latency and number of errors and had a positive effect of improvement of learning and memory in mice in passive avoidance tests. The elimination half-life (T1/2) was 14.07±1.29, 15.87±1.03h, and the total clearance (CL) values were 0.70±0.11, 0.78±0.13 L/h/kg, respectively. The pharmacokinetic studies showed that DMNG-3 has a slowly clearance and large distribution volume in experimental animals, and its disposition is linear over the range of doses tested. The liver, small intestine, stomach, and large intestine were the major distribution tissues of DMNG-3 in mice. It was found that DMNG-3 could be detected in brain, suggesting that DMNG-3 can cross the blood-brain barrier. The present study shows that DMNG-3 can be possible developed as a new drug for the treatment of Alzheimer's disease in the future. PMID:27373949

  7. Synthesis of aminoalkyl-substituted aurone derivatives as acetylcholinesterase inhibitors.

    PubMed

    Lee, Young Hun; Shin, Min Cheol; Yun, Yong Don; Shin, Seo Young; Kim, Jong Min; Seo, Jeong Moo; Kim, Nam-Jung; Ryu, Jong Hoon; Lee, Yong Sup

    2015-01-01

    Alzheimer's disease (AD), a progressive and neurodegenerative disorder of the brain, is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, aurone derivatives were designed and synthesized as AChE inhibitors based on the lead structure of sulfuretin. Of those synthesized, compound 10d showed ca. 1700-fold and 6-fold higher AChE inhibitory activity than sulfuretin and galantamine, respectively. This compound also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2mg/kg. PMID:25468034

  8. Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation.

    PubMed

    Bourne, Yves; Kolb, Hartmuth C; Radić, Zoran; Sharpless, K Barry; Taylor, Palmer; Marchot, Pascale

    2004-02-10

    The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes the formation of its own inhibitor in a highly selective fashion: only a single syn1-triazole regioisomer with defined substitution positions and linker distances is generated from a series of reagent combinations. Inhibition measurements revealed this syn1-triazole isomer to be the highest affinity reversible organic inhibitor of AChE with association rate constants near the diffusion limit. The corresponding anti1 isomer, not formed by the enzyme, proved to be a respectable but weaker inhibitor. The crystal structures of the syn1- and anti1-mouse AChE complexes at 2.45- to 2.65-A resolution reveal not only substantial binding contributions from the triazole moieties, but also that binding of the syn1 isomer induces large and unprecedented enzyme conformational changes not observed in the anti1 complex nor predicted from structures of the apoenzyme and complexes with the precursor reactants. Hence, the freeze-frame reaction offers both a strategically original approach for drug discovery and a means for kinetically controlled capture, as a high-affinity complex between the enzyme and its self-created inhibitor, of a highly reactive minor abundance conformer of a fluctuating protein template.

  9. Freeze-frame inhibitor captures acetylcholinesterase in a unique conformation

    PubMed Central

    Bourne, Yves; Kolb, Hartmuth C.; Radić, Zoran; Sharpless, K. Barry; Taylor, Palmer; Marchot, Pascale

    2004-01-01

    The 1,3-dipolar cycloaddition reaction between unactivated azides and acetylenes proceeds exceedingly slowly at room temperature. However, considerable rate acceleration is observed when this reaction occurs inside the active center gorge of acetylcholinesterase (AChE) between certain azide and acetylene reactants, attached via methylene chains to specific inhibitor moieties selective for the active center and peripheral site of the enzyme. AChE catalyzes the formation of its own inhibitor in a highly selective fashion: only a single syn1-triazole regioisomer with defined substitution positions and linker distances is generated from a series of reagent combinations. Inhibition measurements revealed this syn1-triazole isomer to be the highest affinity reversible organic inhibitor of AChE with association rate constants near the diffusion limit. The corresponding anti1 isomer, not formed by the enzyme, proved to be a respectable but weaker inhibitor. The crystal structures of the syn1- and anti1-mouse AChE complexes at 2.45- to 2.65-Å resolution reveal not only substantial binding contributions from the triazole moieties, but also that binding of the syn1 isomer induces large and unprecedented enzyme conformational changes not observed in the anti1 complex nor predicted from structures of the apoenzyme and complexes with the precursor reactants. Hence, the freeze-frame reaction offers both a strategically original approach for drug discovery and a means for kinetically controlled capture, as a high-affinity complex between the enzyme and its self-created inhibitor, of a highly reactive minor abundance conformer of a fluctuating protein template. PMID:14757816

  10. Solanocapsine derivatives as potential inhibitors of acetylcholinesterase: Synthesis, molecular docking and biological studies.

    PubMed

    García, Manuela E; Borioni, José L; Cavallaro, Valeria; Puiatti, Marcelo; Pierini, Adriana B; Murray, Ana P; Peñéñory, Alicia B

    2015-12-01

    The investigation of natural products in medicinal chemistry is essential today. In this context, acetylcholinesterase (AChE) inhibitors comprise one type of the compounds most actively studied in the search for an effective treatment of symptoms of Alzheimer's disease. This work describes the isolation of a natural compound, solanocapsine, the preparation of its chemical derivatives, the evaluation of AChE inhibitory activity, and the structure-activity analysis of relevant cases. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different reactive parts of the parent molecule. A theoretical study was also carried out into the binding mode of representative compounds to the enzyme through molecular modeling. The biological properties of the series were investigated. Through this study valuable information was obtained of steroidal alkaloid-type compounds as a starting point for the synthesis of AChE inhibitors. PMID:26362598

  11. Effect of the timing of acetylcholinesterase inhibitor ingestion on sleep.

    PubMed

    Song, Hoo Rim; Woo, Young Sup; Wang, Hee-Ryung; Jun, Tae-Youn; Bahk, Won-Myong

    2013-11-01

    Many patients with Alzheimer's disease experience sleep disturbances, and donepezil is usually prescribed for night-time administration. However, increased acetylcholine is associated with cortical arousal. We evaluated whether subjective sleep quality differed according to the timing of medication administration. Ninety-two patients with mild to moderate Alzheimer's disease who had taken donepezil at night (n=54) or galantamine in the morning (n=38) were recruited for this study. Scores on the sleep visual analogue scale (VAS) for sleep quality and daytime drowsiness were obtained. The mean sleep-quality and daytime-drowsiness VAS scores of the donepezil and galantamine groups differed significantly at baseline (44.0±26.4 vs. 55.2±27.3, respectively; P<0.001 and 48.8±28.8 vs. 38.8±25.3, respectively; P<0.001). The patients taking donepezil were then randomly assigned to take donepezil in the morning (n=24) or at night (n=30). Eight weeks later, VAS scores also differed among the three groups (P<0.001 for both sleep quality and daytime drowsiness). The VAS scores of patients taking galantamine and donepezil in the morning were different from those taking donepezil at night at week 8. Significant changes in VAS scores emerged only in the group taking donepezil in the morning (4.6±26.5, P=0.046 for sleep quality; -7.1±26.1, P<0.001 for daytime drowsiness). These results suggest that taking acetylcholinesterase inhibitors in the morning can improve the sleep states of patients with Alzheimer's disease.

  12. A clinical study of lupron depot in the treatment of women with Alzheimer's disease: preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose lupron over 48 weeks.

    PubMed

    Bowen, Richard L; Perry, George; Xiong, Chengjie; Smith, Mark A; Atwood, Craig S

    2015-01-01

    To test the efficacy and safety of leuprolide acetate (Lupron Depot) in the treatment of Alzheimer's disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot (11.25 mg leuprolide acetate), high dose Lupron Depot (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: -0.54, -8.00, and -6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD. PMID:25310993

  13. A clinical study of lupron depot in the treatment of women with Alzheimer's disease: preservation of cognitive function in patients taking an acetylcholinesterase inhibitor and treated with high dose lupron over 48 weeks.

    PubMed

    Bowen, Richard L; Perry, George; Xiong, Chengjie; Smith, Mark A; Atwood, Craig S

    2015-01-01

    To test the efficacy and safety of leuprolide acetate (Lupron Depot) in the treatment of Alzheimer's disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot (11.25 mg leuprolide acetate), high dose Lupron Depot (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: -0.54, -8.00, and -6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD.

  14. PHOTOREGULATION OF BIOLOGICAL ACTIVITY BY PHOTOCROMIC REAGENTS, II. INHIBITORS OF ACETYLCHOLINESTERASE*†

    PubMed Central

    Bieth, Joseph; Vratsanos, Spyros M.; Wassermann, Norbert; Erlanger, Bernard F.

    1969-01-01

    The enzymic activity of acetylcholinesterase can be photoregulated through the mediation of photochromic inhibitors of the enzyme. N-p-phenylazophenyl-N-phenylcarbamyl fluoride, an irreversible inhibitor of acetylcholinesterase, exists as two geometric isomers which are interconvertible through the action of light. The cis isomer, which predominates after exposure to light of 320 nm, is more active than the trans isomer, which results from exposure to light of 420 nm. It was possible, therefore, to use light energy to regulate the inactivation of the enzyme. Similarly, levels of acetylcholinesterase activity could be photo-regulated in a completely reversible manner by means of the photochromic reversible inhibitor p-phenylazophenyltrimethylammonium chloride. These experiments can serve as models for similar phenomena observed in nature, particularly in photoperiodic rhythms of higher animals. Images PMID:5264140

  15. In silico methods to assist drug developers in acetylcholinesterase inhibitor design.

    PubMed

    Bermúdez-Lugo, J A; Rosales-Hernández, M C; Deeb, O; Trujillo-Ferrara, J; Correa-Basurto, J

    2011-01-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by a low acetylcholine (ACh) concentration in the hippocampus and cortex. ACh is a neurotransmitter hydrolyzed by acetylcholinesterase (AChE). Therefore, it is not surprising that AChE inhibitors (AChEIs) have shown better results in the treatment of AD than any other strategy. To improve the effects of AD, many researchers have focused on designing and testing new AChEIs. One of the principal strategies has been the use of computational methods (structural bioinformatics or in silico methods). In this review, we summarize the in silico methods used to enhance the understanding of AChE, particularly at the binding site, to design new AChEIs. Several computational methods have been used, such as docking approaches, molecular dynamics studies, quantum mechanical studies, electronic properties, hindrance effects, partition coefficients (Log P) and molecular electrostatic potentials surfaces, among other physicochemical methods that exhibit quantitative structure-activity relationships.

  16. Oximes: inhibitors of human recombinant acetylcholinesterase. A structure-activity relationship (SAR) study.

    PubMed

    Sepsova, Vendula; Karasova, Jana Zdarova; Korabecny, Jan; Dolezal, Rafael; Zemek, Filip; Bennion, Brian J; Kuca, Kamil

    2013-08-16

    Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

  17. Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors.

    PubMed

    Mantoani, Susimaire P; Chierrito, Talita P C; Vilela, Adriana F L; Cardoso, Carmen L; Martínez, Ana; Carvalho, Ivone

    2016-02-05

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ) protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization.

  18. Identification of non-alkaloid acetylcholinesterase inhibitors from Ferulago campestris (Besser) Grecescu (Apiaceae).

    PubMed

    Dall'Acqua, Stefano; Maggi, Filippo; Minesso, Paola; Salvagno, Marina; Papa, Fabrizio; Vittori, Sauro; Innocenti, Gabbriella

    2010-12-01

    Inhibition of Acetylcholinesterase (AChE) is still considered as a strategy for the treatment of neurological disorders such as Alzheimer's disease. Many plant derived alkaloids (such as galantamine and rivastigmine) are known for their AChE inhibitory activity. Recently, other classes of natural compounds such as terpenoids, sesquiterpene glycosides and coumarins have been studied as new AChE inhibitors, with the aim to discover less toxic compounds compared to alkaloidal ones. The Ferulago campestris roots dichloromethane extract was used for a bioassay-guided fractionation for the search of AChE inhibitors. Three coumarin derivatives (umbelliprenin 1, coladonin 2 and coladin 3), three daucane ester derivatives (siol anisate 4, ferutinin 5 and 1-acetyl-5-angeloyl lapiferol 6), two phenol derivatives (2-epilaserine 7 and epielmanticine 8) and one polyacetylene (9-epoxyfalcarindiol 9) were isolated by the bioassay-guided approach. Their structures were characterized on the basis of spectral methods (1D and 2D NMR, and MS spectroscopy). All the isolated compounds were able to inhibit the AChE (IC(50) 1.2-0.1mM) although at higher doses if compared to galantamine (6.7 μM) measured in the same conditions. The most active compounds were the daucane derivative siol anisate 4 and the epielmanticine 8, with IC(50) of 0.172 and 0.175 mM respectively.

  19. Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques.

    PubMed

    Gupta, Shikhar; Fallarero, Adyary; Järvinen, Päivi; Karlsson, Daniela; Johnson, Mark S; Vuorela, Pia M; Mohan, C Gopi

    2011-02-15

    Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer's disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the β-amyloid (Aβ) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I-VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads--Specs1 (IC(50)=3.279 μM) and Spec2 (IC(50)=5.986 μM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity. PMID:21273074

  20. Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques.

    PubMed

    Gupta, Shikhar; Fallarero, Adyary; Järvinen, Päivi; Karlsson, Daniela; Johnson, Mark S; Vuorela, Pia M; Mohan, C Gopi

    2011-02-15

    Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer's disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the β-amyloid (Aβ) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I-VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads--Specs1 (IC(50)=3.279 μM) and Spec2 (IC(50)=5.986 μM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity.

  1. Interpretation of honeybees contact toxicity associated to acetylcholinesterase inhibitors.

    PubMed

    Dulin, Fabienne; Halm-Lemeille, Marie-Pierre; Lozano, Sylvain; Lepailleur, Alban; Santos, Jana Sopkova-de Oliveira; Rault, Sylvain; Bureau, Ronan

    2012-05-01

    The widespread use of different pesticides generates adverse effects on non target organisms like honeybees. Organophosphorous and carbamates kill honeybees through the inactivation of acetylcholinesterase (AChE), thereby interfering with nerve signaling and function. For this class of pesticides, it is fundamental to understand the relationship between their structures and the contact toxicity for honeybees. A Quantitative Structure-Activity Relationship (QSAR) study was carried out on 45 derivatives by a genetic algorithm approach starting from more than 2500 descriptors. In parallel, a new 3D model of AChE associated to honeybees was defined. Physicochemical properties of the receptor and docking studies of the derivatives allow understanding the meaningful of three descriptors and the implication of several amino acids in the overall toxicity of the pesticides.

  2. Detoxification of acetylcholinesterase inhibitors. Final report, 1 June 1984-30 November 1986

    SciTech Connect

    Wild, J.R.; O'Donovan, G.A.; Chang, T.

    1987-02-19

    The research support by ARO contract 21288-LS entitled Detoxification of acetylcholinesterase inhibitors resulted in the cloning and partial sequence of two opd genes from Pseudomonas diminuta and Flavobacterium species. It has been possible to isolate the enzyme in association with a small membrane fraction and initiate an evaluation of the organophosphate hydrolase. Collaborative interactions with research scientists at the Chemical Defense Research Command have suggested that the Pseudomonas species is competent to degrade selected types of biological neurotoxins.

  3. Association between acetylcholinesterase inhibitors and risk of stroke in patients with dementia

    PubMed Central

    Lin, Yi-Ting; Wu, Ping-Hsun; Chen, Cheng-Sheng; Yang, Yi-Hsin; Yang, Yuan-Han

    2016-01-01

    Patients with dementia are at increased risk of stroke. Acetylcholinesterase inhibitors (AChEIs) have endothelial function protection effects and anti-inflammatory properties. We investigated the ischemic stroke risk in AChEIs use in dementia patients without stroke history. Using Taiwan National Health Insurance Database from 1999 to 2008, 37,352 dementia patients over 50 years old without stroke history were eligible. The results were analyzed by propensity score–matched Cox proportional hazard models with competing risk adjustment. AChEIs users had lower incidence of ischemic stroke (160.3/10,000 person-years), compared to the propensity score–matched reference (240.8/10,000 person-years). The adjusted hazard ratio for ischemic stroke based on propensity score–matched Cox proportional hazard model was 0.508 (95% confidence interval, 0.434–0.594; P < 0.001). There was no significant difference in all-cause mortality between AChEIs users and nonusers. In conclusion, among dementia patients without previous ischemic stroke history, AChEIs treatment was associated with a decreased risk of ischemic stroke but not greater survival. PMID:27377212

  4. Virtual Screening of Acetylcholinesterase Inhibitors Using the Lipinski's Rule of Five and ZINC Databank

    PubMed Central

    Nogara, Pablo Andrei; Saraiva, Rogério de Aquino; Caeran Bueno, Diones; Lissner, Lílian Juliana; Lenz Dalla Corte, Cristiane; Braga, Marcos M.; Rosemberg, Denis Broock; Rocha, João Batista Teixeira

    2015-01-01

    Alzheimer's disease (AD) is a progressive and neurodegenerative pathology that can affect people over 65 years of age. It causes several complications, such as behavioral changes, language deficits, depression, and memory impairments. One of the methods used to treat AD is the increase of acetylcholine (ACh) in the brain by using acetylcholinesterase inhibitors (AChEIs). In this study, we used the ZINC databank and the Lipinski's rule of five to perform a virtual screening and a molecular docking (using Auto Dock Vina 1.1.1) aiming to select possible compounds that have quaternary ammonium atom able to inhibit acetylcholinesterase (AChE) activity. The molecules were obtained by screening and further in vitro assays were performed to analyze the most potent inhibitors through the IC50 value and also to describe the interaction models between inhibitors and enzyme by molecular docking. The results showed that compound D inhibited AChE activity from different vertebrate sources and butyrylcholinesterase (BChE) from Equus ferus (EfBChE), with IC50 ranging from 1.69 ± 0.46 to 5.64 ± 2.47 µM. Compound D interacted with the peripheral anionic subsite in both enzymes, blocking substrate entrance to the active site. In contrast, compound C had higher specificity as inhibitor of EfBChE. In conclusion, the screening was effective in finding inhibitors of AChE and BuChE from different organisms. PMID:25685814

  5. Acetylcholinesterase Inhibitors with Photoswitchable Inhibition of β-Amyloid Aggregation

    PubMed Central

    2014-01-01

    Photochromic cholinesterase inhibitors were obtained from cis-1,2-α-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved “photoswitchable”. The AChE-induced β-amyloid (Aβ) aggregation assay gave further experimental support to this finding: Aβ1–40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ring-open and -closed form indicate a difference in binding. Although both forms can interact with the PAS, more stable interactions are observed for the ring-open form based upon stabilization of a water molecule network within the enzyme, whereas the ring-closed form lacks the required conformational flexibility for an analogous binding mode. The photoswitchable inhibitor identified might serve as valuable molecular tool to investigate the different biological properties of AChE as well as its role in pathogenesis of AD in in vitro assays. PMID:24628027

  6. Some new carbacylamidophosphates as inhibitors of acetylcholinesterase and butyrylcholinesterase.

    PubMed

    Gholivand, Khodayar; Alizadehgan, Ahlam Madani; Mojahed, Fresia; Dehghan, Gholamreza; Mohammadirad, Azadeh; Abdollahi, Mohammad

    2008-01-01

    The differences in the inhibition activity of organophosphorus agents are a manifestation of different molecular properties of the inhibitors involved in the interaction with the active site of enzyme. We were interested in comparing the inhibition potency of four known synthesized carbacylamidophosphates with the general formula RC(O)NHP(O)Cl2, constituting organophosphorus compounds, where R = CCl3 (1), CHCl2 (2), CH2Cl (3) and CF3 (4), and four new ones with the general formula RC(O)NHP(O)(R')2, where R' = morpholine and R = CCl3 (5), CHCl2 (6), CH2Cl (7), CF3 (8), on AChE and BuChE activities. In addition, in vitro activities of all eight compounds on BuChE were determined. Besides, in vivo inhibition potency of compounds 2 and 6, which had the highest inhibition potency among the tested compounds, was studied. The data demonstrated that compound 2 from the compound series 1 to 4 and compound 6 from the compound series 5 to 8 are the most sensitive as AChE and BuChE inhibitors, respectively. Comparing the IC50 values of these compounds, it was clear that the inhibition potency of these compounds for AChE are 2- to 100-fold greater than for BuChE inhibition. Comparison of the kinetics (IC50, Ki, kp, KA and KD) of AChE and BuChE inactivation by these compounds resulted in no significant difference for the measured variables except for compounds 2 and 6, which appeared to be more sensitive to AChE and BuChE by significantly higher kp and Ki values and a lower IC50 value in comparison with the other compounds. The LD50 value of compounds 2 and 6, after oral administration, and the changes of erythrocyte AChE and plasma BuChE activities in albino mice were studied. The in vivo experiments, similar to the in vitro results, showed that compound 2 is a stronger AChE and BuChE inhibitor than the other synthesized carbacylamidophosphates. Furthermore, in this study, the importance of electropositivity of the phosphorus atom, steric hindrance and leaving group specificity

  7. Xanthenedione derivatives, new promising antioxidant and acetylcholinesterase inhibitor agents.

    PubMed

    Seca, Ana M L; Leal, Stephanie B; Pinto, Diana C G A; Barreto, Maria Carmo; Silva, Artur M S

    2014-01-01

    Natural and synthetic xanthone derivatives are well-known for their ability to act as antioxidants and/or enzyme inhibitors. This paper aims to present a successful synthetic methodology towards xanthenedione derivatives and the study of their aromatization to xanthones. Additionally their ability to reduce Fe(III), to scavenge DPPH radicals and to inhibit AChE was evaluated. The results demonstrated that xanthenedione derivative 5e, bearing a catechol unit, showed higher reduction capacity than BHT and similar to quercetin, strong DPPH scavenging activity (EC50 = 3.79 ± 0.06 µM) and it was also showed to be a potent AChEI (IC50 = 31.0 ± 0.09 µM) when compared to galantamine (IC50 = 211.8 ± 9.5 µM). PMID:24950437

  8. Donepezil, an acetylcholinesterase inhibitor, attenuates nicotine self-administration and reinstatement of nicotine seeking in rats.

    PubMed

    Kimmey, Blake A; Rupprecht, Laura E; Hayes, Matthew R; Schmidt, Heath D

    2014-07-01

    Nicotine craving and cognitive impairments represent core symptoms of nicotine withdrawal and predict relapse in abstinent smokers. Current smoking cessation pharmacotherapies have limited efficacy in preventing relapse and maintaining abstinence during withdrawal. Donepezil is an acetylcholinesterase inhibitor that has been shown previously to improve cognition in healthy non-treatment-seeking smokers. However, there are no studies examining the effects of donepezil on nicotine self-administration and/or the reinstatement of nicotine-seeking behavior in rodents. The present experiments were designed to determine the effects of acute donepezil administration on nicotine taking and the reinstatement of nicotine-seeking behavior, an animal model of relapse in abstinent human smokers. Moreover, the effects of acute donepezil administration on sucrose self-administration and sucrose seeking were also investigated in order to determine whether donepezil's effects generalized to other reinforced behaviors. Acute donepezil administration (1.0 or 3.0 mg/kg, i.p.) attenuated nicotine, but not sucrose self-administration maintained on a fixed-ratio 5 schedule of reinforcement. Donepezil administration also dose-dependently attenuated the reinstatement of both nicotine- and sucrose-seeking behaviors. Commonly reported adverse effects of donepezil treatment in humans are nausea and vomiting. However, at doses required to attenuate nicotine self-administration in rodents, no effects of donepezil on nausea/malaise as measured by pica were observed. Collectively, these results indicate that increased extracellular acetylcholine levels are sufficient to attenuate nicotine taking and seeking in rats and that these effects are not due to adverse malaise symptoms such as nausea.

  9. A reversed-phase compatible thin-layer chromatography autography for the detection of acetylcholinesterase inhibitors.

    PubMed

    Ramallo, I Ayelen; García, Paula; Furlan, Ricardo L E

    2015-11-01

    A dual readout autographic assay to detect acetylcholinesterase inhibitors present in complex matrices adsorbed on reversed-phase or normal-phase thin-layer chromatography plates is described. Enzyme gel entrapment with an amphiphilic copolymer was used for assay development. The effects of substrate and enzyme concentrations, pH, incubation time, and incubation temperature on the sensitivity and the detection limit of the assay were evaluated. Experimental design and response surface methodology were used to optimize conditions with a minimum number of experiments. The assay allowed the detection of 0.01% w/w of physostigmine in both a spiked Sonchus oleraceus L. extract chromatographed on normal phase and a spiked Pimenta racemosa (Mill.) J.W. Moore leaf essential oil chromatographed on reversed phase. Finally, the reversed-phase thin-layer chromatography assay was applied to reveal the presence of an inhibitor in the Cymbopogon citratus (DC.) Stapf essential oil. The developed assay is able to detect acetylcholinesterase inhibitors present in complex matrixes that were chromatographed in normal phase or reversed-phase thin-layer chromatography. The detection limit for physostigmine on both normal and reversed phase was of 1×10(-4) μg. The results can be read by a change in color and/or a change in fluorescence. PMID:26489065

  10. A reversed-phase compatible thin-layer chromatography autography for the detection of acetylcholinesterase inhibitors.

    PubMed

    Ramallo, I Ayelen; García, Paula; Furlan, Ricardo L E

    2015-11-01

    A dual readout autographic assay to detect acetylcholinesterase inhibitors present in complex matrices adsorbed on reversed-phase or normal-phase thin-layer chromatography plates is described. Enzyme gel entrapment with an amphiphilic copolymer was used for assay development. The effects of substrate and enzyme concentrations, pH, incubation time, and incubation temperature on the sensitivity and the detection limit of the assay were evaluated. Experimental design and response surface methodology were used to optimize conditions with a minimum number of experiments. The assay allowed the detection of 0.01% w/w of physostigmine in both a spiked Sonchus oleraceus L. extract chromatographed on normal phase and a spiked Pimenta racemosa (Mill.) J.W. Moore leaf essential oil chromatographed on reversed phase. Finally, the reversed-phase thin-layer chromatography assay was applied to reveal the presence of an inhibitor in the Cymbopogon citratus (DC.) Stapf essential oil. The developed assay is able to detect acetylcholinesterase inhibitors present in complex matrixes that were chromatographed in normal phase or reversed-phase thin-layer chromatography. The detection limit for physostigmine on both normal and reversed phase was of 1×10(-4) μg. The results can be read by a change in color and/or a change in fluorescence.

  11. Effects of donepezil, an acetylcholinesterase inhibitor, on neurogenesis in a rat model of vascular dementia.

    PubMed

    Kwon, Kyoung Ja; Kim, Min Kyeong; Lee, Eun Joo; Kim, Jung Nam; Choi, Bo-Ryoung; Kim, Soo Young; Cho, Kyu Suk; Han, Jung-Soo; Kim, Hahn Young; Shin, Chan Young; Han, Seol-Heui

    2014-12-15

    Vascular dementia (VaD) is the second most common form of dementia caused by cerebrovascular disease. Several recent reports demonstrated that cholinergic deficits are implicated in the pathogenesis of VaD and that cholinergic therapies have shown improvement of cognitive function in patients with VaD. However, the precise mechanisms by which donepezil achieves its effects on VaD are not fully understood. Donepezil hydrochloride is an acetylcholinesterase inhibitor (AChEI) currently used for the symptomatic treatment of Alzheimer's disease (AD). Several lines of evidence have demonstrated that AChEIs such as donepezil promote neurogenesis in the central nervous system. We investigated whether donepezil regulated hippocampal neurogenesis after bilateral common carotid artery occlusion (BCCAO) in rats, a commonly used animal model of VaD. To evaluate the effect of donepezil on neurogenesis, we orally treated rats with donepezil (10mg/kg) once a day for 3weeks, and injected BrdU over the same 3-week period to label newborn cells. The doses of donepezil that we used have been reported to activate cholinergic activity in rats. After 3weeks, a water maze task was performed on these rats to test spatial learning, and a subsequent histopathological evaluation was conducted. Donepezil improved memory impairment and increased the number of BrdU-positive cells in the dentate gyrus (DG) of BCCAO animals. These results indicated that donepezil improves cognitive function and enhances the survival of newborn neurons in the DG in our animal model of VaD, possibly by enhancing the expression of choline acetyltransferase and brain-derived neurotropic factor.

  12. Double layer structure-based virtual screening reveals 3'-Hydroxy-A-Naphthoflavone as novel inhibitor candidate of human acetylcholinesterase

    NASA Astrophysics Data System (ADS)

    Ichsan, Mochammad; Pangastuti, Ardini; Habibi, Mohammad Wildan; Juliana, Kartika

    2016-03-01

    One of the most effective target for Alzheimer's disease's (AD) treatment is the inhibition of human acetylcholinesterase (hAChE) eventhough it has many side effects. So that, this study was aimed to discover a new candidate of hAChE's inhibitor that has more negative binding affinity than existing drugs. hAChE's 3D model used in this study has a good quality according to its number of residues in most favoured regions (92%), three bad contacts, >50 ERRAT's score (85,870) and successfully passed the VERIFY 3D threshold (>80%). Based on the first layer of SBVS againts more than 12.180.630 ligands, we discovered 11.806 hits and then we found 359 hits from the second layer of SBVS. Based on our previous steps, we found that 3'-Hydroxy-a-Naphthoflavone was the only one candidate, that directly interacted with Trp286 via hydrogen bond and hydrophobic interactions and also has the most negative binding affinity (-10,6 kcal/mol) and also has more negative than existing hAChE's inhibitors, such as tacrine, donepezil, etc. 3'-Hydroxy-a-Naphthoflavone is the best candidate of hAChE's inhibitor based on its binding affinity (-10,6 kcal/mol) that is more negative than existing hAChE's inhibitors, such as tacrine, donepezil, etc.

  13. The herbicide glyphosate is a weak inhibitor of acetylcholinesterase in rats.

    PubMed

    Larsen, Karen E; Lifschitz, Adrián L; Lanusse, Carlos E; Virkel, Guillermo L

    2016-07-01

    The current work evaluated the inhibitory potency of the herbicide glyphosate (GLP) on acetylcholinesterase (AChE) activity in male and female rat tissues. The AChE activity in brain was higher (p<0.05) than those observed in kidney (females: 2.2-fold; males: 1.9-fold), liver (females: 6-fold; males: 6.9-fold) and plasma (females: 14.7-fold; males: 25.3-fold). Enzyme activities were higher in presence of 10mM GLP compared to those measured at an equimolar concentration of the potent AChE inhibitor dichlorvos (DDVP). Moreover, IC50s for GLP resulted between 6×10(4)- and 6.8×10(5)-fold higher than those observed for DDVP. In conclusion, GLP is a weak inhibitor of AChE in rats. PMID:27258137

  14. Screening of β-secretase and acetylcholinesterase inhibitors from plant resources.

    PubMed

    Murata, Kazuya; Matsumura, Shinichi; Yoshioka, Yuri; Ueno, Yoshihiro; Matsuda, Hideaki

    2015-01-01

    The therapeutic agents for dementia are limited due to the complex system underlying the mechanisms. Taking a preventive point of view, we focused on the inhibition of β-secretase and acetylcholinesterase (AChE). In addition, plant resources including herbs and spices have been widely consumed, and further, may be consumed for a long period over a lifetime. Considering this background, we screened β-secretase and AChE inhibitors from curry spices. Amongst them, curry leaf, black pepper, and turmeric extracts were effective to inhibit β-secretase. Furthermore, black pepper and turmeric extracts were also effective to inhibit AChE. Having these results in hand, we focused on the investigation of β-secretase inhibitors since the inhibitor of this enzyme has not previously been well investigated. As a result, α- and β-caryophyllene, β-caryophyllene oxide (from curry leaf), piperine (from black pepper), curcumin, demethoxycurcumin, and bisdemethoxycurcumin (from turmeric) were successfully identified as low molecular inhibitors. This is the first report to determine α- and β-caryophyllene, β-caryophyllene oxide, and piperine as β-secretase inhibitors. These compounds may pass through the blood brain barrier since their molecular weights are relatively low. PMID:25119528

  15. Efforts toward treatments against aging of organophosphorus-inhibited acetylcholinesterase.

    PubMed

    Zhuang, Qinggeng; Young, Amneh; Callam, Christopher S; McElroy, Craig A; Ekici, Özlem Dogan; Yoder, Ryan J; Hadad, Christopher M

    2016-06-01

    Aging is a dealkylation reaction of organophosphorus (OP)-inhibited acetylcholinesterase (AChE). Despite many studies to date, aged AChE cannot be reactivated directly by traditional pyridinium oximes. This review summarizes strategies that are potentially valuable in the treatment against aging in OP poisoning. Among them, retardation of aging seeks to lower the rate of aging through the use of AChE effectors. These drugs should be administered before AChE is completely aged. For postaging treatment, realkylation of aged AChE by appropriate alkylators may pave the way for oxime treatment by neutralizing the oxyanion at the active site of aged AChE. The other two strategies, upregulation of AChE expression and introduction of exogenous AChE, cannot resurrect aged AChE but may compensate for lowered active AChE levels by in situ production or external introduction of active AChE. Upregulation of AChE expression can be triggered by some peptides. Sources of exogenous AChE can be whole blood or purified AChE, either from human or nonhuman species. PMID:27327269

  16. Inhibitor Profile of bis(n)-tacrines and N-methylcarbamates on Acetylcholinesterase from Rhipicephalus (Boophilus) microplus and Phlebotomus papatasi

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The cattle tick, Rhipicephalus (Boophilus) microplus (Bm), and the sand fly, Phlebotomus papatasi (Pp), are disease vectors to cattle and humans, respectively. The purpose of this study was to characterize the inhibitor profile of acetylcholinesterases from Bm (BmAChE1) and Pp (PpAchE) compared to h...

  17. Wild Argentinian Amaryllidaceae, a new renewable source of the acetylcholinesterase inhibitor galanthamine and other alkaloids.

    PubMed

    Ortiz, Javier E; Berkov, Strahil; Pigni, Natalia B; Theoduloz, Cristina; Roitman, German; Tapia, Alejandro; Bastida, Jaume; Feresin, Gabriela E

    2012-11-13

    The Amaryllidaceae family is well known for its pharmacologically active alkaloids. An important approach to treat Alzheimer’s disease involves the inhibition of the enzyme acetylcholinesterase (AChE). Galanthamine, an Amaryllidaceae alkaloid, is an effective, selective, reversible, and competitive AchE inhibitor. This work was aimed at studying the alkaloid composition of four wild Argentinian Amarillydaceae species for the first time, as well as analyzing their inhibitory activity on acetylcholinesterase. Alkaloid content was characterized by means of GC-MS analysis. Chloroform basic extracts from Habranthus jamesonii, Phycella herbertiana, Rhodophiala mendocina and Zephyranthes filifolia collected in the Argentinian Andean region all contained galanthamine, and showed a strong AChE inhibitory activity (IC50 between 1.2 and 2 µg/mL). To our knowledge, no previous reports on alkaloid profiles and AChEIs activity of wild Argentinian Amarillydaceae species have been publisihed. The demand for renewable sources of industrial products like galanthamine and the need to protect plant biodiversity creates an opportunity for Argentinian farmers to produce such crops.

  18. Screening of acetylcholinesterase inhibitors by CE after enzymatic reaction at capillary inlet.

    PubMed

    Martín-Biosca, Yolanda; Asensi-Bernardi, Lucia; Villanueva-Camañas, Rosa M; Sagrado, Salvador; Medina-Hernández, Maria J

    2009-05-01

    In this study the development of a procedure based on capillary electrophoresis after enzymatic reaction at capillary inlet methodology for the screening and in vitro evaluation of the biological activity of acetylcholinesterase (AChE) inhibitors is presented. The progress of the enzymatic reaction of the hydrolysis of acetylthiocholine at pH 8 in the presence of AChE and the inhibitor studied is determined by measuring at 230 nm the peak area of the reaction product thiocholine (TCh). In the method employed the capillary was first filled with 30 mM borate-phosphate buffer (pH 8.0) and subsequently, plugs of: (i) water, (ii) AChE solution, (iii) substrate solution with or without inhibitor, (iv) AChE solution, and (v) water, were hydrodynamically injected into the capillary, and were allowed to stand (and react) during a waiting period of 2 min. The applicability of the proposed methodology to estimate different kinetic parameters of interest such as inhibition constants K(i), identification of inhibitory action mechanism and IC(50), is evaluated using compounds with known activity, tacrine edrophonium, and neostigmine. The results obtained are compared with bibliographic values and confirm the effectiveness of the methodology proposed. Finally a method for AChE Inhibitor screening is proposed.

  19. 1H NMR Relaxation Investigation of Inhibitors Interacting with Torpedo californica Acetylcholinesterase

    NASA Astrophysics Data System (ADS)

    Delfini, Maurizio; Gianferri, Raffaella; Dubbini, Veronica; Manetti, Cesare; Gaggelli, Elena; Valensin, Gianni

    2000-05-01

    Two naphthyridines interacting with Torpedo californica acetylcholinesterase (AChE) were investigated. 1H NMR spectra were recorded and nonselective, selective, and double-selective spin-lattice relaxation rates were measured. The enhancement of selective relaxation rates could be titrated by different ligand concentrations at constant AChE (yielding 0.22 and 1.53 mM for the dissociation constants) and was providing evidence of a diverse mode of interaction. The double-selective relaxation rates were used to evaluate the motional correlation times of bound ligands at 34.9 and 36.5 ns at 300 K. Selective relaxation rates of bound inhibitors could be interpreted also in terms of dipole-dipole interactions with protons in the enzyme active site.

  20. Discovery of Potent Carbonic Anhydrase and Acetylcholinesterase Inhibitors: 2-Aminoindan β-Lactam Derivatives

    PubMed Central

    Genç, Hayriye; Kalin, Ramazan; Köksal, Zeynep; Sadeghian, Nastaran; Kocyigit, Umit M.; Zengin, Mustafa; Gülçin, İlhami; Özdemir, Hasan

    2016-01-01

    β-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. β-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that β-lactams are inhibitors of hCA I, II and AChE. The Ki values of β-lactams (2a–k) were 0.44–6.29 nM against hCA I, 0.93–8.34 nM against hCA II, and 0.25–1.13 nM against AChE. Our findings indicate that β-lactams (2a–k) inhibit both carbonic anhydrases (CA) isoenzymes and AChE at low nanomolar concentrations. PMID:27775608

  1. Role of acetylcholinesterase inhibitors in the metabolism of amyloid precursor protein.

    PubMed

    Pakaski, M; Kasa, P

    2003-06-01

    Potentiation of central cholinergic activity has been proposed as a therapeutic approach for improving the cognitive function in patients with Alzheimer's disease (AD). Increasing the acetylcholine concentration in the brain by modulating acetylcholine-sterase (AChE) activity is among the most promising therapeutic strategies. Efforts to treat the underlying pathology based on the modulation of amyloid precursor protein (APP) processing in order to decrease the accumulation of beta-amyloid are also very important. Alterations in APP metabolism have recently been proposed to play a key role in the long-lasting effects of AChE inhibitors. This review surveys recent data from in vivo and in vitro studies that have contributed to our understanding of the role of AChE inhibitors in APP processing. The regulatory mechanisms relating to the muscarinic agonist effect, protein kinase C activation and mitogen-activated protein kinase phosphorylation, involving the alpha-secretase or the 5 -UTR region of the APP gene, are also discussed. Further work is warranted to elucidate the exact roles in APP metabolism of the AChE inhibitors used in AD therapy at present. PMID:12769797

  2. Exposure to Acetylcholinesterase Inhibitors Alters the Physiology and Motor Function of Honeybees

    PubMed Central

    Williamson, Sally M.; Moffat, Christopher; Gomersall, Martha A. E.; Saranzewa, Nastja; Connolly, Christopher N.; Wright, Geraldine A.

    2013-01-01

    Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24 h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15 min. At a 10 nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1 μM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival. PMID:23386834

  3. Exposure to acetylcholinesterase inhibitors alters the physiology and motor function of honeybees.

    PubMed

    Williamson, Sally M; Moffat, Christopher; Gomersall, Martha A E; Saranzewa, Nastja; Connolly, Christopher N; Wright, Geraldine A

    2013-01-01

    Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health. Here, we investigate the behavioral effects on honeybees of exposure to a selection of pesticides that target cholinergic signaling by inhibiting acetylcholinesterase (AChE). To examine how continued exposure to AChE inhibitors affected motor function, we fed adult foraging worker honeybees sub-lethal concentrations of these compounds in sucrose solution for 24 h. Using an assay for locomotion in bees, we scored walking, stopped, grooming, and upside down behavior continuously for 15 min. At a 10 nM concentration, all the AChE inhibitors caused similar effects on behavior, notably increased grooming activity and changes in the frequency of bouts of behavior such as head grooming. Coumaphos caused dose-dependent effects on locomotion as well as grooming behavior, and a 1 μM concentration of coumaphos induced symptoms of malaise such as abdomen grooming and defecation. Biochemical assays confirmed that the four compounds we assayed (coumaphos, aldicarb, chlorpyrifos, and donepezil) or their metabolites acted as AChE inhibitors in bees. Furthermore, we show that transcript expression levels of two honeybee AChE inhibitors were selectively upregulated in the brain and in gut tissues in response to AChE inhibitor exposure. The results of our study imply that the effects of pesticides that rely on this mode of action have subtle yet profound effects on physiological effects on behavior that could lead to reduced survival.

  4. In silico analysis of binding of neurotoxic venom ligands with acetylcholinesterase for therapeutic use in treatment of Alzheimer's disease.

    PubMed

    Waqar, Maleeha; Batool, Sidra

    2015-05-01

    Acetylcholinesterases (AChE) are enzymes that function in hydrolyzing the neurotransmitter acetylcholine. Diminished levels of acetylcholine have been reported for various neurodegenerative diseases, especially Alzheimer's. Therefore, acetylcholinesterase inhibitors are being considered quite effective in treating these diseases. Fasciculin 2 is a toxin isolated from Eastern green mamba that had been reported as a reversible acetylcholinesterase inhibitor. In this study, we have reported the in silico analysis of venom toxins via various computational tools used for drug designing, to find out the protein-protein interaction of these toxins in complex with acetylcholinesterase enzyme. In total 15 toxins have been selected from the venoms of various species as ligand dataset, to study their binding interactions with the acetylcholinesterase enzyme. PMID:25747777

  5. Conformational remodeling of femtomolar inhibitor-acetylcholinesterase complexes in the crystalline state

    PubMed Central

    Bourne, Yves; Radic, Zoran; Taylor, Palmer; Marchot, Pascale

    2010-01-01

    The active center of acetylcholinesterase (AChE), a target site for competitive inhibitors, resides centrosymmetric to the subunit at the base of a deep, narrow gorge lined by aromatic residues. At the gorge entry, a peripheral site encompasses overlapping binding loci for non-competitive inhibitors, which alter substrate access to the gorge. The click-chemistry inhibitor TZ2PA6 links the active center ligand, tacrine, to the peripheral site ligand, propidium, through a biorthogonal reaction of an acetylene and an azide that forms either a syn1 or an anti1 triazole. Compared with wild-type mouse AChE, a Tyr337Ala mutant displays full catalytic activity, albeit with two to three orders of magnitude higher affinities for the TZ2PA6 syn1 and anti1 regioisomers, reflected in low femtomolar Kd values, diffusion-limited association and dissociation half-times greater than one month and one week, respectively. Three structures of each of the co-crystallized syn1 and anti1 complexes of the Tyr337Ala mutant were solved at three distinct times of crystal maturation, consistent with or exceeding the half-lives of the complexes in solution, while crystalline complexes obtained from soaked Tyr337Ala crystals led to picturing “freshly formed” complexes. The structures, at 2.55-2.75Å resolution, reveal a range of unprecedented conformations of the bound regioisomers, not observed in the wild-type AChE complexes, associated with concerted positional rearrangements of side chains in the enzyme gorge. Moreover, time-dependent conformational remodeling of the crystalline complexes appears to correlate with the dissociation half-times of the solution complexes. Hence for the tight-binding TZ2PA6 inhibitors, the initial complexes kinetically driven in solution slowly form more stable complexes governed by thermodynamic equilibrium and observable in mature crystals. PMID:21090615

  6. [Effects of the association of sulbutiamine with an acetylcholinesterase inhibitor in early stage and moderate Alzheimer disease].

    PubMed

    Ollat, H; Laurent, B; Bakchine, S; Michel, B-F; Touchon, J; Dubois, B

    2007-01-01

    The efficacy of the inhibitors of acetylcholinesterase in Alzheimer's Disease (AD) is moderated and some patients do not respond to these treatments. Sulbutiamine potentializes cholinergic and glutamatergic transmissions, mainly in hippocampus and prefrontal cortex. This multicentric, randomized and double-blind trial evaluates the effects of the association of sulbutiamine to an anticholinesterasic drug in cognitive functions in patients with AD at an early stage (episodic memory, working memory, executive functions, attention). Patients had first donepezil (D) or sulbutiamine (S) during three months. During this period, only attention improved in both groups. During the three following months, a placebo (P) in patients D and donepezil in patients S were added. Compared to entry results, episodic memory decreased in group D + P but improved in group S + D. At the same time the improvement of attention persisted in both groups. Daylife activities only improved in group S + D. In conclusion sulbutiamine can be an adjuvant to treatment in early stage and moderate AD by anticholinesterasic drugs. PMID:17675917

  7. [Effects of the association of sulbutiamine with an acetylcholinesterase inhibitor in early stage and moderate Alzheimer disease].

    PubMed

    Ollat, H; Laurent, B; Bakchine, S; Michel, B-F; Touchon, J; Dubois, B

    2007-01-01

    The efficacy of the inhibitors of acetylcholinesterase in Alzheimer's Disease (AD) is moderated and some patients do not respond to these treatments. Sulbutiamine potentializes cholinergic and glutamatergic transmissions, mainly in hippocampus and prefrontal cortex. This multicentric, randomized and double-blind trial evaluates the effects of the association of sulbutiamine to an anticholinesterasic drug in cognitive functions in patients with AD at an early stage (episodic memory, working memory, executive functions, attention). Patients had first donepezil (D) or sulbutiamine (S) during three months. During this period, only attention improved in both groups. During the three following months, a placebo (P) in patients D and donepezil in patients S were added. Compared to entry results, episodic memory decreased in group D + P but improved in group S + D. At the same time the improvement of attention persisted in both groups. Daylife activities only improved in group S + D. In conclusion sulbutiamine can be an adjuvant to treatment in early stage and moderate AD by anticholinesterasic drugs.

  8. Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase.

    PubMed

    Sun, Qi; Peng, Da-Yong; Yang, Sheng-Gang; Zhu, Xiao-Lei; Yang, Wen-Chao; Yang, Guang-Fu

    2014-09-01

    Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.

  9. The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies

    PubMed Central

    2011-01-01

    Background Alzheimer's disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD. Methods In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5) program based on a set of known AChE inhibitors. Results The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R2 = 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site. Conclusions The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites. PMID:21251245

  10. TMPyP4, a Stabilizer of Nucleic Acid Secondary Structure, Is a Novel Acetylcholinesterase Inhibitor

    PubMed Central

    Fujiwara, Nana; Mazzola, Michael; Cai, Elizabeth; Wang, Meng; Cave, John W.

    2015-01-01

    The porphyrin compound, TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine), is widely used as a photosensitizer and a modulator of nucleic acid secondary structure stability. Our group recently showed in cultured cells and forebrain slice cultures that this compound can also down regulate expression of Tyrosine hydroxylase (Th), which encodes the rate-limiting enzyme in catecholamine biosynthesis, by stabilizing DNA secondary structures in the Th proximal promoter. The current study sought to establish whether treatment with TMPyP4 could modify mouse Th expression levels in vivo. Intraperitoneal administration of low TMPyP4 doses (10mg/kg), similar to those used for photosensitization, did not significantly reduce Th transcript levels in several catecholaminergic regions. Administration of a high dose (40 mg/kg), similar to those used for tumor xenograph reduction, unexpectedly induced flaccid paralysis in an age and sex-dependent manner. In vitro analyses revealed that TMPyP4, but not putative metabolites, inhibited Acetylcholinesterase activity and pre-treatment of TMPyP4 with Hemeoxygenase-2 (HO-2) rescued Acetylcholinesterase function. Age-dependent differences in HO-2 expression levels may account for some of the variable in vivo effects of high TMPyP4 doses. Together, these studies indicate that only low doses of TMPyP4, such as those typically used for photosensitization, are well tolerated in vivo. Thus, despite its widespread use in vitro, TMPyP4 is not ideal for modifying neuronal gene expression in vivo by manipulating nucleic acid secondary structure stability, which highlights the need to identify more clinically suitable compounds that can modulate nucleic acid secondary structure and gene expression. PMID:26402367

  11. TMPyP4, a Stabilizer of Nucleic Acid Secondary Structure, Is a Novel Acetylcholinesterase Inhibitor.

    PubMed

    Fujiwara, Nana; Mazzola, Michael; Cai, Elizabeth; Wang, Meng; Cave, John W

    2015-01-01

    The porphyrin compound, TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine), is widely used as a photosensitizer and a modulator of nucleic acid secondary structure stability. Our group recently showed in cultured cells and forebrain slice cultures that this compound can also down regulate expression of Tyrosine hydroxylase (Th), which encodes the rate-limiting enzyme in catecholamine biosynthesis, by stabilizing DNA secondary structures in the Th proximal promoter. The current study sought to establish whether treatment with TMPyP4 could modify mouse Th expression levels in vivo. Intraperitoneal administration of low TMPyP4 doses (10mg/kg), similar to those used for photosensitization, did not significantly reduce Th transcript levels in several catecholaminergic regions. Administration of a high dose (40 mg/kg), similar to those used for tumor xenograph reduction, unexpectedly induced flaccid paralysis in an age and sex-dependent manner. In vitro analyses revealed that TMPyP4, but not putative metabolites, inhibited Acetylcholinesterase activity and pre-treatment of TMPyP4 with Hemeoxygenase-2 (HO-2) rescued Acetylcholinesterase function. Age-dependent differences in HO-2 expression levels may account for some of the variable in vivo effects of high TMPyP4 doses. Together, these studies indicate that only low doses of TMPyP4, such as those typically used for photosensitization, are well tolerated in vivo. Thus, despite its widespread use in vitro, TMPyP4 is not ideal for modifying neuronal gene expression in vivo by manipulating nucleic acid secondary structure stability, which highlights the need to identify more clinically suitable compounds that can modulate nucleic acid secondary structure and gene expression. PMID:26402367

  12. Novel Selective and Irreversible Mosquito Acetylcholinesterase Inhibitors for Controlling Malaria and Other Mosquito-Borne Diseases

    NASA Astrophysics Data System (ADS)

    Dou, Dengfeng; Park, Jewn Giew; Rana, Sandeep; Madden, Benjamin J.; Jiang, Haobo; Pang, Yuan-Ping

    2013-01-01

    We reported previously that insect acetylcholinesterases (AChEs) could be selectively and irreversibly inhibited by methanethiosulfonates presumably through conjugation to an insect-specific cysteine in these enzymes. However, no direct proof for the conjugation has been published to date, and doubts remain about whether such cysteine-targeting inhibitors have desirable kinetic properties for insecticide use. Here we report mass spectrometric proof of the conjugation and new chemicals that irreversibly inhibited African malaria mosquito AChE with bimolecular inhibition rate constants (kinact/KI) of 3,604-458,597 M-1sec-1 but spared human AChE. In comparison, the insecticide paraoxon irreversibly inhibited mosquito and human AChEs with kinact/KI values of 1,915 and 1,507 M-1sec-1, respectively, under the same assay conditions. These results further support our hypothesis that the insect-specific AChE cysteine is a unique and unexplored target to develop new insecticides with reduced insecticide resistance and low toxicity to mammals, fish, and birds for the control of mosquito-borne diseases.

  13. Potent acetylcholinesterase inhibitors: Synthesis, biological assay and docking study of nitro acridone derivatives.

    PubMed

    Parveen, Mehtab; Aslam, Afroz; Nami, Shahab A A; Malla, Ali Mohammed; Alam, Mahboob; Lee, Dong-Ung; Rehman, Sumbul; Silva, P S Pereira; Silva, M Ramos

    2016-08-01

    The reaction of o-halobenzoic acid with aniline derivatives and their subsequent cyclization reaction yielded the acridone derivatives. The series of nitro acridone derivatives were prepared by Ullmann condensation in presence of copper as catalyst and were characterized by FTIR, (1)H, (13)C NMR and mass spectra. The structure of 5-nitro-(2-phenyl amino) benzoic acid (4) was confirmed by X-ray crystallography and was found to crystallize in P21/c space group. The in vitro efficacy of the compounds for their acetylcholinesterase (AChE) and antimicrobial inhibitory activities have been evaluated against the standard drugs Ampicillin and Gentamicin against Gram positive and Gram negative bacteria. 1,7-Dinitroacridone was found to be the most potent AChE inhibitor (IC50=0.22μM). Moreover, the compounds have been screened for their antioxidant activity using the DPPH assay. Also, docking study results were found to be in good agreement with the results obtained through in vitro experiments. The docking study further predicted possible binding conformation. PMID:27295412

  14. Steric and Dynamic Parameters Influencing In Situ Cycloadditions to Form Triazole Inhibitors with Crystalline Acetylcholinesterase.

    PubMed

    Bourne, Yves; Sharpless, K Barry; Taylor, Palmer; Marchot, Pascale

    2016-02-10

    Ligand binding sites on acetylcholinesterase (AChE) comprise an active center, at the base of a deep and narrow gorge lined by aromatic residues, and a peripheral site at the gorge entry. These features launched AChE as a reaction vessel for in situ click-chemistry synthesis of high-affinity TZ2PA6 and TZ2PA5 inhibitors, forming a syn-triazole upon cycloaddition within the gorge from alkyne and azide reactants bound at the two sites, respectively. Subsequent crystallographic analyses of AChE complexes with the TZ2PA6 regioisomers demonstrated that syn product association is accompanied by side chain reorganization within the gorge, freezing-in-frame a conformation distinct from an unbound state or anti complex. To correlate inhibitor dimensions with reactivity and explore whether in situ cycloaddition could be accelerated in a concentrated, crystalline template, we developed crystal-soaking procedures and solved structures of AChE complexes with the TZ2PA5 regioisomers and their TZ2/PA5 precursors (2.1-2.7 Å resolution). The structures reveal motions of residue His447 in the active site and, unprecedentedly, residue Tyr341 at the gorge mouth, associated with TZ2 binding and coordinated with other side chain motions in the gorge that may guide AChE toward a transient state favoring syn-triazole formation. Despite precursor binding to crystalline AChE, coupling of rapid electric field fluctuations in the gorge with proper alignments of the azide and alkyne reactants to form the triazole remains a likely limiting step. These observations point to a prime requirement for AChE to interconvert dynamically between sequential conformations to promote favorable electrostatic factors enabling a productive apposition of the reactants for reactivity. PMID:26731630

  15. Design and prediction of new acetylcholinesterase inhibitor via quantitative structure activity relationship of huprines derivatives.

    PubMed

    Zhang, Shuqun; Hou, Bo; Yang, Huaiyu; Zuo, Zhili

    2016-05-01

    Acetylcholinesterase (AChE) is an important enzyme in the pathogenesis of Alzheimer's disease (AD). Comparative quantitative structure-activity relationship (QSAR) analyses on some huprines inhibitors against AChE were carried out using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR) methods. Three highly predictive QSAR models were constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have values of r (2) = 0.988, q (2) = 0.757, ONC = 6; r (2) = 0.966, q (2) = 0.645, ONC = 5; and r (2) = 0.957, q (2) = 0.736, ONC = 6. The predictabilities were validated using an external test sets, and the predictive r (2) values obtained by the three models were 0.984, 0.973, and 0.783, respectively. The analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the AChE to further understand the vital interactions between huprines and the protease. On the basis of the QSAR study, 14 new potent molecules have been designed and six of them are predicted to be more active than the best active compound 24 described in the literature. The final QSAR models could be helpful in design and development of novel active AChE inhibitors.

  16. Selective and Irreversible Inhibitors of Aphid Acetylcholinesterases: Steps Toward Human-Safe Insecticides

    PubMed Central

    Pang, Yuan-Ping; Singh, Sanjay K.; Gao, Yang; Lassiter, T. Leon; Mishra, Rajesh K.; Zhu, Kun Yan; Brimijoin, Stephen

    2009-01-01

    Aphids, among the most destructive insects to world agriculture, are mainly controlled by organophosphate insecticides that disable the catalytic serine residue of acetylcholinesterase (AChE). Because these agents also affect vertebrate AChEs, they are toxic to non-target species including humans and birds. We previously reported that a cysteine residue (Cys), found at the AChE active site in aphids and other insects but not mammals, might serve as a target for insect-selective pesticides. However, aphids have two different AChEs (termed AP and AO), and only AP-AChE carries the unique Cys. The absence of the active-site Cys in AO-AChE might raise concerns about the utility of targeting that residue. Herein we report the development of a methanethiosulfonate-containing small molecule that, at 6.0 µM, irreversibly inhibits 99% of all AChE activity extracted from the greenbug aphid (Schizaphis graminum) without any measurable inhibition of the human AChE. Reactivation studies using β-mercaptoethanol confirm that the irreversible inhibition resulted from the conjugation of the inhibitor to the unique Cys. These results suggest that AO-AChE does not contribute significantly to the overall AChE activity in aphids, thus offering new insight into the relative functional importance of the two insect AChEs. More importantly, by demonstrating that the Cys-targeting inhibitor can abolish AChE activity in aphids, we can conclude that the unique Cys may be a viable target for species-selective agents to control aphids without causing human toxicity and resistance problems. PMID:19194505

  17. Esterase detoxification of acetylcholinesterase inhibitors by human or rat liver in vitro

    EPA Science Inventory

    Organophosphate (OP) and N-methylcarbamate pesticides inhibit acetylcholinesterase (AChE), but differences in metabolism and detoxification can influence potency of these pesticides across and within species. Carboxylesterase (CaE) and A-esterase (paraoxonase, PON) are considered...

  18. EEG SPECTRA, BEHAVIORAL STATES AND MOTOR ACTIVITY IN RATS EXPOSED TO ACETYLCHOLINESTERASE INHIBITOR CHLORPYRIFOS.

    EPA Science Inventory

    Exposure to organophosphate pesticides (OP) has been associated with sleep disorders: insomnia and ?excessive dreaming'. However neuronal mechanisms of these effects have not been analyzed. OP inhibit acetylcholinesterase activity leading to a hyperativity of the brain cholin...

  19. Selective and irreversible inhibitors of mosquito acetylcholinesterases for controlling malaria and other mosquito-borne diseases.

    PubMed

    Pang, Yuan-Ping; Ekström, Fredrik; Polsinelli, Gregory A; Gao, Yang; Rana, Sandeep; Hua, Duy H; Andersson, Björn; Andersson, Per Ola; Peng, Lei; Singh, Sanjay K; Mishra, Rajesh K; Zhu, Kun Yan; Fallon, Ann M; Ragsdale, David W; Brimijoin, Stephen

    2009-01-01

    New insecticides are urgently needed because resistance to current insecticides allows resurgence of disease-transmitting mosquitoes while concerns for human toxicity from current compounds are growing. We previously reported the finding of a free cysteine (Cys) residue at the entrance of the active site of acetylcholinesterase (AChE) in some insects but not in mammals, birds, and fish. These insects have two AChE genes (AP and AO), and only AP-AChE carries the Cys residue. Most of these insects are disease vectors such as the African malaria mosquito (Anopheles gambiae sensu stricto) or crop pests such as aphids. Recently we reported a Cys-targeting small molecule that irreversibly inhibited all AChE activity extracted from aphids while an identical exposure caused no effect on the human AChE. Full inhibition of AChE in aphids indicates that AP-AChE contributes most of the enzymatic activity and suggests that the Cys residue might serve as a target for developing better aphicides. It is therefore worth investigating whether the Cys-targeting strategy is applicable to mosquitocides. Herein, we report that, under conditions that spare the human AChE, a methanethiosulfonate-containing molecule at 6 microM irreversibly inhibited 95% of the AChE activity extracted from An. gambiae s. str. and >80% of the activity from the yellow fever mosquito (Aedes aegypti L.) or the northern house mosquito (Culex pipiens L.) that is a vector of St. Louis encephalitis. This type of inhibition is fast ( approximately 30 min) and due to conjugation of the inhibitor to the active-site Cys of mosquito AP-AChE, according to our observed reactivation of the methanethiosulfonate-inhibited AChE by 2-mercaptoethanol. We also note that our sulfhydryl agents partially and irreversibly inhibited the human AChE after prolonged exposure (>4 hr). This slow inhibition is due to partial enzyme denaturation by the inhibitor and/or micelles of the inhibitor, according to our studies using atomic force

  20. Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers

    PubMed Central

    Ashare, R L; Kimmey, B A; Rupprecht, L E; Bowers, M E; Hayes, M R; Schmidt, H D

    2016-01-01

    Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg−1 per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg−1 galantamine and 3.0 mg kg−1 donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects. PMID:26784967

  1. Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers.

    PubMed

    Ashare, R L; Kimmey, B A; Rupprecht, L E; Bowers, M E; Hayes, M R; Schmidt, H D

    2016-01-19

    Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg(-1) per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg(-1) galantamine and 3.0 mg kg(-1) donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects.

  2. Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers.

    PubMed

    Ashare, R L; Kimmey, B A; Rupprecht, L E; Bowers, M E; Hayes, M R; Schmidt, H D

    2016-01-01

    Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg(-1) per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg(-1) galantamine and 3.0 mg kg(-1) donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects. PMID:26784967

  3. Identification of Potential Herbal Inhibitor of Acetylcholinesterase Associated Alzheimer's Disorders Using Molecular Docking and Molecular Dynamics Simulation

    PubMed Central

    Seniya, Chandrabhan; Khan, Ghulam Jilani; Uchadia, Kuldeep

    2014-01-01

    Cholinesterase inhibitors (ChE-Is) are the standard for the therapy of AD associated disorders and are the only class of approved drugs by the Food and Drug Administration (FDA). Additionally, acetylcholinesterase (AChE) is the target for many Alzheimer's dementia drugs which block the function of AChE but have some side effects. Therefore, in this paper, an attempt was made to elucidate cholinesterase inhibition potential of secondary metabolite from Cannabis plant which has negligible or no side effect. Molecular docking of 500 herbal compounds, against AChE, was performed using Autodock 4.2 as per the standard protocols. Molecular dynamics simulations have also been carried out to check stability of binding complex in water for 1000 ps. Our molecular docking and simulation have predicted high binding affinity of secondary metabolite (C28H34N2O6) to AChE. Further, molecular dynamics simulations for 1000 ps suggest that ligand interaction with the residues Asp72, Tyr70-121-334, and Phe288 of AChE, all of which fall under active site/subsite or binding pocket, might be critical for the inhibitory activity of AChE. This approach might be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer's disease. The study provides evidence for consideration of C28H34N2O6 as a valuable small ligand molecule in treatment and prevention of AD associated disorders and further in vitro and in vivo investigations may prove its therapeutic potential. PMID:25054066

  4. Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation.

    PubMed

    Zha, Gao-Feng; Zhang, Cheng-Pan; Qin, Hua-Li; Jantan, Ibrahim; Sher, Muhammad; Amjad, Muhammad Wahab; Hussain, Muhammad Ajaz; Hussain, Zahid; Bukhari, Syed Nasir Abbas

    2016-05-15

    A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1-42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1-42 aggregation. The compound 3o exhibited best AChE (IC50=0.037μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.

  5. Computational analysis of novel drugs designed for use as acetylcholinesterase inhibitors and histamine H3 receptor antagonists for Alzheimer's disease by docking, scoring and de novo evolution

    PubMed Central

    CHEN, PO-YUAN; TSAI, CHING-TSAN; OU, CHE-YEN; HSU, WEI-TSE; JHUO, MIEN-DE; WU, CHIEH-HSI; SHIH, TZU-CHING; CHENG, TZU-HURNG; CHUNG, JING-GUNG

    2012-01-01

    Alzheimer's disease (AD) was first described by Alois Alzheimer in 1907. AD is the most prevalent dementia- related disease, affecting over 20 million individuals worldwide. Currently, however, only a handful of drugs are available and they are at best only able to offer some relief of symptoms. Acetylcholinesterase (AChE) inhibitors, antioxidants, metal chelators, monoamine oxidase inhibitors, anti-inflammatory drugs and NMDA inhibitors are usually used to attempt to cure this disease. AChE inhibitors are the most effective therapy for AD at present. Researchers have found that histamine H3 receptor antagonists decrease re-uptake of acetylcholine and the nervous transmitter substance acetylcholine increases. In this study, we designed compounds by using docking, de novo evolution and adsorption, distribution, metabolism, excretion and toxicity (ADMET) analysis to AChE inhibitors as well as histamine H3 receptor antagonists to forward drug research and investigate the potent compounds which can pass through the blood-brain barrier. The novel drugs may be useful for the treatment of AD, based on the results of this theoretical calculation study. We will subsequently examine them in future experiments. PMID:22267207

  6. Computational analysis of novel drugs designed for use as acetylcholinesterase inhibitors and histamine H3 receptor antagonists for Alzheimer's disease by docking, scoring and de novo evolution.

    PubMed

    Chen, Po-Yuan; Tsai, Ching-Tsan; Ou, Che-Yen; Hsu, Wei-Tse; Jhuo, Mien-De; Wu, Chieh-Hsi; Shih, Tzu-Ching; Cheng, Tzu-Hurng; Chung, Jing-Gung

    2012-04-01

    Alzheimer's disease (AD) was first described by Alois Alzheimer in 1907. AD is the most prevalent dementia- related disease, affecting over 20 million individuals worldwide. Currently, however, only a handful of drugs are available and they are at best only able to offer some relief of symptoms. Acetylcholinesterase (AChE) inhibitors, antioxidants, metal chelators, monoamine oxidase inhibitors, anti-inflammatory drugs and NMDA inhibitors are usually used to attempt to cure this disease. AChE inhibitors are the most effective therapy for AD at present. Researchers have found that histamine H3 receptor antagonists decrease re-uptake of acetylcholine and the nervous transmitter substance acetylcholine increases. In this study, we designed compounds by using docking, de novo evolution and adsorption, distribution, metabolism, excretion and toxicity (ADMET) analysis to AChE inhibitors as well as histamine H3 receptor antagonists to forward drug research and investigate the potent compounds which can pass through the blood-brain barrier. The novel drugs may be useful for the treatment of AD, based on the results of this theoretical calculation study. We will subsequently examine them in future experiments.

  7. Esterase detoxication of acetylcholinesterase inhibitors using human liver samples in vitro.

    PubMed

    Moser, Virginia C; Padilla, Stephanie

    2016-04-15

    Organophosphorus (OP) and N-methylcarbamate pesticides inhibit acetylcholinesterase (AChE), but differences in metabolism and detoxication can influence potency of these pesticides across and within species. Carboxylesterase (CaE) and A-esterase (paraoxonase, PON1) are considered factors underlying age-related sensitivity differences. We used an in vitro system to measure detoxication of AChE-inhibiting pesticides mediated via these esterases. Recombinant human AChE was used as a bioassay of inhibitor concentration following incubation with detoxifying tissue: liver plus Ca(+2) (to stimulate PON1s, measuring activity of both esterases) or EGTA (to inhibit PON1s, thereby measuring CaE activity). AChE inhibitory concentrations of aldicarb, chlorpyrifos oxon, malaoxon, methamidophos, oxamyl, paraoxon, and methylparaoxon were incubated with liver homogenates from adult male rat or one of 20 commercially provided human (11-83 years of age) liver samples. Detoxication was defined as the difference in inhibition produced by the pesticide alone and inhibition measured in combination with liver plus Ca(+2) or liver plus EGTA. Generally, rat liver produced more detoxication than did the human samples. There were large detoxication differences across human samples for some pesticides (especially malaoxon, chlorpyrifos oxon) but not for others (e.g., aldicarb, methamidophos); for the most part these differences did not correlate with age or sex. Chlorpyrifos oxon was fully detoxified only in the presence of Ca(+2) in both rat and human livers. Detoxication of paraoxon and methylparaoxon in rat liver was greater with Ca(+2), but humans showed less differentiation than rats between Ca(+2) and EGTA conditions. This suggests the importance of PON1 detoxication for these three OPs in the rat, but mostly only for chlorpyrifos oxon in human samples. Malaoxon was detoxified similarly with Ca(+2) or EGTA, and the differences across humans correlated with metabolism of p

  8. The pharmacology of novel acetylcholinesterase inhibitors, (+/-)-huprines Y and X, on the Torpedo electric organ.

    PubMed

    Ros, E; Aleu, J; Gómez de Aranda, I; Muñoz-Torrero, D; Camps, P; Badia, A; Marsal, J; Solsona, C

    2001-06-01

    The effects of the tacrine-huperzine A hybrid acetylcholinesterase inhibitors, (+/-)-12-amino-3-chloro-9-methyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride ((+/-)-huprine Y) and (+/-)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride ((+/-)-huprine X), were tested on spontaneous synaptic activity by measuring the amplitude, the rise time, the rate of rise, the half-width and the area or the electrical charge of the miniature endplate potentials (m.e.p.ps) recorded extracellularly on Torpedo electric organ fragments. (+/-)-Huprine Y and (+/-)-huprine X at a concentration of 500 nM increased all the m.e.p.p. variables analyzed. The effect of (+/-)-huprine Y was smaller than that of (+/-)-huprine X for all the variables except for the rate of rise where there was no significant difference. The effects of these drugs were also tested on nicotinic receptors by analyzing the currents elicited by acetylcholine (100 microM) in Xenopus laevis oocytes, transplanted with membranes from Torpedo electric organ. Both drugs inhibited the currents in a reversible manner, (+/-)-huprine Y (IC(50)=452 nM) being more effective than (+/-)-huprine X (IC(50)=4865 nM). The Hill coefficient was 0.5 for both drugs. The inhibition of the nicotinic receptor was voltage-dependent and decreased at depolarizing potentials, and there was no significant difference in the effects between (+/-)-huprine Y and (+/-)-huprine X at concentrations near to their IC(50) values. At depolarizing potentials between -20 and +15 mV, these drugs did not have any detectable effect on the blockade of the nicotinic receptor. Both huprines increased the desensitization of the nicotinic receptors since the current closed quickly in the presence of the drugs, and there was no significant difference in this effect between (+/-)-huprine Y (500 nM) and (+/-)-huprine X (5 microM). We conclude that (+/-)-huprine Y and (+/-)-huprine X increase the level of

  9. Esterase detoxification of acetylcholinesterase inhibitors using human liver samples in vitro

    EPA Science Inventory

    Organophosphate (OP) and N-methylcarbamate pesticides inhibit acetylcholinesterase (AChE), but differences in metabolism and detoxification can influence potency of these pesticides across and within species. Carboxylesterase (CaE) and A-esterase (paraoxonase, PON1) are consider...

  10. Computational studies of acetylcholinesterase complexed with fullerene derivatives: a new insight for Alzheimer disease treatment.

    PubMed

    da Silva Gonçalves, Arlan; França, Tanos Celmar Costa; Vital de Oliveira, Osmair

    2016-06-01

    Here, we propose five fullerene (C60) derivatives as new drugs against Alzheimer's disease (AD). These compounds were designed to act as new human acetylcholinesterase (HssAChE) inhibitors by blocking its fasciculin II (FASII) binding site. Docking and molecular dynamic results show that our proposals bind to the HssAChE tunnel entrance, forming stable complex, and further binding free energy calculations suggest that three of the derivatives proposed here could be potent HssAChE inhibitors. We found a region formed by a set of residues (Tyr72, Asp74, Trp286, Gln291, Tyr341, and Pro344) which can be further exploited in the drug design of new inhibitors of HssAChE based on C60 derivatives. Results presented here report for the first time by a new class of molecules that can become effective drugs against AD.

  11. Distribution of Intravenously Administered Acetylcholinesterase Inhibitor and Acetylcholinesterase Activity in the Adrenal Gland: 11C-Donepezil PET Study in the Normal Rat

    PubMed Central

    Watabe, Tadashi; Naka, Sadahiro; Ikeda, Hayato; Horitsugi, Genki; Kanai, Yasukazu; Isohashi, Kayako; Ishibashi, Mana; Kato, Hiroki; Shimosegawa, Eku; Watabe, Hiroshi; Hatazawa, Jun

    2014-01-01

    Purpose Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered 11C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands. Methods The distribution of 11C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight  = 220±8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of 11C-DNP (45.0±10.7 MBq). The whole-body distribution of the 11C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs. Results The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of 11C-DNP in the body (following the liver) (13.33±1.08 and 19.43±1.29 ml/cm3, respectively), indicating that the distribution of 11C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9±1.6, 83.1±3.0, and 38.5±8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands. Conclusions We demonstrated the whole-body distribution of 11C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of 11C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors. PMID:25225806

  12. Affinity binding-guided fluorescent nanobiosensor for acetylcholinesterase inhibitors via distance modulation between the fluorophore and metallic nanoparticle.

    PubMed

    Zhang, Yaodong; Hei, Tingting; Cai, Yanan; Gao, Qunqun; Zhang, Qi

    2012-03-20

    The magnitude of fluorescence enhancement was found to depend strongly on the distance between fluorophores and metal nanostructures in metal-enhanced fluorescence (MEF). However, the precise placement of the particle in front of the molecule with nanometer accuracy and distance control is a great challenge. We describe a method using acetylcholinesterase (AChE) to modulate the distance between a gold nanoparticle (AuNP) and the fluorophore 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one) (DDAO). We found that DDAO is a reversible mixed type-I AChE inhibitor. DDAO binds to the peripheral anionic site and penetrates into the active gorge site of AChE via inhibition kinetics test and molecular docking study. The affinity ligand DDAO bound to AChE which was immobilized onto AuNPs, and its fluorescence was sharply enhanced due to MEF. The fluorescence was reduced by distance variations between the AuNP and DDAO, which resulted from other inhibitors competitively binding with AChE and partly or completely displacing DDAO. Experimental results show that changes in fluorescence intensity are related to the concentration of inhibitors present in the solution. In addition, the nanobiosensor has high sensitivity, with detection limits as low as 0.4 μM for paraoxon and 10 nM for tacrine, and also exhibits different reduction efficiencies for the two types of inhibitor. Thus, instead of an inhibition test, a new type of affinity binding-guided fluorescent nanobiosensor was fabricated to detect AChE inhibitors, determine AChE inhibitor binding mode, and screen more potent AChE inhibitors. The proposed strategy may be applied to other proteins or protein domains via changes in the affinity ligand.

  13. Automated Docking with Protein Flexibility in the Design of Femtomolar “Click Chemistry” Inhibitors of Acetylcholinesterase

    PubMed Central

    Morris, Garrett M.; Green, Luke G.; Radić, Zoran; Taylor, Palmer; Sharpless, K. Barry; Olson, Arthur J.; Grynszpan, Flavio

    2013-01-01

    The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands.1 Here we describe the application of the program AutoDock2 to the design of a focused library that was used in the “click chemistry in-situ” generation of the most potent non-covalent inhibitor of the enzyme acetylcholinesterase (AChE) yet developed (Kd = ~100 fM).3 AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid sidechains of the target protein. PMID:23451944

  14. Galantamine, an acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, attenuates nicotine taking and seeking in rats.

    PubMed

    Hopkins, Thomas J; Rupprecht, Laura E; Hayes, Matthew R; Blendy, Julie A; Schmidt, Heath D

    2012-09-01

    Current smoking cessation pharmacotherapies have limited efficacy in preventing relapse and maintaining abstinence during withdrawal. Galantamine is an acetylcholinesterase inhibitor that also acts as a positive allosteric modulator of nicotinic acetylcholine receptors. Galantamine has recently been shown to reverse nicotine withdrawal-induced cognitive impairments in mice, which suggests that galantamine may function to prevent relapse in human smokers. However, there are no studies examining whether galantamine administration modulates nicotine self-administration and/or reinstatement of nicotine seeking in rodents. The present experiments were designed to determine the effects of galantamine administration on nicotine taking and reinstatement of nicotine-seeking behavior, an animal model of relapse. Moreover, the effects of galantamine on sucrose-maintained responding and sucrose seeking were also examined to determine whether galantamine's effects generalized to other reinforced behaviors. An inverted U-shaped dose-response curve was obtained when animals self-administered different unit doses of nicotine with the highest responding for 0.03 mg/kg per infusion of nicotine. Acute galantamine administration (5.0 mg/kg, i.p.) attenuated nicotine self-administration when animals were maintained on either a fixed-ratio 5 (FR5) or progressive ratio (PR) schedule of reinforcement. Galantamine administration also attenuated the reinstatement of nicotine-seeking behavior. No significant effects of galantamine on sucrose self-administration or sucrose reinstatement were noted. Acetylcholinesterase inhibitors have also been shown to produce nausea and vomiting in humans. However, at doses required to attenuate nicotine self-administration, no effects of galantamine on nausea/malaise as measured by pica were noted. These results indicate that increased extracellular acetylcholine levels and/or nicotinic acetylcholine receptor stimulation is sufficient to attenuate

  15. Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals

    PubMed Central

    Amat-ur-Rasool, Hafsa; Ahmed, Mehboob

    2015-01-01

    Alzheimer's disease (AD), a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh). The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE), an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD. PMID:26325402

  16. Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals.

    PubMed

    Amat-Ur-Rasool, Hafsa; Ahmed, Mehboob

    2015-01-01

    Alzheimer's disease (AD), a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh). The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE), an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD. PMID:26325402

  17. A cationic surfactant-decorated liquid crystal sensing platform for simple and sensitive detection of acetylcholinesterase and its inhibitor.

    PubMed

    Wang, Yi; Hu, Qiongzheng; Guo, Yongxian; Yu, Li

    2015-10-15

    In this paper, construction of the liquid crystal (LC)-based sensing platform for simple and sensitive detection of acetylcholinesterase (AChE) and its inhibitor using a cationic surfactant-decorated LC interface was demonstrated. A change of the optical images of LCs from bright to dark appearance was observed when the cationic surfactant, myristoylcholine chloride (Myr), was transferred onto the aqueous/LC interface, due to the formation of a stable surfactant monolayer at the interface. A dark-to-bright change of the optical appearance was then observed when AChE was transferred onto the Myr-decorated LC interface. The sensitivity of this new type of LC-based sensor is 3 orders of magnitude higher in the serum albumin solution than that only in the buffer solution. Noteworthy is that the AChE LC sensor shows a very high sensitivity for the detection of the enzyme inhibitor, which is around 1 fM. The constructed low-cost LC-based sensor is quite simple and convenient, showing high promise for label-free detection of AChE and its inhibitors. PMID:25957073

  18. Acetylcholinesterase liquid crystal biosensor based on modulated growth of gold nanoparticles for amplified detection of acetylcholine and inhibitor.

    PubMed

    Liao, Shuzhen; Qiao, Yanan; Han, Wenting; Xie, Zhaoxia; Wu, Zhaoyang; Shen, Guoli; Yu, Ruqin

    2012-01-01

    A novel acetylcholinesterase (AChE) liquid crystal (LC) biosensor based on enzymatic growth of gold nanoparticles (Au NPs) has been developed for amplified detection of acetylcholine (ACh) and AChE inhibitor. In this method, AChE mediates the hydrolysis of acetylthiocholine (ATCl) to form thiocholine, and the latter further reduces AuCl(4)(-) to Au NPs without Au nanoseeds. This process, termed biometallization, leads to a great enhancement in the optical signal of the LC biosensor due to the large size of Au NPs, which can greatly disrupt the orientational arrangement of LCs. On the other hand, the hydrolysis of ATCl is inhibited in the presence of ACh or organophosphate pesticides (OPs, a AChE inhibitor), which will decrease the catalytic growth of Au NPs and, as a result, reduce the orientational response of LCs. On the basis of such an inhibition mechanism, the AChE LC biosensor can be used as an effective way to realize the detection of ACh and AChE inhibitors. The results showed that the AChE LC biosensor was highly sensitive to ACh with a detection limit of 15 μmol/L and OPs with a detection limit of 0.3 nmol/L. This study provides a simple and sensitive AChE LC biosensing approach and offers effective signal enhanced strategies for the development of enzyme LC biosensors. PMID:22148672

  19. Flow-through enzyme immobilized amperometric detector for the rapid screening of acetylcholinesterase inhibitors by flow injection analysis.

    PubMed

    Vandeput, Marie; Parsajoo, Cobra; Vanheuverzwijn, Jérôme; Patris, Stéphanie; Yardim, Yavuz; le Jeune, Alexandre; Sarakbi, Ahmad; Mertens, Dominique; Kauffmann, Jean-Michel

    2015-01-01

    A commercially available thin-layer flow-through amperometric detector, with the sensing block customized in an original design, was applied to the screening of drug compounds known as acetylcholinesterase (AChE) inhibitors. AChE from electric eel was covalently immobilized onto a cysteamine modified gold disk adjacent to a silver disk working electrode. On-line studies were performed by flow injection analysis (FIA) in PBS buffer pH 7.4. Seven commercially available AChE inhibitors used in the medical field, namely neostigmine, eserine, tacrine, donepezil, rivastigmine, pyridostigmine and galantamine as well as two natural compounds, quercetin and berberine, were investigated. The same trend of inhibitory potency as described in the literature was observed. Of particular interest and in addition to the determination of the IC50 values, this flow-through system allowed the study of both, the stability of the enzyme-inhibitor complex and the kinetic of the enzyme activity recovery. PMID:25459923

  20. Inhibitor profile of bis(n)-tacrines and N-methylcarbamates on acetylcholinesterase from Rhipicephalus (Boophilus) microplus and Phlebotomus papatasi

    PubMed Central

    Swale, Daniel R.; Tong, Fan; Temeyer, Kevin B.; Li, Andrew; Lam, Polo C-H.; Totrov, Maxim M.; Carlier, Paul R.; Pérez de León, Adalberto A.; Bloomquist, Jeffrey R.

    2013-01-01

    The cattle tick, Rhipicephalus (Boophilus) microplus (Bm), and the sand fly, Phlebotomus papatasi (Pp), are disease vectors to cattle and humans, respectively. The purpose of this study was to characterize the inhibitor profile of acetylcholinesterases from Bm (BmAChE1) and Pp (PpAChE) compared to human and bovine AChE, in order to identify divergent pharmacology that might lead to selective inhibitors. Results indicate that BmAChE has low sensitivity (IC50 = 200 μM) toward tacrine, a monovalent catalytic site inhibitor with sub micromolar blocking potency in all previous species tested. Similarly, a series of bis(n)-tacrine dimer series, bivalent inhibitors and peripheral site AChE inhibitors possess poor potency toward BmAChE. Molecular homology models suggest the rBmAChE enzyme possesses a W384F orthologous substitution near the catalytic site, where the larger tryptophan side chain obstructs the access of larger ligands to the active site, but functional analysis of this mutation suggests it only partially explains the low sensitivity to tacrine. In addition, BmAChE1 and PpAChE have low nanomolar sensitivity to some experimental carbamate anticholinesterases originally designed for control of the malaria mosquito, Anopheles gambiae. One experimental compound, 2-((2-ethylbutyl)thio)phenyl methylcarbamate, possesses >300-fold selectivity for BmAChE1 and PpAChE over human AChE, and a mouse oral LD50 of >1500 mg/kg, thus providing an excellent new lead for vector control. PMID:24187393

  1. Exploration of a Library of 3,4-(Methylenedioxy)aniline-Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design, Synthesis, and Evaluation.

    PubMed

    Tripathi, Rati K P; Rai, Gopal K; Ayyannan, Senthil R

    2016-06-01

    A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro- or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl)semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 =4.52±0.032 μm), MAO-B (IC50 =0.059±0.002 μm), and AChE (IC50 =0.0087±0.0002 μm) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO-A and MAO-B, and mixed-type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme-inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug-like characteristics.

  2. Exploration of a Library of 3,4-(Methylenedioxy)aniline-Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design, Synthesis, and Evaluation.

    PubMed

    Tripathi, Rati K P; Rai, Gopal K; Ayyannan, Senthil R

    2016-06-01

    A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro- or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl)semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 =4.52±0.032 μm), MAO-B (IC50 =0.059±0.002 μm), and AChE (IC50 =0.0087±0.0002 μm) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO-A and MAO-B, and mixed-type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme-inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug-like characteristics. PMID:27135466

  3. Primary Investigation for the Mechanism of Biatractylolide from Atractylodis Macrocephalae Rhizoma as an Acetylcholinesterase Inhibitor.

    PubMed

    Xie, Yong-Chao; Ning, Ning; Zhu, Li; Li, Dan-Ning; Feng, Xing; Yang, Xiao-Ping

    2016-01-01

    Biatractylolide was isolated from ethyl acetate extract of dried Atractylodis Macrocephalae Rhizoma root by multistep chromatographic processing. Structure of biatractylolide was confirmed by (1)H-NMR and (13)C-NMR. The IC50 on acetylcholinesterase (AChE) activity was 6.5458 μg/mL when the control IC50 value of huperzine A was 0.0192 μg/mL. Molecular Docking Software (MOE) was used to discover molecular sites of action between biatractylolide and AChE protein by regular molecular docking approaches. Moreover, biatractylolide downregulated the expression of AChE of MEF and 293T cells in a dose-dependent manner. These results demonstrated that the molecular mechanisms of inhibitory activities of biatractylolide on AChE are not only through binding to AChE, but also via reducing AChE expression by inhibiting the activity of GSK3β. PMID:27642355

  4. Primary Investigation for the Mechanism of Biatractylolide from Atractylodis Macrocephalae Rhizoma as an Acetylcholinesterase Inhibitor

    PubMed Central

    Xie, Yong-Chao; Ning, Ning; Zhu, Li; Li, Dan-Ning

    2016-01-01

    Biatractylolide was isolated from ethyl acetate extract of dried Atractylodis Macrocephalae Rhizoma root by multistep chromatographic processing. Structure of biatractylolide was confirmed by 1H-NMR and 13C-NMR. The IC50 on acetylcholinesterase (AChE) activity was 6.5458 μg/mL when the control IC50 value of huperzine A was 0.0192 μg/mL. Molecular Docking Software (MOE) was used to discover molecular sites of action between biatractylolide and AChE protein by regular molecular docking approaches. Moreover, biatractylolide downregulated the expression of AChE of MEF and 293T cells in a dose-dependent manner. These results demonstrated that the molecular mechanisms of inhibitory activities of biatractylolide on AChE are not only through binding to AChE, but also via reducing AChE expression by inhibiting the activity of GSK3β.

  5. Primary Investigation for the Mechanism of Biatractylolide from Atractylodis Macrocephalae Rhizoma as an Acetylcholinesterase Inhibitor

    PubMed Central

    Xie, Yong-Chao; Ning, Ning; Zhu, Li; Li, Dan-Ning

    2016-01-01

    Biatractylolide was isolated from ethyl acetate extract of dried Atractylodis Macrocephalae Rhizoma root by multistep chromatographic processing. Structure of biatractylolide was confirmed by 1H-NMR and 13C-NMR. The IC50 on acetylcholinesterase (AChE) activity was 6.5458 μg/mL when the control IC50 value of huperzine A was 0.0192 μg/mL. Molecular Docking Software (MOE) was used to discover molecular sites of action between biatractylolide and AChE protein by regular molecular docking approaches. Moreover, biatractylolide downregulated the expression of AChE of MEF and 293T cells in a dose-dependent manner. These results demonstrated that the molecular mechanisms of inhibitory activities of biatractylolide on AChE are not only through binding to AChE, but also via reducing AChE expression by inhibiting the activity of GSK3β. PMID:27642355

  6. Graphene quantum dots for ultrasensitive detection of acetylcholinesterase and its inhibitors

    NASA Astrophysics Data System (ADS)

    Li, Nan; Wang, Xuewan; Chen, Jie; Sun, Lei; Chen, Peng

    2015-09-01

    Graphene quantum dots (GQDs) are emerging zero-dimensional materials promising a wide spectrum of novel applications including development of optical sensors. Herein, a GQD-based fluorometric sensor is devised to detect acetylcholinesterase (AChE, a critical enzyme in central nervous system and neuromuscular junctions) with an ultralow detection limit (0.58 pM with S/N of 5.0), using a photoluminescence ‘turn-off’ mechanism. This simple ‘mix-and-detect’ platform can also be employed to sense a variety of compounds that can directly or indirectly inhibit the enzymatic activities of AChE, such as nerve gases, pesticides, and therapeutic drugs. As the proof-of-concept demonstrations, we show the sensitive detection of paraoxon (a pesticide), tacrine (a drug to treat Alzheimer’s disease), and dopamine (an important neurotransmitter).

  7. Synthesis of imperatorin analogs and their evaluation as acetylcholinesterase and butyrylcholinesterase inhibitors.

    PubMed

    Granica, Sebastian; Kiss, Anna K; Jarończyk, Małgorzata; Maurin, Jan K; Mazurek, Aleksander P; Czarnocki, Zbigniew

    2013-11-01

    In this study, we synthesized several imperatorin analogs using imperatorin and xanthotoxin as substrates. The anti-cholinesterase activities of all compounds were evaluated in in vitro experiments according to the modified Ellman's method. For each synthesized compound, IC50 values for both enzymes were established. Galantamine hydrobromide was used as a positive control in the enzymatic experiments. All active compounds showed selectivity toward butyrylcholinesterase (BuChE) rather than acetylcholinesterase. The most active ones were 8-(3-methylbutoxy)-psoralen and 8-hexoxypsoralen with IC50 values for BuChE of around 16.5 and 16.4 µM, respectively. The results of our study may be considered as the beginning of a search for potential anti-Alzheimer's disease drugs based on the structure of natural furocoumarins. PMID:24123207

  8. Dihydroquinoline Carbamate Derivatives as "Bio-oxidizable" Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [¹¹C] Radiosynthesis and Biological Evaluation.

    PubMed

    Bohn, Pierre; Gourand, Fabienne; Papamicaël, Cyril; Ibazizène, Méziane; Dhilly, Martine; Gembus, Vincent; Alix, Florent; Ţînţaş, Mihaela-Liliana; Marsais, Francis; Barré, Louisa; Levacher, Vincent

    2015-05-20

    With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original "bio-oxidizable" prodrug strategy. After peripheral injection of the prodrug 1a [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug 2a [IC50 = 20 nM (hAChE)] through central redox activation of 1a. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in 2a promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug 1a was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [(11)C]1a, while identification of [(11)C]2a and [(11)C]3a both accounts for central redox activation of 1a and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite 3a as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite 3a might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors. PMID:25695305

  9. In vivo labelling of hippocampal beta-amyloid in triple-transgenic mice with a fluorescent acetylcholinesterase inhibitor released from nanoparticles.

    PubMed

    Härtig, Wolfgang; Kacza, Johannes; Paulke, Bernd-Reiner; Grosche, Jens; Bauer, Ute; Hoffmann, Anke; Elsinghorst, Paul W; Gütschow, Michael

    2010-01-01

    The drastic loss of cholinergic projection neurons in the basal forebrain is a hallmark of Alzheimer's disease (AD), and drugs most frequently applied for the treatment of dementia include inhibitors of the acetylcholine-degrading enzyme acetylcholinesterase (AChE). This protein is known to act as a ligand of beta-amyloid (Abeta) in senile plaques, a further neuropathological sign of AD. Recently, we have shown that the fluorescent, heterodimeric AChE inhibitor PE154 allows for the histochemical staining of cortical Abeta plaques in triple-transgenic (TTG) mice with age-dependent beta-amyloidosis and tau hyperphosphorylation, an established animal model for aspects of AD. In the present study, we have primarily demonstrated the targeting of Abeta-immunopositive plaques with PE154 in vivo for 4 h up to 1 week after injection into the hippocampi of 13-20-month-old TTG mice. Numerous plaques, double-stained for PE154 and Abeta-immunoreactivity, were revealed by confocal laser-scanning microscopy. Additionally, PE154 targeted hippocampal Abeta deposits in aged TTG mice after injection of carboxylated polyglycidylmethacrylate nanoparticles delivering the fluorescent marker in vivo. Furthermore, biodegradable core-shell polystyrene/polybutylcyanoacrylate nanoparticles were found to be suitable, alternative vehicles for PE154 as a useful in vivo label of Abeta. Moreover, we were able to demonstrate that PE154 targeted Abeta, but neither phospho-tau nor reactive astrocytes surrounding the plaques. In conclusion, nanoparticles appear as versatile carriers of AChE inhibitors and other promising drugs for the treatment of AD.

  10. EEG spectra, behavioral states and motor activity in rats exposed to acetylcholinesterase inhibitor chlorpyrifos.

    PubMed

    Timofeeva, Olga A; Gordon, Christopher J

    2002-06-01

    Exposure to organophosphates (OP) has been associated with sleep disorders such as insomnia and "excessive dreaming." The central mechanisms of these effects are not well understood. OPs inhibit acetylcholinesterase (AChE) activity, leading to a hyperactivity of the brain cholinergic systems that are involved in sleep regulation. We studied alterations in the EEG, behavioral states, motor activity and core temperature in rats orally administered with 10 or 40 mg/kg of the OP insecticide chlorpyrifos (CHP). Occipital EEG, motor activity and core temperature were recorded with telemetric transmitters. Behavioral sleep-wake states were visually scored. Both doses of CHP produced alterations of the EEG (decrease in power of sigma/beta and increase in slow theta and fast gamma bands) characteristic of arousal. EEG alterations were consistent with behavioral changes such as an increase in wakefulness and a decrease in sleep. Waking immobility was a prevalent behavior. We did not detect any overt signs of CHP toxicity, such as an abnormal posture or gait, suggesting that reduced locomotion can be a result of central effects of CHP (such as activation of cholinergic motor inhibitory system) rather than peripheral (such as an impairment of neuromuscular function). Changes in the EEG and behavior occurred independently of the decrease in core temperature. Increased wakefulness together with reduced motor activity after exposure to CHP seems to be a result of hyperactivity in brain cholinergic neuronal networks. PMID:12175464

  11. Virtual Screening and Biological Evaluation of Piperazine Derivatives as Human Acetylcholinesterase Inhibitors

    PubMed Central

    Varadaraju, Kavitha Raj; Kumar, Jajur Ramanna; Mallesha, Lingappa; Muruli, Archana; Mohana, Kikkeri Narasimha Shetty; Mukunda, Chethan Kumar; Sharanaiah, Umesha

    2013-01-01

    The piperazine derivatives have been shown to inhibit human acetylcholinesterase. Virtual screening by molecular docking of piperazine derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K), 4-(4-methyl)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S1), and 4-(4-chloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S3) has been shown to bind at peripheral anionic site and catalytic sites, whereas 4-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S4) and 4-(2,5-dichloro)-benzenesulfonyl-1-(1,4-benzodioxane-2-carbonyl) piperazine (S7) do not bind either to peripheral anionic site or catalytic site with hydrogen bond. All the derivatives have differed in number of H-bonds and hydrophobic interactions. The peripheral anionic site interacting molecules have proven to be potential therapeutics in inhibiting amyloid peptides aggregation in Alzheimer's disease. All the piperazine derivatives follow Lipinski's rule of five. Among all the derivatives 1-(1,4-benzodioxane-2-carbonyl) piperazine (K) was found to have the lowest TPSA value. PMID:24288651

  12. Donepezil, an acetylcholinesterase inhibitor, attenuates LPS-induced inflammatory response in murine macrophage cell line RAW 264.7 through inhibition of nuclear factor kappa B translocation.

    PubMed

    Arikawa, Mikihiko; Kakinuma, Yoshihiko; Noguchi, Tatsuya; Todaka, Hiroshi; Sato, Takayuki

    2016-10-15

    We have previously demonstrated that the pharmacotherapy with donepezil, an acetylcholinesterase inhibitor, suppresses cardiac remodeling in a mouse model of ischemic heart failure after myocardial infarction (MI). However, the precise mechanisms of the cardioprotective effect of donepezil have not been completely delineated. Because post-ischemic inflammation is a pathological key event in the cardiac remodeling process following MI, we investigated the hypothesis that donepezil acts as an inhibitor of inflammatory mediators. RAW 264.7 murine macrophage cells were pretreated with donepezil (100µM) prior to a pro-inflammatory stimulation by administration of lipopolysaccharide (LPS, 10ng/ml). Donepezil significantly reduced intra- and extracellular levels of various kinds of inflammatory mediators such as TNF-α, IL-1β, IL-2, IL-6 and IL-18 after the LPS stimulation, and attenuated LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB). These results indicate that donepezil possesses an anti-inflammatory property. However, the inhibitory effect of donepezil on the macrophage inflammatory responses was never reproduced by ACh, nor was disrupted by ACh receptor blockers. Moreover, other kinds of acetylcholinesterase inhibitors failed to inhibit the inflammatory responses in LPS-stimulated macrophage cells. These results suggest that a cholinergic anti-inflammatory pathway would not be involved in the anti-inflammatory effect of donepezil and that the specific characteristics of donepezil in suppressing the LPS-induced cytokine release and the NF-κB activation would be independent of its acetylcholinesterase inhibition. The present study showed that donepezil exerts an anti-inflammatory effect independently of acetylcholinesterase inhibitory action, thereby donepezil may contribute to cardioprotection during cardiac remodeling process in an ischemic heart failure after MI.

  13. Phenserine, a novel acetylcholinesterase inhibitor, attenuates impaired learning of rats in a 14-unit T-maze induced by blockade of the N-methyl-D-aspartate receptor.

    PubMed

    Patel, N; Spangler, E L; Greig, N H; Yu, Q S; Ingram, D K; Meyer, R C

    1998-01-01

    The present study evaluated the interaction of the glutamatergic and acetylcholinergic systems in memory formation, with an overall emphasis on developing multi-system approaches for treating age-related cognitive decline and Alzheimer' s disease. Specifically, we used a 14-unit T-maze to investigate whether phenserine (PHEN), a long-acting acetylcholinesterase inhibitor, could overcome a learning deficit in rats induced by the NMDA receptor antagonist, 3-(+/-) 2-carboxypiperzin-4-yl) propyl phosphonic acid (CPP). Prior to drug treatment, 3-month-old male Fischer-344 rats were trained to criterion (13 of 15 shock avoidances) in a straight runway. Twenty-four hours later, rats were given i.p. injections of saline (SAL), CPP (9 mg/kg) + SAL or CPP + PHEN (0.25, 0.5 or 0.75 mg/kg) and received 15 massed training trials in a 14-unit T-maze. CPP significantly increased the number of errors made in the maze relative to controls, and phenserine significantly reduced the number of errors made relative to rats receiving CPP only, with the lowest dose being the most effective. These results provide further support of phenserine's potent, cognitive-enhancing properties, and suggest that combined modulation of glutamatergic and acetylcholinergic systems may be of potential benefit in developing new pharmacotherapies for Alzheimer's disease and age-related cognitive decline. PMID:9592071

  14. Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase.

    PubMed

    Camerino, Eugene; Wong, Dawn M; Tong, Fan; Körber, Florian; Gross, Aaron D; Islam, Rafique; Viayna, Elisabet; Mutunga, James M; Li, Jianyong; Totrov, Maxim M; Bloomquist, Jeffrey R; Carlier, Paul R

    2015-10-15

    Malaria is a devastating disease in sub-Saharan Africa, and current vector control measures are threatened by emerging resistance mechanisms. With the goal of developing new, selective, resistance-breaking insecticides we explored α-fluorinated methyl ketones as reversible covalent inhibitors of Anopheles gambiae acetylcholinesterase (AgAChE). Trifluoromethyl ketones 5 demonstrated remarkable volatility in microtiter plate assays, but 5c,e-h exhibited potent (1-100 nM) inhibition of wild type (WT) AgAChE and weak inhibition of resistant mutant G119S mutant AgAChE. Fluoromethyl ketones 10c-i exhibited submicromolar to micromolar inhibition of WT AgAChE, but again only weakly inhibited G119S AgAChE. Interestingly, difluoromethyl ketone inhibitors 9c and 9g had single digit nanomolar inhibition of WT AgAChE, and 9g had excellent potency against G119S AgAChE. Approach to steady-state inhibition was quite slow, but after 23 h incubation an IC50 value of 25.1 ± 1.2 nM was measured. We attribute the slow, tight-binding G119S AgAChE inhibition of 9g to a balance of steric size and electrophilicity. However, toxicities of 5g, 9g, and 10g to adult A. gambiae in tarsal contact, fumigation, and injection assays were lower than expected based on WT AgAChE inhibition potency and volatility. Potential toxicity-limiting factors are discussed. PMID:26386602

  15. Brain regional acetylcholinesterase activity and muscarinic acetylcholine receptors in rats after repeated administration of cholinesterase inhibitors and its withdrawal

    SciTech Connect

    Kobayashi, Haruo . E-mail: hk1664@iwate-u.ac.jp; Suzuki, Tadahiko; Sakamoto, Maki; Hashimoto, Wataru; Kashiwada, Keiko; Sato, Itaru; Akahori, Fumiaki; Satoh, Tetsuo

    2007-03-15

    Activity of acetylcholinesterase (AChE) and specific binding of [{sup 3}H]quinuclidinyl benzilate (QNB), [{sup 3}H]pirenzepine (PZP) and [{sup 3}H]AF-DX 384 to muscarinic acetylcholine receptor (mAChR) preparations in the striatum, hippocampus and cortex of rats were determined 1, 6 and 11 days after the last treatment with an organophosphate DDVP, a carbamate propoxur or a muscarinic agonist oxotremorine as a reference for 7 and 14 days. AChE activity was markedly decreased in the three regions 1 day after the treatment with DDVP for 7 and 14 days with a gradual recovery 6 to 11 days, and much less decreased 1, 6 and 11 days after the treatment with propoxur for 7 days but not for 14 days in the hippocampus and cortex. The binding of [{sup 3}H]-QNB, PZP and AF-DX 384 in the three regions was generally decreased by the treatment with DDVP for 7 and 14 days. Such down-regulations were generally restored 6 or 11 days after the treatment for 7 but not for 14 days. The down-regulation or up-regulation as measured by [{sup 3}H]-QNB, PZP and AF-DX 384 was observed 1, 6 or 11 days after treatment with propoxur for 7 days and/or 14 days. Repeated treatment with oxotremorine produced similar effects except AChE activity to DDVP. These results suggest that repeated inhibition of AChE activity may usually cause down-regulation of mAChRs with some exception in the hippocampus when a reversible antiChE propoxur is injected.

  16. 2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase.

    PubMed

    Leong, Sze Wei; Abas, Faridah; Lam, Kok Wai; Shaari, Khozirah; Lajis, Nordin H

    2016-08-15

    In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6μM and 0.6μM, respectively. Further structure-activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes' inhibition. The Lineweaver-Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer. PMID:27328658

  17. The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors

    SciTech Connect

    Grandič, Marjana; Aráoz, Romulo; Molgó, Jordi; Turk, Tom; Sepčić, Kristina; Benoit, Evelyne; Frangež, Robert

    2012-12-01

    APS12-2, a non-competitive acetylcholinesterase inhibitor, is one of the synthetic analogs of polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In the present work the effects of APS12-2 were studied on isolated mouse phrenic nerve–hemidiaphragm muscle preparations, using twitch tension measurements and electrophysiological recordings. APS12-2 in a concentration-dependent manner blocked nerve-evoked isometric muscle contraction (IC{sub 50} = 0.74 μM), without affecting directly-elicited twitch tension up to 2.72 μM. The compound (0.007–3.40 μM) decreased the amplitude of miniature endplate potentials until a complete block by concentrations higher than 0.68 μM, without affecting their frequency. Full size endplate potentials, recorded after blocking voltage-gated muscle sodium channels, were inhibited by APS12-2 in a concentration-dependent manner (IC{sub 50} = 0.36 μM) without significant change in the resting membrane potential of the muscle fibers up to 3.40 μM. The compound also blocked acetylcholine-evoked inward currents in Xenopus oocytes in which Torpedo (α1{sub 2}β1γδ) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC{sub 50} = 0.0005 μM), indicating a higher affinity of the compound for Torpedo (α1{sub 2}β1γδ) than for the mouse (α1{sub 2}β1γε) nAChR. Our data show for the first time that APS12-2 blocks neuromuscular transmission by a non-depolarizing mechanism through an action on postsynaptic nAChRs of the skeletal neuromuscular junction. -- Highlights: ► APS12-2 produces concentration-dependent inhibition of nerve-evoked muscle contraction in vitro. ► APS12-2 blocks MEPPs and EPPs at the neuromuscular junction. APS12-2 blocks ACh-activated current in Xenopus oocytes incorporated with Torpedo nAChRs.

  18. Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose co-transporter 2: advancement in Alzheimer's disease- diabetes type 2 linkage via an enzoinformatics study.

    PubMed

    Rizvi, Syed M D; Shakil, Shahnawaz; Biswas, Deboshree; Shakil, Shazi; Shaikh, Sibhghatulla; Bagga, Paramdeep; Kamal, Mohammad A

    2014-04-01

    Acetylcholinesterase (AChE) is a primary target for Alzheimer's therapy while recently sodium glucose cotransporter 2 (SGLT2) has gained importance as a potential target for Type 2 Diabetes Mellitus (T2DM) therapy. The present study emphasizes the molecular interactions between a new Food and Drug Administration (FDA) approved antidiabetic drug 'Invokana' (chemically known as Canagliflozin) with AChE and SGLT2 to establish a link between the treatment of T2DM and Alzheimer's Disease (AD). Docking study was performed using 'Autodock4.2'. Both hydrophobic and π-π interactions play an important role in the correct positioning of Canagliflozin within SGLT2 and catalytic site (CAS) of AChE to permit docking. Free energy of binding (ΔG) for 'Canagliflozin-SGLT2' interaction and 'Canagliflozin - CAS domain of AChE' interaction were found to be -10.03 kcal/mol and -9.40 kcal/mol, respectively. During 'Canagliflozin-SGLT2' interaction, Canagliflozin was found to interact with the most important amino acid residue Q457 of SGLT2. This residue is known for its interaction with glucose during reabsorption in kidney. However, 'Canagliflozin-CAS domain of AChE' interaction revealed that out of the three amino acids constituting the catalytic triad (S203, H447 and E334), two amino acid residues (S203 and H447) interact with Canagliflozin. Hence, Invokana (Canagliflozin) might act as a potent dual inhibitor of AChE and SGLT2. However, scope still remains in the determination of the three-dimensional structure of SGLT2-Canagliflozin and AChE-Canagliflozin complexes by X-ray crystallography to validate the described data. Since the development of diabetes is associated with AD, the design of new AChE inhibitors based on antidiabetic drug scaffolds would be particularly beneficial. Moreover, the present computational study reveals that Invokana (Canagliflozin) is expected to form the basis of a future dual therapy against diabetes associated neurological disorders.

  19. Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease.

    PubMed

    Zhou, An; Hu, Jianping; Wang, Lirong; Zhong, Guochen; Pan, Jian; Wu, Zeyu; Hui, Ailing

    2015-10-01

    Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green).

  20. Synthesis, Pharmacological Assessment, and Molecular Modeling of Acetylcholinesterase/Butyrylcholinesterase Inhibitors: Effect against Amyloid-β-Induced Neurotoxicity

    PubMed Central

    2013-01-01

    The synthesis, molecular modeling, and pharmacological analysis of phenoxyalkylamino-4-phenylnicotinates (2–7), phenoxyalkoxybenzylidenemalononitriles (12, 13), pyridonepezils (14–18), and quinolinodonepezils (19–21) are described. Pyridonepezils 15–18 were found to be selective and moderately potent regarding the inhibition of hAChE, whereas quinolinodonepezils 19–21 were found to be poor inhibitors of hAChE. The most potent and selective hAChE inhibitor was ethyl 6-(4-(1-benzylpiperidin-4-yl)butylamino)-5-cyano-2-methyl-4-phenylnicotinate (18) [IC50 (hAChE) = 0.25 ± 0.02 μM]. Pyridonepezils 15–18 and quinolinodonepezils 20–21 are more potent selective inhibitors of EeAChE than hAChE. The most potent and selective EeAChE inhibitor was ethyl 6-(2-(1-benzylpiperidin-4-yl)ethylamino)-5-cyano-2-methyl-4-phenylnicotinate (16) [IC50 (EeAChE) = 0.0167 ± 0.0002 μM], which exhibits the same inhibitory potency as donepezil against hAChE. Compounds 2, 7, 13, 17, 18, 35, and 36 significantly prevented the decrease in cell viability caused by Aβ1–42. All compounds were effective in preventing the enhancement of AChE activity induced by Aβ1–42. Compounds 2–7 caused a significant reduction whereas pyridonepezils 17 and 18, and compound 16 also showed some activity. The pyrazolo[3,4-b]quinolines 36 and 38 also prevented the upregulation of AChE induced by Aβ1–42. Compounds 2, 7, 12, 13, 17, 18, and 36 may act as antagonists of voltage sensitive calcium channels, since they significantly prevented the Ca2+ influx evoked by KCl depolarization. Docking studies show that compounds 16 and 18 adopted different orientations and conformations inside the active-site gorges of hAChE and hBuChE. The structural and energetic features of the 16-AChE and 18-AChE complexes compared to the 16-BuChE and 18-BuChE complexes account for a higher affinity of the ligand toward AChE. The present data indicate that compounds 2, 7, 17, 18, and 36 may represent attractive

  1. The natural product dihydrotanshinone I provides a prototype for uncharged inhibitors that bind specifically to the acetylcholinesterase peripheral site with nanomolar affinity.

    PubMed

    Beri, Veena; Wildman, Scott A; Shiomi, Kazuro; Al-Rashid, Ziyad F; Cheung, Jonah; Rosenberry, Terrone L

    2013-10-22

    Cholinergic synaptic transmission often requires extremely rapid hydrolysis of acetylcholine by acetylcholinesterase (AChE). AChE is inactivated by organophosphates (OPs) in chemical warfare nerve agents. The resulting accumulation of acetylcholine disrupts cholinergic synaptic transmission and can lead to death. A potential long-term strategy for preventing AChE inactivation by OPs is based on evidence that OPs must pass through a peripheral site or P-site near the mouth of the AChE active site gorge before reacting with a catalytic serine in an acylation site or A-site at the base of the gorge. An ultimate goal of this strategy is to design compounds that bind tightly at or near the P-site and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site with ligands and potential drugs that selectively restrict access, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. We apply here an inhibitor competition assay that can correctly determine whether an AChE inhibitor binds to the P-site, the A-site, or both sites. We have used this assay to examine three uncharged, natural product inhibitors of AChE, including aflatoxin B1, dihydrotanshinone I, and territrem B. The first two of these inhibitors are predicted by the competition assay to bind selectively to the P-site, while territrem B is predicted to span both the P- and A-sites. These predictions have recently been confirmed by X-ray crystallography. Dihydrotanshinone I, with an observed binding constant (KI) of 750 nM, provides a good lead compound for the development of high-affinity, uncharged inhibitors with specificity for the P-site. PMID:24040835

  2. BZYX, a novel acetylcholinesterase inhibitor, significantly improved chemicals-induced learning and memory impairments on rodents and protected PC12 cells from apoptosis induced by hydrogen peroxide.

    PubMed

    Zhang, Jing; Zhu, Difeng; Sheng, Rong; Wu, Honghai; Hu, Yongzhou; Wang, Feng; Cai, Tianyu; Yang, Bo; He, Qiaojun

    2009-06-24

    BZYX was designed as a dual-binding-site acetylcholinesterase (AChE) inhibitor and selected from series of indanone derivatives. The present study was designed to examine the cognition-enhanced, anti-cholinesterase, and neuroprotective effects of BZYX. In the passive avoidance performance and radial arm maze, BZYX showed a comparable effect to donepezil and rivastigmine on memory deficits in different stages induced by scopolamine, NaNO(2) and ethanol, respectively. Ellman's assay indicated BZYX exhibited high inhibition on AChE activity. IC(50) values for BZYX: 0.058+/-0.022 microM; donepezil: 0.019+/-0.004 microM; rivastigmine: 3.81+/-2.81 microM; glantamine: 3.01+/-1.85 microM and huperzine A: 0.053+/-0.016 microM. BZYX also presented great neuroprotecive function from apoptosis induced by hydrogen peroxide(H(2)O(2)) in PC12 cells. MTT assay and Annexin V-FITC Apoptosis Detection showed the viability of PC12 cells remarkably decreased with 400 microM H(2)O(2), while it significantly increased when the cells were pretreated with 0.1-1.0 microM BZYX. BZYX pretreatment remarkably reversed the loss of mitochondria membrane potential (DeltaPsim), scavenged reactive oxygen species formation induced by H(2)O(2) and resulted in up-regulation of procaspase3 and xIAP protein level and down-regulation of phosphorylated JNK protein, p53 protein level and cleavage of caspase 3. It is speculated that the mitochondrial pathway, mediated by Bcl-2 family and Mitogen-Activated Protein Kinases (MAPKs), might involved in the neuroprotection of BZYX. These results first demonstrated that BZYX had neuroprotective effects as well as cognition enhancement and acetylcholinesterase inhibition. It is hopeful that BZYX becomes a potential candidate for use in the intervention for neurodegenerative diseases. PMID:19345205

  3. Tacrine, an oral acetylcholinesterase inhibitor, induced hepatic oxidative damage, which was blocked by liquiritigenin through GSK3-beta inhibition.

    PubMed

    Park, Sang Mi; Ki, Sung Hwan; Han, Nu Ri; Cho, Il Je; Ku, Sae Kwang; Kim, Sang Chan; Zhao, Rong Jie; Kim, Young Woo

    2015-01-01

    Although the cholinesterase inhibitor tacrine has been successfully used for the treatment of Alzheimer's disease, it is known to have hepatotoxic effects. Liquiritigenin (LQ), an active flavonoid in Glycyrrhizae radix, exerts protective effects against liver damage. This study investigated the toxic effect of tacrine on hepatocytes and the beneficial effect of LQ on tacrine intoxication in vivo and in vitro, and the underlying mechanism involved. In hepatocyte cell lines, tacrine induced cell death and oxidative stress, as indicated by decreases in cell viability and glutathione (GSH) contents, which were blocked by pretreatment with LQ. Fluorescent activated cell sorter (FACS) analysis revealed that LQ inhibited cellular H2O2 production and mitochondrial dysfunction induced by tacrine in HepG2 cells. Furthermore, LQ promoted inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β) and prevented decreases in GSK3β phosphorylation induced by tacrine. In rats treatment with tacrine at 30 mg/kg increased hepatic damage as assessed by blood biochemistry and histopathology. Administration of LQ (10 or 30 mg/kg/d, per os (p.o.)) or the hepatoprotective drug sylimarin (100 mg/kg/d) for 3 d inhibited elevations in alanine aminotransferase, aspartate aminotransferase, and histological changes induced by tacrine. These results show that LQ efficaciously protects the rat liver against tacrine-induced liver damage, and suggest that LQ is a therapeutic candidate for ameliorating the hepatotoxic effects of tacrine. PMID:25747977

  4. Structural Studies on Acetylcholinesterase and Paraoxonase Directed Towards Development of Therapeutic Biomolecules for the Treatment of Degenerative Diseases and Protection Against Chemical Threat Agents

    NASA Astrophysics Data System (ADS)

    Sussman, Joel L.; Silman, Israel

    Acetylcholinesterase and paraoxonase are important targets for treatment of degenerative diseases, Alzheimer's disease and atherosclerosis, respectively, both of which impose major burdens on the health care systems in Western society. Acetylcholinesterase is the target of lethal nerve agents, and paraoxonase is under consideration as a bioscavenger for their detoxification. Both are thus the subject of research and development in the context of nerve agent toxicology. The crystal structures of the two enzymes are described, and structure/function relationships are discussed in the context of drug development and of development of means of protection against chemical threats.

  5. Acetylcholinesterase biosensor for inhibitor measurements based on glassy carbon electrode modified with carbon black and pillar[5]arene.

    PubMed

    Shamagsumova, Rezeda V; Shurpik, Dmitry N; Padnya, Pavel L; Stoikov, Ivan I; Evtugyn, Gennady A

    2015-11-01

    New acetylcholinesterase (AChE) biosensor based on unsubstituted pillar[5]arene (P[5]A) as electron mediator was developed and successfully used for highly sensitive detection of organophosphate and carbamate pesticides. The AChE from electric eel was immobilized by carbodiimide binding on carbon black (CB) placed on glassy carbon electrode. The working potential of 200mV was obtained in chronoamperometric mode with the measurement time of 180 s providing best inter-biosensors precision of the results. The AChE biosensor developed made it possible to detect 1×10(-11)-1×10(-6) M of malaoxon, 1×10(-8)-7×10(-6) M of methyl-paraoxon, 1×10(-10)-2×10(-6) M of carbofuran and 7×10(-9)-1×10(-5) M of aldicarb with 10 min incubation. The limits of detection were 4×10(-12), 5×10(-9), 2×10(-11) and 6×10(-10) M, respectively. The AChE biosensor was tested in the analysis of pesticide residuals in spiked samples of peanut and beetroot. The protecting effect of P[5]A derivative bearing quaternary ammonia groups on malaoxon inhibition was shown. PMID:26452862

  6. Taspine: Bioactivity-Guided Isolation and Molecular Ligand–Target Insight of a Potent Acetylcholinesterase Inhibitor from Magnolia x soulangiana

    PubMed Central

    Rollinger, Judith M.; Schuster, Daniela; Baier, Elisabeth; Ellmerer, Ernst P.; Langer, Thierry; Stuppner, Hermann

    2012-01-01

    A bioactivity-guided approach was taken to identify the acetylcholinesterase (AChE, EC 3.1.1.7) inhibitory agent in a Magnolia x soulangiana extract using a microplate enzyme assay with Ellman’s reagent. This permitted the isolation of the alkaloids taspine (1) and (−)-asimilobine (2), which were detected for the first time in this species. Compound 1 showed a significantly higher effect on AChE than the positive control galanthamine and selectively inhibited the enzyme in a long-lasting and concentration-dependent fashion with an IC50 value of 0.33 ± 0.07 μM. Extensive molecular docking studies were performed with human and Torpedo californica-AChE employing Gold software to rationalize the binding interaction. The results suggested ligand 1 to bind in an alternative binding orientation when compared to galanthamine. While this is located in close vicinity to the catalytic amino acid triad, the 1–AChE complex was found to be stabilized by (i) sandwich-like π-stacking interactions between the planar aromatic ligand (1) and the Trp84 and Phe330 of the enzyme, (ii) an esteratic site anchoring with the amino side chain, and (iii) a hydrogen-bonding network. PMID:16989531

  7. Acetylcholinesterase biosensor for inhibitor measurements based on glassy carbon electrode modified with carbon black and pillar[5]arene.

    PubMed

    Shamagsumova, Rezeda V; Shurpik, Dmitry N; Padnya, Pavel L; Stoikov, Ivan I; Evtugyn, Gennady A

    2015-11-01

    New acetylcholinesterase (AChE) biosensor based on unsubstituted pillar[5]arene (P[5]A) as electron mediator was developed and successfully used for highly sensitive detection of organophosphate and carbamate pesticides. The AChE from electric eel was immobilized by carbodiimide binding on carbon black (CB) placed on glassy carbon electrode. The working potential of 200mV was obtained in chronoamperometric mode with the measurement time of 180 s providing best inter-biosensors precision of the results. The AChE biosensor developed made it possible to detect 1×10(-11)-1×10(-6) M of malaoxon, 1×10(-8)-7×10(-6) M of methyl-paraoxon, 1×10(-10)-2×10(-6) M of carbofuran and 7×10(-9)-1×10(-5) M of aldicarb with 10 min incubation. The limits of detection were 4×10(-12), 5×10(-9), 2×10(-11) and 6×10(-10) M, respectively. The AChE biosensor was tested in the analysis of pesticide residuals in spiked samples of peanut and beetroot. The protecting effect of P[5]A derivative bearing quaternary ammonia groups on malaoxon inhibition was shown.

  8. Changes in EEG power spectra and behavioral states in rats exposed to the acetylcholinesterase inhibitor chlorpyrifos and muscarinic agonist oxotremorine.

    PubMed

    Timofeeva, O A; Gordon, C J

    2001-03-01

    Organophosphates (OPs) inhibit acetylcholinesterase (AChE) activity causing cholinergic stimulation in the central nervous system (CNS). Cholinergic systems are crucial in electroencephalogram (EEG) generation and regulation of behavior; however, little is known about how OP exposure affects the EEG and behavioral states. We recorded EEG, core temperature and motor activity before and after exposure to the OP pesticide chlorpyrifos (CHP) in adult female rats implanted with telemetric transmitters. The recording and reference electrodes were placed in the occipital and frontal bones, respectively. The animals received CHP, 25 mg/kg, p.o., or oxotremorine (OX), 0.2 mg/kg, s.c. CHP led to a significant increase in delta (0.1-3.5 Hz), slow theta (4-6.5 Hz), gamma 2 (35.5-50 Hz), reduction in fast theta (7-8.5 Hz), alpha/sigma (9-14 Hz), beta 1 (14.5-24 Hz), beta 2 (24.5-30 Hz) and gamma 1 (30.5-35 Hz) powers, slowing of peak frequencies in 1-9 Hz range, hypothermia and decrease in motor activity. The drop in 7-14 Hz was associated with cholinergic suppression of sleep spindles. Changes in behavioral state were characterized by dramatic diminution of sleep postures and exploring activity and prolongation of quiet waking. There was recovery in all bands in spite of continued inhibition of AChE activity [44,45] in rats exposed to CHP. OX-induced EEG and behavioral alterations were similar to CHP except there was no increase in delta and the onset and recovery were more rapid. We did not find a correlation between the EEG and core temperature alterations. Overall, changes in EEG (except in delta band) and behavior following CHP were attributable to muscarinic stimulation. Cortical arousal together with increased quiet waking and decreased sleep after CHP occurred independently from inhibition of motor activity and lowering of core temperature. PMID:11223004

  9. Digestibility and Bioavailability of the Active Components of Erica australis L. Aqueous Extracts and Their Therapeutic Potential as Acetylcholinesterase Inhibitors

    PubMed Central

    Dias, Pilar; Falé, Pedro L.; Martins, Alice; Rauter, Amélia P.

    2015-01-01

    Erica australis L. (Ericaceae) is used in traditional medicine to treat many free-radical related ailments. In the present work, the stability and biological activity of the plant aqueous extracts submitted to an in vitro digestive process were investigated. Chemical stability was monitored by HPLC-DAD and LC-MS/MS, while the bioactivities were evaluated through the inhibition of acetylcholinesterase (AChE) and DPPH radical scavenging activity. Both extracts, whose main components were flavonol glycosides, inhibited AChE, showing IC50 values of 257.9 ± 6.2 µg/mL and 296.8 ± 8.8 µg/mL for the decoction and for the infusion, respectively. Significant radical scavenging activities were also revealed by both extracts, as denoted by the IC50 values for the decoction, 6.7 ± 0.1 µg/mL, and for the infusion, 10.5 ± 0.3 µg/mL. After submission to gastric and pancreatic juices, no remarkable alterations in the composition or in the bioactivities were observed, suggesting that the extracts may pass through the gastrointestinal tract, keeping their composition and therefore their biological properties. Moreover, the bioavailability of the components of both extracts, as studied in a Caco-2 cell model, showed that compounds can permeate the membrane, which is a condition to exert their biological activities. Our results add further support to the potential of E. australis for its antioxidant and neuroprotective properties. PMID:26347794

  10. 3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae

    PubMed Central

    Verma, Astha; Wong, Dawn M.; Islam, Rafique; Tong, Fan; Ghavami, Maryam; Mutunga, James M.; Slebodnick, Carla; Li, Jianyong; Viayna, Elisabet; Lam, Polo C.-H.; Totrov, Maxim M.; Bloomquist, Jeffrey R.; Carlier, Paul R.

    2015-01-01

    To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification. PMID:25684426

  11. Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents.

    PubMed

    Pisani, Leonardo; Farina, Roberta; Catto, Marco; Iacobazzi, Rosa Maria; Nicolotti, Orazio; Cellamare, Saverio; Mangiatordi, Giuseppe Felice; Denora, Nunzio; Soto-Otero, Ramon; Siragusa, Lydia; Altomare, Cosimo Damiano; Carotti, Angelo

    2016-07-28

    Aiming at modulating two key enzymatic targets for Alzheimer's disease (AD), i.e., acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), a series of multitarget ligands was properly designed by linking the 3,4-dimethylcoumarin scaffold to 1,3- and 1,4-substituted piperidine moieties, thus modulating the basicity to improve the hydrophilic/lipophilic balance. After in vitro enzymatic inhibition assays, multipotent inhibitors showing potencies in the nanomolar and in the low micromolar range for hMAO B and eeAChE, respectively, were prioritized and evaluated in human SH-SY5Y cell-based models for their cytotoxicity and neuroprotective effect against oxidative toxins (H2O2, rotenone, and oligomycin-A). The present study led to the identification of a promising multitarget hit compound (5b) exhibiting high hMAO B inhibitory activity (IC50 = 30 nM) and good MAO B/A selectivity (selectivity index, SI = 94) along with a micromolar eeAChE inhibition (IC50 = 1.03 μM). Moreover, 5b behaves as a water-soluble, brain-permeant neuroprotective agent against oxidative insults without interacting with P-gp efflux system. PMID:27347731

  12. Insect-specific irreversible inhibitors of acetylcholinesterase in pests including the bed bug, the eastern yellowjacket, German and American cockroaches, and the confused flour beetle.

    PubMed

    Polsinelli, Gregory A; Singh, Sanjay K; Mishra, Rajesh K; Suranyi, Robert; Ragsdale, David W; Pang, Yuan-Ping; Brimijoin, Stephen

    2010-09-01

    Insecticides directed against acetylcholinesterase (AChE) are facing increased resistance among target species as well as increasing concerns for human toxicity. The result has been a resurgence of disease vectors, insects destructive to agriculture, and residential pests. We previously reported a free cysteine (Cys) residue at the entrance to the AChE active site in some insects but not higher vertebrates. We also reported Cys-targeting methanethiosulfonate molecules (AMTSn), which, under conditions that spared human AChE, caused total irreversible inhibition of aphid AChE, 95% inhibition of AChE from the malaria vector mosquito (Anopheles gambia), and >80% inhibition of activity from the yellow fever mosquito (Aedes aegypti) and northern house mosquito (Culex pipiens). We now find the same compounds inhibit AChE from cockroaches (Blattella germanica and Periplaneta americana), the flour beetle (Tribolium confusum), the multi-colored Asian ladybird beetle (Harmonia axyridis), the bed bug (Cimex lectularius), and a wasp (Vespula maculifrons), with IC(50) values of approximately 1-11muM. Our results support further study of Cys-targeting inhibitors as conceptually novel insecticides that may be free of resistance in a range of insect pests and disease vectors and, compared with current compounds, should demonstrate much lower toxicity to mammals, birds, and fish. PMID:20109441

  13. Nicotinic receptor-dependent and -independent effects of galantamine, an acetylcholinesterase inhibitor, on the non-neuronal acetylcholine system in C2C12 cells.

    PubMed

    Oikawa, Shino; Mano, Asuka; Iketani, Mitsue; Kakinuma, Yoshihiko

    2015-11-01

    We previously reported that satellite cells possess the ability to produce angiogenic factors, including fibroblast growth factor (FGF)-2 and vascular endothelial growth factor (VEGF) in vivo. However, whether C2C12 cells possess a non-neuronal cholinergic system (NNCS) or non-neuronal ACh (NNA) remains to be studied; therefore, we investigated the system using C2C12 cells and its regulatory mechanisms. C2C12 cells synthesized ACh, the level of which was comparable with that of cardiomyocytes, and the synthesis was augmented by the acetylcholinesterase inhibitor galantamine. The ChAT promoter activity was upregulated by nicotine or galantamine, partly through nicotinic receptors for both agents as well as through a non-nicotinic receptor pathway for galantamine. Further, VEGF secretion by C2C12 cells was also increased by nicotine or galantamine through nicotinic receptors as well as partly through non-nicotinic pathways in the case of galantamine. These results suggest that C2C12 cells are equipped with NNCS or NNA, which is positively regulated through nicotinic or non-nicotinic pathways, particularly in the case of galantamine. These results provide a novel concept that myogenic cells expressing NNA can be a therapeutic target for regulating angiogenic factor synthesis. PMID:25979761

  14. Pre- and post-treatment effect of physostigmine on soman-inhibited human erythrocyte and muscle acetylcholinesterase in vitro

    SciTech Connect

    Herkert, N.M.; Schulz, S.; Wille, T.; Thiermann, H.; Hatz, R.A.; Worek, F.

    2011-05-15

    Standard treatment of organophosphorus (OP) poisoning includes administration of an antimuscarinic (e.g., atropine) and of an oxime-based reactivator. However, successful oxime treatment in soman poisoning is limited due to rapid aging of phosphylated acetylcholinesterase (AChE). Hence, the inability of standard treatment procedures to counteract the effects of soman poisoning resulted in the search for alternative strategies. Recently, results of an in vivo guinea pig study indicated a therapeutic effect of physostigmine given after soman. The present study was performed to investigate a possible pre- and post-treatment effect of physostigmine on soman-inhibited human AChE given at different time intervals before or after perfusion with soman by using a well-established dynamically working in vitro model for real-time analysis of erythrocyte and muscle AChE. The major findings were that prophylactic physostigmine prevented complete inhibition of AChE by soman and resulted in partial spontaneous recovery of the enzyme by decarbamylation. Physostigmine given as post-treatment resulted in a time-dependent reduction of the protection from soman inhibition and recovery of AChE. Hence, these date indicate that physostigmine given after soman does not protect AChE from irreversible inhibition by the OP and that the observed therapeutic effect of physostigmine in nerve agent poisoning in vivo is probably due to other factors.

  15. A DKP Cyclo(L-Phe-L-Phe) Found in Chicken Essence Is a Dual Inhibitor of the Serotonin Transporter and Acetylcholinesterase

    PubMed Central

    Tsuruoka, Nobuo; Beppu, Yoshinori; Koda, Hirofumi; Doe, Nobutaka; Watanabe, Hiroshi; Abe, Keiichi

    2012-01-01

    Diketopiperazines (DKPs) are naturally-occurring cyclic dipeptides with a small structure and are found in many organisms and in large amounts in some foods and beverages. We found that a chicken essence beverage, which is popular among Southeast Asians as a traditional remedy and a rich source of DKPs, inhibited the serotonin transporter (SERT) and suppressed serotonin uptake from rat brain synaptosomes, which prompted us to isolate and identify the active substance(s). We purified a SERT inhibitor from the chicken essence beverage and identified it as the DKP cyclo(L-Phe-L-Phe). Interestingly, it was a naturally occurring dual inhibitor that inhibited both SERT and acetylcholinesterase (AChE) in vitro. The DKP increased extracellular levels of the cerebral monoamines serotonin, norepinephrine, and dopamine in the medial prefrontal cortex and acetylcholine in the ventral hippocampus of freely moving rats when administered orally. Moreover, cyclo(L-Phe-L-Phe) significantly shortened escape latency in the water maze test in depressed mice previously subjected to a repeated open-space swimming task, which induces a depression-like state. Cyclo(L-Phe-L-Phe) also significantly improved accuracy rates in a radial maze test in rats and increased step-through latencies in a passive avoidance test in mice with scopolamine-induced amnesia. These animal test results suggest that cyclo(L-Phe-L-Phe), which is present abundantly in some foods such as chicken essence, may abrogate the onset of depression and, thus, contribute to preventing the development of Alzheimer’s disease and other dementia, because senile depression is a risk factor for dementia. PMID:23209830

  16. Carbon dots-assisted colorimetric and fluorometric dual-mode protocol for acetylcholinesterase activity and inhibitors screening based on the inner filter effect of silver nanoparticles.

    PubMed

    Zhao, Dan; Chen, Chuanxia; Sun, Jian; Yang, Xiurong

    2016-06-01

    In this work, we proposed an original and versatile dual-readout (colorimetric and fluorometric) protocol by means of silver nanoparticles (AgNPs) and fluorescent carbon dots (CDs), which was amenable to rapid, ultrasensitive assay of acetylcholinesterase (AChE) activity and its inhibitors. The sensing mechanism was based on the non-fluorescence state of CDs resulting from the inner filter effect (IFE) of AgNPs and the specific AChE-catalyzed hydrolysis of acetylthiocholine (ATCh) into thiocholine (TCh). Herein, the generated positively-charged and thiol-bearing TCh at trace concentration levels could trigger the aggregation of AgNPs through the well-known electrostatic and Ag-SH interactions, thereby turning the sensing solutions grey and recovering the IFE-quenched fluorescence simultaneously. Furthermore, the existence of IFE mechanism was conceivably confirmed by combining the zeta potentials, fluorescence spectra, UV-vis spectra, fluorescence lifetime and TEM measurements. As far as we know, the present study has reported the first dual-mode proposal for assessing AChE activity by using a CDs-based IFE sensing strategy, where the detection limit was as low as 0.021 mU mL(-1) and 0.016 mU mL(-1) by colorimetric and fluorometric measurements, respectively. On the other hand, the proposed assay was feasible to screen AChE inhibitors such as tacrine and carbaryl. Meanwhile, this rationally designed dual-mode sensing platform featured simplicity, rapidity, flexibility and diversity, which was demonstrated by the quantitative detection of spiked carbaryl in apple juice samples with satisfactory results. PMID:27099097

  17. Aromatase inhibitors in the treatment of endometriosis

    PubMed Central

    Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  18. Aromatase inhibitors in the treatment of endometriosis.

    PubMed

    Słopień, Radosław; Męczekalski, Błażej

    2016-03-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  19. Molecular Docking Guided Comparative GFA, G/PLS, SVM and ANN Models of Structurally Diverse Dual Binding Site Acetylcholinesterase Inhibitors.

    PubMed

    Gupta, Shikhar; Fallarero, Adyary; Vainio, Mikko J; Saravanan, P; Santeri Puranen, J; Järvinen, Päivi; Johnson, Mark S; Vuorela, Pia M; Mohan, C Gopi

    2011-08-01

    Recently discovered 42 AChE inhibitors binding at the catalytic and peripheral anionic site were identified on the basis of molecular docking approach, and its comparative quantitative structure-activity relationship (QSAR) models were developed. These structurally diverse inhibitors were obtained by our previously reported high-throughput in vitro screening technique using 384-well plate's assay based on colorimetric method of Ellman. QSAR models were developed using (i) genetic function algorithm, (ii) genetic partial least squares, (iii) support vector machine and (iv) artificial neural network techniques. The QSAR model robustness and significance was critically assessed using different cross-validation techniques on test data set. The generated QSAR models using thermodynamic, electrotopological and electronic descriptors showed that nonlinear methods are more robust than linear methods, and provide insight into the structural features of compounds that are important for AChE inhibition.

  20. KH-30 Parafin Inhibitor Treatment

    SciTech Connect

    Rochelle, J.

    2001-09-30

    United Energy Corporation (UNRG) and the U.S. Department of Energy personnel tested KH-30 at the Rocky Mountain Oilfield Testing Center (RMOTC) outside Casper, Wyoming on two separate occasions. KH-30 is a non-toxic, non-hazardous product, which combines the functions of a solvent dispersant, crystal modifier and inhibitor into a single solution. The first test was held in March of 2001, wherein five wells were treated with a mixture of KH-30 and brine water, heated to 180 degrees F. No increase in production was attained in these tests. In June, 2001, three shallow, low pressure RMOTC wells with 30 years of production were treated with a mixture of 40% KH-30 and 60% diesel. Increases were seen in three wells. The wells then returned to their original rates.

  1. From Bitopic Inhibitors to Multitarget Drugs for the Future Treatment of Alzheimer's Disease.

    PubMed

    Pérez, Daniel I; Martínez, Ana; Gil, Carmen; Campillo, Nuria E

    2015-01-01

    Dementia is one of the main causes of the disease burden in developed regions. According to the World Health Organization (WHO), it will become the world's second leading cause of death by the middle of the century, overtaking cancer. This will have a dramatic impact on medical care, and have important social and economic implications, unless more effective preventive procedures or treatments become available. Alzheimer's disease (AD) is the most common cause of dementia, accounting for approximately 50-75% of all dementias worldwide, followed by vascular dementia, mixed dementia, and Lewy body dementia. Currently, acetylcholinesterase (AChE) inhibitors, such as donepezil, rivastigmine and galantamine are used to treat mild to moderate AD. An alternative therapy for severe AD is memantine, an antagonist of the NMDA-subtype of glutamate receptors. However, these drugs provide only temporary symptom improvement, and do not alter disease progression, except temporarily in some patients. In recent years different approaches have been developed to provide a more effective treatment for AD. These approached include the discovery of emerging targets and new drugs aiming at a single target, but given the complexity of the disease, different targets may need to be engaged simultaneously. New strategies have explored bitopic inhibitors, for example a single drug that acts on different sites of the acetylcholinesterase enzyme to produce at least two different activities, and multitarget drugs that act on multiple therapeutic targets. In this review, we explore the journey from a bitopic inhibitor strategy to multitarget drugs for the future treatment of AD. PMID:26264921

  2. Development of 3D-QSAR Model for Acetylcholinesterase Inhibitors Using a Combination of Fingerprint, Molecular Docking, and Structure-Based Pharmacophore Approaches.

    PubMed

    Lee, Sehan; Barron, Mace G

    2015-11-01

    Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in animals, has been used as a target for drugs and pesticides. With the increasing availability of AChE crystal structures, with or without ligands bound, structure-based approaches have been successfully applied to AChE inhibitors (AChEIs). The major limitation of these approaches has been the small applicability domain due to the lack of structural diversity in the training set. In this study, we developed a 3 dimensional quantitative structure-activity relationship (3D-QSAR) for inhibitory activity of 89 reversible and irreversible AChEIs including drugs and insecticides. A 3D-fingerprint descriptor encoding protein-ligand interactions was developed using molecular docking and structure-based pharmacophore to rationalize the structural requirements responsible for the activity of these compounds. The obtained 3D-QSAR model exhibited high correlation value (R(2) = 0.93) and low mean absolute error (MAE = 0.32 log units) for the training set (n = 63). The model was predictive across a range of structures as shown by the leave-one-out cross-validated correlation coefficient (Q(2) = 0.89) and external validation results (n = 26, R(2) = 0.89, and MAE = 0.38 log units). The model revealed that the compounds with high inhibition potency had proper conformation in the active site gorge and interacted with key amino acid residues, in particular Trp84 and Phe330 at the catalytic anionic site, Trp279 at the peripheral anionic site, and Gly118, Gly119, and Ala201 at the oxyanion hole. The resulting universal 3D-QSAR model provides insight into the multiple molecular interactions determining AChEI potency that may guide future chemical design and regulation of toxic AChEIs.

  3. Clinical Significance of Repetitive Compound Muscle Action Potentials in Patients with Myasthenia Gravis: A Predictor for Cholinergic Side Effects of Acetylcholinesterase Inhibitors

    PubMed Central

    Lee, Hyo Eun; Kim, Yool-hee; Kim, Seung Min

    2016-01-01

    Background and Purpose Acetylcholinesterase inhibitors (AChEIs) are widely used to treat myasthenia gravis (MG). Although AChEIs are usually tolerated well, some MG patients suffer from side effects. Furthermore, a small proportion of MG patients show cholinergic hypersensitivity and cannot tolerate AChEIs. Because repetitive compound muscle action potentials (R-CMAPs) are an electrophysiologic feature of cholinergic neuromuscular hyperactivity, we investigated the clinical characteristics of MG patients with R-CMAPs to identify their clinical usefulness in therapeutic decision-making. Methods We retrospectively reviewed the clinical records and electrodiagnostic findings of MG patients who underwent electrodiagnostic studies and diagnostic neostigmine testing (NT). Results Among 71 MG patients, 9 could not tolerate oral pyridostigmine bromide (PB) and 17 experienced side effects of PB. R-CMAPs developed in 24 patients after NT. The highest daily dose of PB was lower in the patients with R-CMAPs (240 mg/day vs. 480 mg/day, p<0.001). The frequencies of PB intolerance and side effects were higher in the patients with R-CMAPs than in those without R-CMAPs [37.5% vs. 0% (p<0.001) and 45.8% vs. 12.8% (p=0.002), respectively]. The MG Foundation of America postintervention status did not differ significantly between MG patients with and without R-CMAPs, and the response to immunotherapy was also good in both groups. Conclusions Side effects of and intolerance to AChEIs are more common in MG patients with R-CMAPs than in those without R-CMAPs. AChEIs should be used carefully in MG patients with R-CMAPs. The presence of R-CMAPs after NT may be a good indicator of the risks of PB side effects and intolerance.

  4. Gold nanoclusters-Cu(2+) ensemble-based fluorescence turn-on and real-time assay for acetylcholinesterase activity and inhibitor screening.

    PubMed

    Sun, Jian; Yang, Xiurong

    2015-12-15

    Based on the specific binding of Cu(2+) ions to the 11-mercaptoundecanoic acid (11-MUA)-protected AuNCs with intense orange-red emission, we have proposed and constructed a novel fluorescent nanomaterials-metal ions ensemble at a nonfluorescence off-state. Subsequently, an AuNCs@11-MUA-Cu(2+) ensemble-based fluorescent chemosensor, which is amenable to convenient, sensitive, selective, turn-on and real-time assay of acetylcholinesterase (AChE), could be developed by using acetylthiocholine (ATCh) as the substrate. Herein, the sensing ensemble solution exhibits a marvelous fluorescent enhancement in the presence of AChE and ATCh, where AChE hydrolyzes its active substrate ATCh into thiocholine (TCh), and then TCh captures Cu(2+) from the ensemble, accompanied by the conversion from fluorescence off-state to on-state of the AuNCs. The AChE activity could be detected less than 0.05 mU/mL within a good linear range from 0.05 to 2.5 mU/mL. Our proposed fluorescence assay can be utilized to evaluate the AChE activity quantitatively in real biological sample, and furthermore to screen the inhibitor of AChE. As far as we know, the present study has reported the first analytical proposal for sensing AChE activity in real time by using a fluorescent nanomaterials-Cu(2+) ensemble or focusing on the Cu(2+)-triggered fluorescence quenching/recovery. This strategy paves a new avenue for exploring the biosensing applications of fluorescent AuNCs, and presents the prospect of AuNCs@11-MUA-Cu(2+) ensemble as versatile enzyme activity assay platforms by means of other appropriate substrates/analytes. PMID:26141104

  5. Development of 3D-QSAR Model for Acetylcholinesterase Inhibitors Using a Combination of Fingerprint, Molecular Docking, and Structure-Based Pharmacophore Approaches.

    PubMed

    Lee, Sehan; Barron, Mace G

    2015-11-01

    Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in animals, has been used as a target for drugs and pesticides. With the increasing availability of AChE crystal structures, with or without ligands bound, structure-based approaches have been successfully applied to AChE inhibitors (AChEIs). The major limitation of these approaches has been the small applicability domain due to the lack of structural diversity in the training set. In this study, we developed a 3 dimensional quantitative structure-activity relationship (3D-QSAR) for inhibitory activity of 89 reversible and irreversible AChEIs including drugs and insecticides. A 3D-fingerprint descriptor encoding protein-ligand interactions was developed using molecular docking and structure-based pharmacophore to rationalize the structural requirements responsible for the activity of these compounds. The obtained 3D-QSAR model exhibited high correlation value (R(2) = 0.93) and low mean absolute error (MAE = 0.32 log units) for the training set (n = 63). The model was predictive across a range of structures as shown by the leave-one-out cross-validated correlation coefficient (Q(2) = 0.89) and external validation results (n = 26, R(2) = 0.89, and MAE = 0.38 log units). The model revealed that the compounds with high inhibition potency had proper conformation in the active site gorge and interacted with key amino acid residues, in particular Trp84 and Phe330 at the catalytic anionic site, Trp279 at the peripheral anionic site, and Gly118, Gly119, and Ala201 at the oxyanion hole. The resulting universal 3D-QSAR model provides insight into the multiple molecular interactions determining AChEI potency that may guide future chemical design and regulation of toxic AChEIs. PMID:26202430

  6. Synthesis of α, β-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: characterization, molecular modeling, QSAR studies and effect against amyloid β-induced cytotoxicity.

    PubMed

    Bukhari, Syed Nasir Abbas; Jantan, Ibrahim; Masand, Vijay H; Mahajan, Devidas T; Sher, Muhammad; Naeem-ul-Hassan, M; Amjad, Muhammad Wahab

    2014-08-18

    A series of novel carbonyl compounds was synthesized by a simple, eco-friendly and efficient method. These compounds were screened for anti-oxidant activity, in vitro cytotoxicity and for inhibitory activity for acetylcholinesterase and butyrylcholinesterase. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. Among them, compound 14 exhibited strong free radical scavenging activity (18.39 μM) while six compounds (1, 3, 4, 13, 14, and 19) were found to be the most protective against Aβ-induced neuronal cell death in PC12 cells. Compounds 4 and 14, containing N-methyl-4-piperidone linker, showed high acetylcholinesterase inhibitory activity as compared to reference drug donepezil. Molecular docking and QSAR (Quantitative Structure-Activity Relationship) studies were also carried out to determine the structural features that are responsible for the acetylcholinesterase and butyrylcholinesterase inhibitory activity.

  7. Effects of harmine, an acetylcholinesterase inhibitor, on spatial learning and memory of APP/PS1 transgenic mice and scopolamine-induced memory impairment mice.

    PubMed

    He, Dandan; Wu, Hui; Wei, Yue; Liu, Wei; Huang, Fei; Shi, Hailian; Zhang, Beibei; Wu, Xiaojun; Wang, Changhong

    2015-12-01

    Harmine, a β-carboline alkaloid present in Peganum harmala with a wide spectrum of pharmacological activities, has been shown to exert strong inhibition against acetylcholinesterase in vitro. However, whether it can rescue the impaired cognition has not been elucidated yet. In current study, we examined its effects on scopolamine-induced memory impairment mice and APP/PS1 transgenic mice, one of the models for Alzheimer's disease, using Morris Water Maze test. In addition, whether harmine could penetrate blood brain barrier, interact with and inhibit acetylcholinesterase, and activate downstream signaling network was also investigated. Our results showed that harmine (20mg/kg) administered by oral gavage for 2 weeks could effectively enhance the spatial cognition of C57BL/6 mice impaired by intraperitoneal injection of scopolamine (1mg/kg). Meanwhile, long-term consumption of harmine (20mg/kg) for 10 weeks also slightly benefited the impaired memory of APP/PS1 mice. Furthermore, harmine could pass through blood brain barrier, penetrate into the brain parenchyma shortly after oral administration, and modulate the expression of Egr-1, c-Jun and c-Fos. Molecular docking assay disclosed that harmine molecule could directly dock into the catalytic active site of acetylcholinesterase, which was partially confirmed by its in vivo inhibitory activity on acetylcholinesterase. Taken together, all these results suggested that harmine could ameliorate impaired memory by enhancement of cholinergic neurotransmission via inhibiting the activity of acetylcholinesterase, which may contribute to its clinical use in the therapy of neurological diseases characterized with acetylcholinesterase deficiency.

  8. Reanalysis with optimized power of red blood cell acetylcholinesterase activity from a 1-year dietary treatment of dogs to chlorpyrifos.

    PubMed

    Mattsson, J L; Holden, L; Eisenbrandt, D L; Gibson, J E

    2001-03-01

    A no-observed-effect level (NOEL) of 0.1 mg/kg/day was reported for inhibition of red blood cell (RBC) acetylcholinesterase (AChE) in two groups of Beagle dogs fed chlorpyrifos (0, 0.01, 0.03, 0.1, 1 or 3 mg/kg/day) in the diet for 1 or 2 years (McCollister et al., Food Cosmet. Toxicol. 12 (1974) 45-61). The statistical analyses were by t-test that had low statistical power due to small sample sizes. Common time points for blood samples in both phases allowed a reanalysis of the grouped data over a 1-year time period. The reanalysis increased statistical power by increasing the sample size to n=14 from n=3 or 4, and decreasing the variance, by statistical step-by-step aggregation of the data from both phases, both sexes, and four sample periods. Factors retained in the ANOVA were dose, sex, and phase (sex-by-dose was not significant). Contrasts with one-sided t-tests indicated the 1 and 3 mg/kg/day groups had significantly inhibited RBC AChE (P<0.0001). At alpha=0.05, the uncorrected one-sided model had 80% power to detect a 12% decrease, 93% power for a 15% decrease, and 99.5% power for a 20% decrease in AChE activity. Overall, the reanalysis had high power to detect a clinically significant decrease in RBC AChE activity, and substantiated the original NOEL for chronic treatment of dogs to dietary chlorpyrifos at 0.1 mg/kg/day. PMID:11246135

  9. Galanthamine, an acetylcholine inhibitor, prevents prepulse inhibition deficits induced by adolescent social isolation or MK-801 treatment.

    PubMed

    Shao, Shuang; Li, Man; Du, Wei; Shao, Feng; Wang, Weiwen

    2014-11-17

    Adolescence is a critical period for neurodevelopment. MK-801 treatment and social isolation are important animal models for various neurodevelopmental disorders. Dysfunctions in the central cholinergic system are involved in creating the cognitive deficits observed in neurological diseases. In the present study, we aimed to investigate whether the acetylcholinesterase inhibitor galanthamine could reverse pre-cognitive prepulse inhibition (PPI) deficits and spatial learning deficits of adult rats in the Morris water maze. We induced these effects using either adolescent MK-801 treatment or social isolation from postnatal day (PND) 38-51. Our results showed that both adolescent social isolation and MK-801 treatment impaired PPI in adult rats, but neither had an effect on spatial learning. Furthermore, galanthamine injections over 7 days significantly enhanced PPI of normal rats and improved PPI disruption induced by adolescent pharmacological and rearing interventions. The results suggest that acetylcholinesterase inhibitors, such as galanthamine, might have the potential to improve pre-cognition in neurodevelopmental diseases by improving auditory sensory gating. PMID:25281804

  10. Development of 3D-QSAR model for acetylcholinesterase inhibitors using a combination of fingerprint, molecular docking, and structure-based pharmacophore approaches

    EPA Science Inventory

    Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in animals, has been used as a target for drugs and pesticides. With the increasing availability of AChE crystal structures, with or without ligands bound, structure-based appr...

  11. Development of a 3D-QSAR model for acetylcholinesterase inhibitors using a combination of fingerprint, docking, and structure-based pharmacophore approaches - Conference Abstract

    EPA Science Inventory

    Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in animals, has been used as a target for drugs and pesticides. With the increasing availability of AChE crystal structures, with or without ligands bound, structure-based appr...

  12. Acetylcholinesterase inhibitory properties of some benzoic acid derivatives

    NASA Astrophysics Data System (ADS)

    Yildiz, Melike; Kiliç, Deryanur; Ünver, Yaǧmur; Şentürk, Murat; Askin, Hakan; Küfrevioǧlu, Ömer Irfan

    2016-04-01

    Acetylcholinesterase (AChE) hydrolyses the neurotransmitter acetylcholine to acetic acid and choline. AChE inhibitors are used in treatment of several neurodegeneartive disorder and Alzheimer's disease. In the present study, inhibition of AChE with some benzoic acid derivatives were investigated. 3-Chloro-benzoic acid (1), 2-hydroxy-5-sulfobenzoic acid (2), 2-(sulfooxy) benzoic acid (3), 2-hydroxybenzoic acid (4), 2,3-dimethoxybenzoic (5), and 3,4,5-trimethoxybenzoic (6) were calculated IC50 values AChE enzyme. Kinetic investigations showed that similarly to AChE inhibitors. Benzoic acid derivatives (1-6) investigated are encouraging agents which may be used as lead molecules in order to derivative novel AChE inhibitors that might be useful in medical applications.

  13. Rapid binding of a cationic active site inhibitor to wild type and mutant mouse acetylcholinesterase: Brownian dynamics simulation including diffusion in the active site gorge.

    PubMed

    Tara, S; Elcock, A H; Kirchhoff, P D; Briggs, J M; Radic, Z; Taylor, P; McCammon, J A

    1998-12-01

    It is known that anionic surface residues play a role in the long-range electrostatic attraction between acetylcholinesterase and cationic ligands. In our current investigation, we show that anionic residues also play an important role in the behavior of the ligand within the active site gorge of acetylcholinesterase. Negatively charged residues near the gorge opening not only attract positively charged ligands from solution to the enzyme, but can also restrict the motion of the ligand once it is inside of the gorge. We use Brownian dynamics techniques to calculate the rate constant kon, for wild type and mutant acetylcholinesterase with a positively charged ligand. These calculations are performed by allowing the ligand to diffuse within the active site gorge. This is an extension of previously reported work in which a ligand was allowed to diffuse only to the enzyme surface. By setting the reaction criteria for the ligand closer to the active site, better agreement with experimental data is obtained. Although a number of residues influence the movement of the ligand within the gorge, Asp74 is shown to play a particularly important role in this function. Asp74 traps the ligand within the gorge, and in this way helps to ensure a reaction.

  14. Flavoring extracts of Hemidesmus indicus roots and Vanilla planifolia pods exhibit in vitro acetylcholinesterase inhibitory activities.

    PubMed

    Kundu, Anish; Mitra, Adinpunya

    2013-09-01

    Acetylcholinesterase inhibitors (AChEIs) are important for treatment of Alzheimer's disease and other neurological disorders. Search for potent and safe AChEIs from plant sources still continues. In the present work, we explored fragrant plant extracts that are traditionally used in flavoring foods, namely, Hemidesmus indicus and Vanilla planifolia, as possible sources for AChEI. Root and pod extracts of H. indicus and V. planifolia, respectively, produce fragrant phenolic compounds, 2-hydroxy-4-methoxybenzaldehyde (MBALD) and 4-hydroxy-3-methoxybenzaldehyde (vanillin). These methoxybenzaldehydes were shown to have inhibitory potential against acetylcholinesterase (AChE). Vanillin (IC50 = 0.037 mM) was detected as more efficient inhibitor than MBALD (IC50 = 0.047 mM). This finding was supported by kinetic analysis. Thus, plant-based food flavoring agents showed capacity in curing Alzheimer's disease and other neurological dysfunctions.

  15. Repetitive obidoxime treatment induced increase of red blood cell acetylcholinesterase activity even in a late phase of a severe methamidophos poisoning: A case report.

    PubMed

    Steinritz, Dirk; Eyer, Florian; Worek, Franz; Thiermann, Horst; John, Harald

    2016-02-26

    Accidental self-poisoning or deliberate use in suicidal intent of organophosphorus pesticides (OPP), which are widely used in agriculture, represent a health problem worldwide. Symptoms of poisoning are characterized by acute cholinergic crisis caused by inhibition of acetylcholinesterase. A 75-year-old male patient ingested 20ml of an OPP solution containing 10% methamidophos in suicidal intent. In the course of poisoning typical clinical symptoms of cholinergic crisis (miosis, bradycardia, hypotension, hypersalivation and impairment of neurologic status) were evident. Butyryl (plasma) cholinesterase (BChE) and red blood cell acetylcholinesterase (RBC-AChE) revealed decreased activities, thus specific treatment with the enzyme reactivator obidoxime was started. Inhibitory activity of the patient's plasma indicated significant amounts of persisting methamidophos in the circulation and was still found on day 4 after ingestion. Due to missing spontaneous breathing on day 6, obidoxime was administered again. Afterwards a significant increase of RBC-AChE activity was found. The patient was extubated on day 10 and a restitution ad integrum was achieved. In conclusion, obidoxime is a potent reactivator of OPP-inhibited AChE. A repetitive and prolonged administration of obidoxime should be considered in cases of severe methamidophos poisoning and should be tailored with an advanced analytical biomonitoring.

  16. Quantitative measurement of cerebral acetylcholinesterase using.

    PubMed

    Blomqvist, G; Tavitian, B; Pappata, S; Crouzel, C; Jobert, A; Doignon, I; Di Giamberardino, L

    2001-02-01

    [11C]physostigmine, an acetylcholinesterase inhibitor, has been shown to be a promising positron emission tomography ligand to quantify the cerebral concentration of the enzyme in animals and humans in vivo. Here, a quantitative and noninvasive method to measure the regional acetylcholinesterase concentration in the brain is presented. The method is based on the observation that the ratio between regions rich in acetylcholinesterase and white matter, a region almost entirely deprived of this enzyme, was found to become approximately constant after 20 to 30 minutes, suggesting that at late time points the uptake mainly contains information about the distribution volume. Taking the white matter as the reference region, a simplified reference tissue model, with effectively one reversible tissue compartment and three parameters, was found to give a good description of the data in baboons. One of these parameters, the ratio between the total distribution volumes in the target and reference regions, showed a satisfactory correlation with the acetylcholinesterase concentration measured postmortem in two baboon brains. Eight healthy male subjects were also analyzed and the regional enzyme concentrations obtained again showed a good correlation with the known acetylcholinesterase concentrations measured in postmortem studies of human brain.

  17. Controlled-release scale inhibitor for use in fracturing treatments

    SciTech Connect

    Powell, R.J.; Gdanski, R.D.; McCabe, M.A.; Buster, D.C.

    1995-11-01

    This paper describes results of laboratory and field testing of a solid, controlled-release scale inhibitor for use in fracturing treatments. Laboratory testing with a continuous flow apparatus has yielded inhibitor release rates under dynamic conditions. The inhibitor was tested to determine the minimum inhibitor concentration required to inhibit the formation of CaCO{sub 3}, CaSO{sub 4}, and BaSO{sub 4} scales in a brine. A model to predict the long-term release rate of the inhibitor was developed from data collected on the continuous flow apparatus. Data from treated wells will be compared with predictions of the model. Inhibitor release-rate testing in a continuous-flow apparatus shows that a solid, calcium-magnesium polyphosphate inhibitor has a sustained release profile. Release-rate testing shows that the inhibitor can be used up to 175 F. The inhibitor is compatible with both borate and zirconium crosslinked fracturing fluids and foamed fluids. The effective lifetime of the scale treatment can be predicted based on a model developed from laboratory data. The input variables required for the prediction include: temperature, water production, amount of inhibitor, minimum effective concentration of inhibitor for the specific brine. The model can be used to aid in the design of the scale inhibitor treatment.

  18. Virtual screening using MTiOpenScreen and PyRx 0,8 revealed ZINC95486216 as a human acetylcholinesterase inhibitor candidate

    NASA Astrophysics Data System (ADS)

    Sulistyo Dwi K., P.; Arindra Trisna, W.; Vindri Catur P., W.; Wijayanti, Erna; Ichsan, Mochammad

    2016-03-01

    One of the efforts to prevent Alzheimer's disease becomes more severe is by inhibiting the activity of Human acetylcholinesterase enzyme (PDB ID: 4BDT). In this study, virtual screening againts 885 natural compounds from AfroDB has been done using MTIOpenScreen and this step has been successful in identifying ZINC15121024 (-12,9) and ZINC95486216 (-12,7) as the top rank compounds. This data then strengthened by the results of second docking step using Autodock software that has been integrated in PyRx 0.8 software. From this stage, ZINC95486216 (-11,3 kcal/mol) is a compound with the most negative binding affinity compared with four Alzheimer's drugs that have been officially used to date including Rivastigmine (-6,3 Kcal/mol), Donepenzil (-7.9 kcal/mol), Galantamine (-8.4 kcal/mol), and Huprine W (-7.3 kcal/mol). In addition, based on the results of the 2D and 3D visualization using LigPlus and PyMol softwares, respectively, known that the five compounds above are equally capable of binding to several amino acids (Trp 286, Phe295, and Tyr341) located in the active site of Human Acetylcholinesterase enzyme.

  19. AOP description: Acetylcholinesterase inhibition

    EPA Science Inventory

    This adverse outcome pathway (AOP) leverages existing knowledge in the open literature to describe the linkage between inhibition of acetylcholinesterase (AChE) and the subsequent mortality resulting from impacts at cholinergic receptors. The AOP takes a chemical category approa...

  20. Acetylcholinesterase and butyrylcholinesterase--important enzymes of human body.

    PubMed

    Patocka, Jirí; Kuca, Kamil; Jun, Daniel

    2004-01-01

    The serine hydrolases and proteases are a ubiquitous group of enzymes that is fundamental to many critical life-functions. Human tissues have two distinct cholinesterase activities: acetylcholinesterase and butyrylcholinesterase. Acetylcholinesterase functions in the transmission of nerve impulses, whereas the physiological function of butyrylcholinesterase remains unknown. Acetylcholinesterase is one of the crucial enzymes in the central and peripheral nerve system. Organophosphates and carbamates are potent inhibitors of serine hydrolases and well suited probes for investigating the chemical reaction mechanism of the inhibition. Understanding the enzyme's chemistry is essential in preventing and/or treating organophosphate and carbamate poisoning as well as designing new medicaments for cholinergic-related diseases like as Alzheimer's disease.

  1. The acetylcholinesterase inhibitor rivastigmine does not alter total choices for methamphetamine, but may reduce positive subjective effects, in a laboratory model of intravenous self-administration in human volunteers.

    PubMed

    De La Garza, R; Mahoney, J J; Culbertson, C; Shoptaw, S; Newton, T F

    2008-04-01

    A human laboratory model of intravenous methamphetamine self-administration may facilitate study of putative treatments for methamphetamine addiction. We conducted a double-blind, placebo-controlled, between groups investigation of the acetylcholinesterase (AChE) inhibitor rivastigmine in non-treatment-seeking volunteers who met criteria for methamphetamine abuse or dependence. Safety and subjective effects data derived from days 1-10 of this protocol are described in a separate publication. In this report, we describe self-administration outcomes in participants randomized to treatment with rivastigmine (0 mg, N=7; 1.5 mg, N=6; 3 mg, N=9); data that were collected on days 11-15 of the inpatient protocol. On day 11, participants sampled two infusions of methamphetamine (0 and 30 mg, i.v.). On days 12-15, participants made ten choices each day to receive an infusion of either methamphetamine (3 mg, IV) or saline or a monetary alternative ($0.05-$16). The study design allowed for evaluation of differences in behavior on days in which infusions were performed by the physician (experimenter-administered) versus by the participant using a PCA pump (self-administered), and when monetary alternatives were presented in either ascending or descending sequence. The data show that rivastigmine (1.5 and 3 mg), as compared to placebo, did not significantly alter total choices for methamphetamine (p=0.150). Importantly, the number of infusion choices was greater when methamphetamine was available then when saline was available (p<0.0001), and the number of money choices was greater when saline was available then when methamphetamine was available (p<0.0001). The total number of choices for methamphetamine was not altered as a function of a participant's preferred route of methamphetamine use (p=0.57), and did not differ significantly whether they were experimenter-administered or self-administered (p=0.30). In addition, total choices for methamphetamine were similar made when

  2. Acetylcholinesterase inhibition by flavonoids from Agrimonia pilosa.

    PubMed

    Jung, Mankil; Park, Moonso

    2007-09-03

    In a bioassay-guided search for acetylcholinesterase (AChE) inhibitors from 180 medicinal plants, an ethyl acetate extract of whole plants of Agrimonia pilosa ledeb yielded tiliroside (1), 3-methoxy quercetin (2), quercitrin (3) and quercetin (4). We report herein for the first time that all four flavonol compounds showed significant inhibitory effects on AChE, particularly quercetin (4), which showed twice the activity of dehydroevodiamine (DHED).

  3. Discovery – Targeted Treatments and mTOR Inhibitors

    Cancer.gov

    Thanks to discovering the anticancer effects of mTOR inhibitors, cancer treatment for pNet, a rare type of pancreatic cancer, were revolutionized. Through clinical trials, NCI continues to investigate the life-saving potential of mTOR inhibitors.

  4. SHH inhibitors for the treatment of medulloblastoma.

    PubMed

    Samkari, Ayman; White, Jason; Packer, Roger

    2015-01-01

    Medulloblastoma is the most common malignant brain tumor of childhood. It is currently stratified into four molecular variants through the advances in transcriptional profiling. They include: wingless, sonic hedgehog (SHH), Group III, and Group IV. The SHH group is characterized by constitutive activation of the SHH signaling pathway, and genetically characterized by mutations in patched homolog 1 (PTCH1) or other downstream pathway mutations. SHH inhibitors have become of great clinical interest in treating SHH-driven medulloblastoma. Many inhibitors are currently in different stages of development, some already approved for other SHH-driven cancers, such as basal cell carcinoma. In vitro and in vivo medulloblastoma studies have shown efficacy and these findings have been translated into Phase I and II clinical trials. In this review, we present an overview of SHH medulloblastoma, as well as a discussion of currently available SHH inhibitors, and the challenges associated with their use. PMID:26027634

  5. The impact of memantine in combination with acetylcholinesterase inhibitors on admission of patients with Alzheimer's disease to nursing homes: cost-effectiveness analysis in France.

    PubMed

    Touchon, Jacques; Lachaine, Jean; Beauchemin, Catherine; Granghaud, Anna; Rive, Benoit; Bineau, Sébastien

    2014-11-01

    The costs associated with the care of Alzheimer's disease patients are very high, particularly those associated with nursing home placement. The combination of a cholinesterase inhibitor (ChEI) and memantine has been shown to significantly delay admission to nursing homes as compared to treatment with a ChEI alone. The objective of this cost-effectiveness analysis was to evaluate the economic impact of the concomitant use of memantine and ChEI compared to ChEI alone. Markov modelling was used in order to simulate transitions over time among three discrete health states (non-institutionalised, institutionalised and deceased). Transition probabilities were obtained from observational studies and French national statistics, utilities from a previous US survey and costs from French national statistics. The analysis was conducted from societal and healthcare system perspectives. Mean time to nursing home admission was 4.57 years for ChEIs alone and 5.54 years for combination therapy, corresponding to 0.98 additional years, corresponding to a gain in quality adjusted life years (QALYs) of 0.25. From a healthcare system perspective, overall costs were €98,609 for ChEIs alone and €90,268 for combination therapy, representing cost savings of €8,341. From a societal perspective, overall costs were €122,039 and €118,721, respectively, representing cost savings of €3,318. Deterministic and probabilistic (Monte Carlo simulations) sensitivity analyses indicated that combination therapy would be the dominant strategy in most scenarios. In conclusion, combination therapy with memantine and a ChEI is a cost-saving alternative compared to ChEI alone as it is associated with lower cost and increased QALYs from both a societal and a healthcare perspective.

  6. Effect of tissue-specific acetylcholinesterase inhibitor C-547 on α3β4 and αβεδ acetylcholine receptors in COS cells.

    PubMed

    Lindovský, Jiří; Petrov, Konstantin; Krůšek, Jan; Reznik, Vladimir S; Nikolsky, Eugeny E; Vyskočil, František

    2012-08-01

    The C-547 is the most effective muscle and tissue-specific anticholinesterase among alkylammonium derivatives of 6-methyluracil (ADEMS) acting in nanomolar concentrations on locomotor muscles but not on respiratory muscles, smooth muscles and heart and brain acetylcholine esterases (AChE). When applied systematically it could influence peripheral acetylcholine receptors. The aim of the present study was to investigate the effect of C-547 on rat α3β4 (ganglionic type) and αβεδ (muscle type) nicotinic receptors expressed in COS cells. Currents evoked by rapid application of acetylcholine or nicotine were recorded in whole-cell mode by electrophysiological patch-clamp technique 2-4 days after cell transfection by plasmids coding the α3β4 or αβεδ combination of receptor subunits. In cells sensitive to acetylcholine, the application of C-547 evoked no responses. When acetylcholine was applied during an already running application of C-547, acetylcholine responses were only inhibited at concentrations higher than 10(-7)M. This inhibition is not voltage-dependent, but is accompanied by an increased rate of desensitization. Thus in both types of receptors, effective doses are approximately 100 times higher than those inhibiting AChE in leg muscles and similar to those inhibiting respiratory diaphragm muscles and external intercostal muscles. These observations show that C-547 can be considered for symptomatic treatment of myasthenia gravis and other congenital myasthenic syndromes as an inhibitor of AChE in leg muscles at concentrations much lower than those inhibiting muscle and ganglion types of acetylcholine receptors.

  7. Kinetics and Molecular Docking Study of an Anti-diabetic Drug Glimepiride as Acetylcholinesterase Inhibitor: Implication for Alzheimer's Disease-Diabetes Dual Therapy.

    PubMed

    Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Naaz, Deeba; Shakil, Shazi; Ahmad, Adnan; Haneef, Mohd; Abuzenadah, Adel M

    2016-06-01

    At the present time, treatment of two most common degenerative disorders of elderly population i.e., Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD) is a major concern worldwide. As there are several evidences that proved strong linkages between these two disorders, the idea of using dual therapeutic agent for both the diseases might be considered as a good initiative. Earlier reports have revealed that oral anti-diabetic drugs such as peroxisome proliferator activated receptor γ (PPARγ) agonists (thiazolidinediones) when used in T2DM patients suffering from AD showed improved memory and cognition. However, the underlying mechanism still needs to be deciphered. Therefore, the present study was carried out to find whether glimepiride, an oral antidiabetic drug which is a PPARγ agonist could inhibit the activity of acetylcholine esterase (AChE) enzyme. Actually, AChE inhibitors seize the breakdown of acetylcholine which forms the main therapeutic strategy for AD. Here, glimepiride showed dose dependent inhibitory activity against AChE enzyme with IC50 value of 235 μM. Kinetic analysis showed competitive inhibition, which was verified by in silico docking studies. Glimepiride was found to interact with AChE enzyme at the same locus as that of substrate acetylcholine iodide (AChI). Interestingly, amino acid residues, Q71, Y72, V73, D74, W86, N87, Y124, S125, W286, F295, F297, Y337, F338 and Y341 of AChE were found to be common for 'glimepiride-AChE interaction' as well as 'AChI-AChE interaction'. Thus the present computational and kinetics study concludes that glimepiride and other thiazolidinediones derivatives could form the basis of future dual therapy against diabetes associated neurological disorders. PMID:26886763

  8. Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors

    PubMed Central

    2016-01-01

    Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides. PMID:27551784

  9. Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.

    PubMed

    Lockridge, Oksana; Norgren, Robert B; Johnson, Rudolph C; Blake, Thomas A

    2016-09-19

    Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides. PMID:27551784

  10. Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease.

    PubMed

    Parsons, Chris G; Danysz, Wojciech; Dekundy, Andrzej; Pulte, Irena

    2013-10-01

    This review describes the preclinical mechanisms that may underlie the increased therapeutic benefit of combination therapy-with the N-methyl-D-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)-for the treatment of Alzheimer's disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown significant efficacy as monotherapies for the treatment of AD. Furthermore, clinical observations indicate that their complementary mechanisms offer superior benefit as combination therapy. Based on the available literature, the authors have considered the preclinical mechanisms that could underlie such a combined approach. Memantine addresses dysfunction in glutamatergic transmission, while the AChEIs serve to increase pathologically lowered levels of the neurotransmitter acetylcholine. In addition, preclinical studies have shown that memantine has neuroprotective effects, acting to prevent glutamatergic over-stimulation and the resulting neurotoxicity. Interrelations between the glutamatergic and cholinergic pathways in regions of the brain that control learning and memory mean that combination treatment has the potential for a complex influence on disease pathology. Moreover, studies in animal models have shown that the combined use of memantine and the AChEIs can produce greater improvements in measures of memory than either treatment alone. As an effective approach in the clinical setting, combination therapy with memantine and an AChEI has been a welcome advance for the treatment of patients with AD. Preclinical data have shown how these drugs act via two different, but interconnected, pathological pathways, and that their complementary activity may produce greater effects than either drug individually.

  11. Nature: A Substantial Source of Auspicious Substances with Acetylcholinesterase Inhibitory Action

    PubMed Central

    Orhan, Ilkay Erdogan

    2013-01-01

    Acetylcholinesterase (AChE) (EC 3.1.1.7) is an important enzyme that breaks down of acetylcholine in synaptic cleft in neuronal junctions. Inhibition of AChE is associated with treatment of several diseases such as Alzheimer’s disease (AD), myasthenia gravis, and glaucoma as well as the mechanisms of insecticide and anthelmintic drugs. Several AChE inhibitors are available in clinical use currently for the treatment of AD; however, none of them has ability, yet, to seize progress of the disease. Consequently, an extensive research has been going on finding new AChE inhibitors. In this sense, natural inhibitors have gained great attention due to their encouraging effects toward AChE. In this review, promising candidate molecules with marked AChE inhibition from both plant and animal sources will be underlined. PMID:24381529

  12. Metalloprotein Inhibitors for the Treatment of Human Diseases.

    PubMed

    Yang, Yang; Hu, Xue-Qin; Li, Qing-Shan; Zhang, Xing-Xing; Ruan, Ban-Feng; Xu, Jun; Liao, Chenzhong

    2016-01-01

    Metalloproteins have attracted momentous attentions for the treatment of many human diseases, including cancer, HIV, hypertension, etc. This article reviews the progresses that have been made in the field of drug development of metalloprotein inhibitors, putting emphasis on the targets of carbonic anhydrase, histone deacetylase, angiotensin converting enzyme, and HIV-1 integrase. Many other important metalloproteins are also briefly discussed. The binding and coordination modes of different marketed metalloprotein inhibitors are stated, providing insights to design novel metal binding groups and further novel inhibitors for metalloproteins.

  13. ACE Inhibitor in the treatment of cutaneous and lymphatic sarcoidosis.

    PubMed

    Kaura, Vinod; Kaura, Samantha H; Kaura, Claire S

    2007-01-01

    Angiotensin-converting enzyme is used as a marker for sarcoid activity. We describe a case of remission of cutaneous and lymphatic sarcoidosis in a patient treated with an ACE inhibitor for congestive heart failure and hypertension; the remission has continued over 4 years of follow-up. Because this is a report of only one case, there is a possibility of sampling error. Whether the patient's remission in this case was a serendipitous spontaneous remission that happened to occur during ACE inhibitor therapy or whether ACE inhibitor therapy can play a role in the treatment of sarcoidosis needs to be determined in a large clinical trial.

  14. Effect of Moringa oleifera flower extract on larval trypsin and acetylcholinesterase activities in Aedes aegypti.

    PubMed

    Pontual, Emmanuel Viana; Napoleão, Thiago Henrique; Dias de Assis, Caio Rodrigo; de Souza Bezerra, Ranilson; Xavier, Haroudo Satiro; Navarro, Daniela Maria do Amaral Ferraz; Coelho, Luana Cassandra Breitenbach Barroso; Paiva, Patrícia Maria Guedes

    2012-03-01

    Aedes aegypti control is crucial to reducing dengue fever. Aedes aegypti larvae have developed resistance to organophosporous insecticides and the use of natural larvicides may help manage larval resistance by increasing elements in insecticide rotation programs. Here, we report on larvicidal activity of Moringa oleifera flower extract against A. aegypti L(1), L(2), L(3), and L(4) as well as the effect of flower extract on gut trypsin and whole-larval acetylcholinesterase from L(4.) In addition, the heated flower extract was investigated for larvicidal activity against L(4) and effect on larval gut trypsin. Moringa oleifera flower extract contains a proteinaceous trypsin inhibitor (M. oleifera flower trypsin inhibitor, MoFTI), triterpene (β-amyrin), sterol (β-sitosterol) as well as flavonoids (kaempferol and quercetin). Larvicidal activity was detected against L(2), L(3), and L(4) (LC(50) of 1.72%, 1.67%, and 0.92%, respectively). Flower extract inhibited L(4) gut trypsin (MoFTI K(i) = 0.6 nM) and did not affect acetylcholinesterase activity. In vivo assay showed that gut trypsin activity from L(4) treated with M. oleifera flower extract decreased over time (0-1,440 min) and was strongly inhibited (98.6%) after 310 min incubation; acetylcholinesterase activity was not affected. Thermal treatment resulted in a loss of trypsin inhibitor and larvicidal activities, supporting the hypothesis that flower extract contains a proteinaceous trypsin inhibitor that may be responsible for the deleterious effects on larval mortality. PMID:22392801

  15. Metabolism considerations for kinase inhibitors in cancer treatment

    PubMed Central

    Duckett, Derek R.; Cameron, Michael D.

    2010-01-01

    Importance of the field A concerted effort by the pharmaceutical industry over the last decade has led to the successful clinical development of protein kinase inhibitors as effective targeted therapies for certain cancers. Areas covered in this review This review details the eight small molecule kinase inhibitors that have been approved for the treatment of cancer in either the United States or Europe as of March 2010: imatinib, sorafenib, gefitinib, erlotinib, dasatinib, lapatinib, sunitinib and nilotinib. These eight compounds vary from the relatively specific inhibitor lapatinib, to the more promiscuous kinase inhibitors dasatinib and sunitinib. What the reader will gain A brief discussion on the biology of each inhibitor, selectivity over other kinases, and toxicity are provided. More detailed discussion on metabolism, drug transporters, drug-drug interactions, and the possible roles of metabolism in compound toxicity is provided for each compound. Take home message The majority of the currently approved kinase inhibitors are heavily influenced by drug transporters and significantly affected by CYP3A4 inhibitors/inducers. At least three, gefitinib, erlotinib, and dasatinib, are metabolized to form reactive metabolites capable of covalently binding biomolecules. PMID:20684746

  16. Aromatase Inhibitors in the Treatment of Short Stature.

    PubMed

    Hero, Matti

    2016-01-01

    Reports published in the 1990s of men with estrogen deficiency caused by defective aromatase or estrogen resistance due to a defective estrogen receptor α confirmed the crucial role of estrogen in bone maturation, closure of the epiphyses and cessation of statural growth. Based on these findings, it became reasonable to postulate that selective inhibition of estrogen synthesis with aromatase inhibitors could increase adult height by delaying bone maturation and prolonging the period of growth in males. To date, aromatase inhibitors have been employed in rare pediatric conditions associated with sex steroid excess, and in randomized controlled trials involving boys with short stature and/or constitutional delay of puberty. Findings from these randomized trials suggest that potent aromatase inhibitors increase predicted height, but final adult height data are scarce. Moreover, several safety issues remain inadequately studied. In this paper, published findings on the use of aromatase inhibitors in growth indications are reviewed with emphasis on treatment efficacy and safety.

  17. Acetylcholinesterases of Blood-feeding Flies and Ticks

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Acetylcholinesterase (AChE) is the biochemical target of organophosphate (OP) and carbamate pesticides for invertebrates, vertebrate nerve agents, and AChE inhibitors used to reduce effects of Alzheimer’s disease. Organophosphate pesticides (OPs) are widely used to control blood-feeding arthropods, ...

  18. Complexity of acetylcholinesterases in biting flies and ticks

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Acetylcholinesterase (AChE) inhibitors function as pesticides for invertebrates, vertebrate nerve agents, and medicine to reduce cognitive effects of Alzheimer’s disease. Organophosphate (OP) pesticides have been widely used to control biting flies and ticks, however, OP-resistance has compromised c...

  19. 1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies.

    PubMed

    Di Pietro, Ornella; Viayna, Elisabet; Vicente-García, Esther; Bartolini, Manuela; Ramón, Rosario; Juárez-Jiménez, Jordi; Clos, M Victòria; Pérez, Belén; Andrisano, Vincenza; Luque, F Javier; Lavilla, Rodolfo; Muñoz-Torrero, Diego

    2014-02-12

    A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (>11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities. PMID:24389509

  20. Old Tyrosine Kinase Inhibitors and Newcomers in Gastrointestinal Cancer Treatment.

    PubMed

    Erika, Giordani; Federica, Zoratto; Martina, Strudel; Anselmo, Papa; Luigi, Rossi; Marina, Minozzi; Davide, Caruso; Eleonora, Zaccarelli; Monica, Verrico; Silverio, Tomao

    2016-01-01

    Gastrointestinal cancer treatment is based more on molecular biology that has provided increasing knowledge about cancer pathogenesis on which targeted therapy is being developed. Precisely, targeted therapy is defined as a "type of treatment that uses drugs, such as monoclonal antibodies or tyrosine kinase inhibitors, to identify and attack specific cancer cells". Nowadays, the United States Food and Drug Administration has approved many targeted therapies for gastrointestinal cancer treatment, as many are in various phases of development as well. In a previous review we discussed the main monoclonal antibodies used and studied in gastrointestinal cancer. In addition to monoclonal antibodies, tyrosine kinase inhibitors represent another class of targeted therapy and following the approval of imatinib for gastrointestinal stromal tumours, other tyrosine kinase inhibitors have been approved for gastrointestinal cancers treatment such as sunitinib, regoragenib, sorafenib and erlotinib. Moving forward, the purpose of this review is to focus on the efficacy data of main tyrosine kinase inhibitors commonly used in the personalized treatment of each gastrointestinal tumour and to provide a comprehensive overview about experimental targeted therapies ongoing in this setting. PMID:26278713

  1. Old Tyrosine Kinase Inhibitors and Newcomers in Gastrointestinal Cancer Treatment.

    PubMed

    Giordani, Erika; Zoratto, Federica; Strudel, Martina; Papa, Anselmo; Rossi, Luigi; Minozzi, Marina; Caruso, Davide; Zaccarelli, Eleonora; Verrico, Monica; Tomao, Silverio

    2016-01-01

    Gastrointestinal cancer treatment is based more on molecular biology that has provided increasing knowledge about cancer pathogenesis on which targeted therapy is being developed. Precisely, targeted therapy is defined as a "type of treatment that uses drugs, such as monoclonal antibodies or tyrosine kinase inhibitors, to identify and attack specific cancer cells". Nowadays, the United States Food and Drug Administration has approved many targeted therapies for gastrointestinal cancer treatment, as many are in various phases of development as well. In a previous review we discussed the main monoclonal antibodies used and studied in gastrointestinal cancer. In addition to monoclonal antibodies, tyrosine kinase inhibitors represent another class of targeted therapy and following the approval of imatinib for gastrointestinal stromal tumours, other tyrosine kinase inhibitors have been approved for gastrointestinal cancers treatment such as sunitinib, regoragenib, sorafenib and erlotinib. Moving forward, the purpose of this review is to focus on the efficacy data of main tyrosine kinase inhibitors commonly used in the personalized treatment of each gastrointestinal tumour and to provide a comprehensive overview about experimental targeted therapies ongoing in this setting.

  2. Discovery of novel inhibitors for the treatment of glaucoma

    PubMed Central

    Cholkar, Kishore; Trinh, Hoang M.; Pal, Dhananjay; Mitra, Ashim K

    2015-01-01

    Introduction Glaucoma is a neurodegenerative disease with heterogeneous causes that result in retinal ganglionic cell death (RGC). The discovery of ocular anti-hypertensives has shifted glaucoma therapy, largely, from surgery to medical intervention. Indeed, several intraocular pressure (IOP) lowering drugs, with different mechanisms of action and RGC protective property, have been developed. Areas covered In this review, the authors discuss the main new class of kinase inhibitors used as glaucoma treatments, which lower IOP by enhancing drainage and/or lowering production of aqueous humor. The authors include novel inhibitors under preclinical evaluation and investigation for their anti-glaucoma treatment. Additionally, the authors look at treatments that are in clinics now and which may be available in the near future. Expert opinion Treatment of glaucoma remains challenging because the exact cause is yet to be delineated. Neuroprotection to the optic nerve head is undisputable. The novel ROCK inhibitors have the capacity to lower IOP and provide optic nerve and RGC protection. In particular, the S-isomer of roscovitine has the capacity to lower IOP and provide neuroprotection. Combinations of selected drugs, which can provide maximal and sustained IOP lowering effects as well as neuroprotection, are paramount to the prevention of glaucoma progression. In the near future, microRNA intervention may be considered as a potential therapeutic target. PMID:25575654

  3. Preliminary studies of acetylcholinesterase activity in the rat brain using N-phenylferrocenecarboxamide labelled by the technetium-99m.

    PubMed

    Mejri, Najoua; Said, Nadia Malek; Guizani, Sihem; Essouissi, Imen; Saidi, Mouldi

    2013-05-01

    There is currently great interest in developing radiolabeled substrates for acetylcholinesterase that would be useful in the in vivo imaging of patients with Alzheimer's disease. The reduction of acetylcholinesterase (AChE) activity in the brain has been measured in dementia disorders such as Alzheimer's disease and dementia with Lewy bodies using (11)C and (18)F-labeled acetylcholine analogues. Our aim was to develop a new 99mTc-labeled acetylcholine analogue: N-phenylferrocenecarboxamide labelled with technetium-99m (99mTc-TPCC) to study acetylcholinesterase activity. In vivo and in vitro studies demonstrated that the labelled compound was a substrate for acetylcholinesterase. The hydrolytic rate of this substrate was measured and the specificity was evaluated using the inhibitor BW 284 C51. In rat experiments, the 99mTc-TPCC showed desirable properties for studying the acetylcholinesterase in the rat brain: high hydrolytic rate and a moderate specificity of the substrate for acetylcholinesterase.

  4. Autophagy inhibitors as a potential antiamoebic treatment for Acanthamoeba keratitis.

    PubMed

    Moon, Eun-Kyung; Kim, So-Hee; Hong, Yeonchul; Chung, Dong-Il; Goo, Youn-Kyoung; Kong, Hyun-Hee

    2015-07-01

    Acanthamoeba cysts are resistant to extreme physical and chemical conditions. Autophagy is an essential pathway for encystation of Acanthamoeba cells. To evaluate the possibility of an autophagic Acanthamoeba encystation mechanism, we evaluated autophagy inhibitors, such as 3-methyladenine (3MA), LY294002, wortmannin, bafilomycin A, and chloroquine. Among these autophagy inhibitors, the use of 3MA and chloroquine showed a significant reduction in the encystation ratio in Acanthamoeba cells. Wortmannin also inhibited the formation of mature cysts, while LY294002 and bafilomycin A did not affect the encystation of Acanthamoeba cells. Transmission electron microscopy revealed that 3MA and wortmannin inhibited autophagy formation and that chloroquine interfered with the formation of autolysosomes. Inhibition of autophagy or autolysosome formation resulted in a significant block in the encystation in Acanthamoeba cells. Clinical treatment with 0.02% polyhexamethylene biguanide (PHMB) showed high cytopathic effects on Acanthamoeba trophozoites and cysts; however, it also revealed high cytopathic effects on human corneal epithelial cells. In this study, we investigated effects of the combination of a low (0.00125%) concentration of PHMB with each of the autophagy inhibitors 3MA, wortmannin, and chloroquine on Acanthamoeba and human corneal epithelial cells. These new combination treatments showed low cytopathic effects on human corneal cells and high cytopathic effects on Acanthamoeba cells. Taken together, these results provide fundamental information for optimizing the treatment of Acanthamoeba keratitis.

  5. Hsp90 Inhibitors for the Treatment of Chronic Myeloid Leukemia

    PubMed Central

    Khajapeer, Kalubai Vari; Baskaran, Rajasekaran

    2015-01-01

    Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (ABL) protooncogene of chromosome 9 with 5′ sequence of truncated break point cluster region (BCR) on chromosome 22. BCR-ABL is a functional oncoprotein p210 that exhibits constitutively activated tyrosine kinase causing genomic alteration of hematopoietic stem cells. BCR-ABL specific tyrosine kinase inhibitors (TKIs) successfully block CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Heat-shock proteins (Hsps) function as molecular chaperones facilitating proper folding of nascent polypeptides. Their increased expression under stressful conditions protects cells by stabilizing unfolded or misfolded peptides. Hsp90 is the major mammalian protein and is required by BCR-ABL for stabilization and maturation. Hsp90 inhibitors destabilize the binding of BCR-ABL protein thus leading to the formation of heteroprotein complex that is eventually degraded by the ubiquitin-proteasome pathway. Results of many novel Hsp90 inhibitors that have entered into various clinical trials are encouraging. The present review targets the current development in the CML treatment by availing Hsp90 specific inhibitors. PMID:26770832

  6. Irreversible thermal denaturation of Torpedo californica acetylcholinesterase.

    PubMed Central

    Kreimer, D. I.; Shnyrov, V. L.; Villar, E.; Silman, I.; Weiner, L.

    1995-01-01

    Thermal denaturation of Torpedo californica acetylcholinesterase, a disulfide-linked homodimer with 537 amino acids in each subunit, was studied by differential scanning calorimetry. It displays a single calorimetric peak that is completely irreversible, the shape and temperature maximum depending on the scan rate. Thus, thermal denaturation of acetylcholinesterase is an irreversible process, under kinetic control, which is described well by the two-state kinetic scheme N-->D, with activation energy 131 +/- 8 kcal/mol. Analysis of the kinetics of denaturation in the thermal transition temperature range, by monitoring loss of enzymic activity, yields activation energy of 121 +/- 20 kcal/mol, similar to the value obtained by differential scanning calorimetry. Thermally denatured acetylcholinesterase displays spectroscopic characteristics typical of a molten globule state, similar to those of partially unfolded enzyme obtained by modification with thiol-specific reagents. Evidence is presented that the partially unfolded states produced by the two different treatments are thermodynamically favored relative to the native state. PMID:8563632

  7. Examination of the change in returning molecular weight obtained during inhibitor squeeze treatments using polyacrylate based inhibitors

    SciTech Connect

    Graham, G.M.; Sorbie, K.S.

    1995-11-01

    Scale inhibitors based on small polyelectrolytes are often employed in oilfield scale prevention treatments. These materials are injected into the near-well formation of producers in a scale inhibitor squeeze treatment. When the well is brought back on production, the objective is for the return concentration level of the inhibitor in the produced brine to be at or above a certain threshold level, C{sub t}. This threshold level is the minimum inhibitor concentration required to prevent the formation of mineral carbonate or sulfate scales in that well. The squeeze lifetime depends strongly on the nature of the interaction between the inhibitor and the formation either through an adsorption or precipitation mechanism. Both adsorption and precipitation processes depend on the molecular weight of the scale inhibitor, as well as on a range of other factors. However, polymeric inhibitor species always display some degree of polydispersity (spread of molecular weight). In this paper, the authors examine the effects of molecular weight on adsorption/desorption phenomena for polyacrylate based inhibitor species. This work shows that, in the inhibitor effluent after a squeeze treatment, the molecular weight of the returning inhibitor may be different from that which was injected. For commercially available polymeric inhibitor species, they demonstrate using core floods that preferential retention of higher molecular weight components occurs and preferential desorption of lower molecular weight components is observed. This leads to a gradation in molecular weight in the return profile, which can lead to increased molecular weight components returning as the inhibitor concentration approaches the threshold level. The significance of this observation to field application of polymeric inhibitor species is discussed.

  8. The effect of memory blocking antibiotics and their analogs on acetylcholinesterase.

    PubMed

    Springer, A D; Schacht, J; Agranoff, B W

    1976-07-01

    The ability of antibiotics to inhibit acetylcholinesterase was measured in homogenates of goldfish brain. Puromycin aminonucleoside was the most potent inhibitor followed by puromycin, cycloheximide and acetoxycycloheximide. Puromycin effectively impaired retention of active-avoidance learning in goldfish when injected either immediately before or after training, while puromycin aminonucleoside did not regardless of injection time. These results suggest that the known amnestic effects of puromycin, cycloheximide and acetoxycycloheximide are not a consequence of interference with acetylcholinesterase.

  9. Current treatment of dyslipidaemia: PCSK9 inhibitors and statin intolerance.

    PubMed

    Koskinas, Konstantinos; Wilhelm, Matthias; Windecker, Stephan

    2016-01-01

    Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse events can occur and constitute an important barrier to maintaining long-term adherence to statin treatment. In patients who cannot tolerate statins, alternative treatments include switch to another statin, intermittent-dosage regimens and non-statin lipid-lowering medications. Nonetheless, a high proportion of statin-intolerant patients are unable to achieve recommended low-density lipoprotein (LDL) cholesterol goals, thereby resulting in substantial residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease implicated in LDL receptor degradation and plays a central role in cholesterol metabolism. In recent studies, PCSK9 inhibition by means of monoclonal antibodies achieved LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies, while maintaining a favourable safety profile. The efficacy and safety of the monoclonal antibodies alirocumab and evolocumab were confirmed in statin-intolerant patients, indicating that PCSK9 inhibitors represent an attractive treatment option in this challenging clinical setting. PCSK9 inhibitors recently received regulatory approval for clinical use and may be considered in properly selected patients according to current consensus documents, including patients with statin intolerance. In this review we summarise current evidence regarding diagnostic evaluation of statin-related adverse events, particularly statin-associated muscle symptoms, and we discuss current recommendations on the management of statin-intolerant patients. In view of emerging evidence of the efficacy and safety of PCSK9 inhibitors, we further discuss the role of monoclonal PCSK9 antibodies in the management of statin-intolerant hypercholesterolaemic patients. PMID:27400448

  10. Plant-insect coevolution and inhibition of acetylcholinesterase.

    PubMed

    Ryan, M F; Byrne, O

    1988-10-01

    The theory of plant-insect coevolution provides for diffuse coevolution and the expectation that plants evolve broad-spectrum chemical defenses with which some insects coevolve by detoxifying and using the compounds as host-location cues. Specific biochemical modes of action have been assigned to relatively few such defense chemicals and one major class, the terpenoids, is investigated here. Six terpenoids inhibited the enzyme acetylcholinesterase (derived from electric eel) and elicited the appropriate in vivo effects of insect paralysis and mortality. The diterpene gossypol was a reversible uncompetitive inhibitor. Five monoterpenes, representing a range of functional groups, were reversible competitive inhibitors apparently occupying at least the hydrophobic site of the enzyme's active center. Such data suggest the involvement of acetylcholinesterase in the coevolved insect response to terpenoids.

  11. Proteasome Inhibitors in the Treatment of Multiple Myeloma

    PubMed Central

    Shah, Jatin J.; Orlowski, Robert Z.

    2016-01-01

    Targeting intracellular protein turnover by inhibiting the ubiquitin-proteasome pathway as a strategy for cancer therapy is a new addition to our chemotherapeutic armamentarium, and has seen its greatest successes against multiple myeloma. The first-in-class proteasome inhibitor bortezomib was initially approved for treatment of patients in the relapsed/refractory setting as a single agent, and was recently shown to induce even greater benefits as part of rationally-designed combinations that overcome chemoresistance. Modulation of proteasome function is also a rational approach to achieve chemosensitization to other anti-myeloma agents, and bortezomib has now been incorporated into the front-line setting. Bortezomib-based induction regimens are able to achieve higher overall response rates and response qualities than was the case with prior standards of care, and unlike these older approaches, maintain efficacy in patients with clinically- and molecularly-defined high-risk disease. Second-generation proteasome inhibitors with novel properties, such as NPI-0052 and carfilzomib, are entering the clinical arena, and showing evidence of anti-myeloma activity. In this spotlight review, we provide an overview of the current state of the art use of bortezomib and other proteasome inhibitors against multiple myeloma, and highlight areas for future study that will further optimize our ability to benefit patients with this disease. PMID:19741722

  12. [Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension].

    PubMed

    Beltrán-Gámez, Miguel E; Sandoval-Zárate, Julio; Pulido, Tomás

    2015-01-01

    In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively. PMID:26047999

  13. [Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension].

    PubMed

    Beltrán-Gámez, Miguel E; Sandoval-Zárate, Julio; Pulido, Tomás

    2015-01-01

    In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively.

  14. Pharmacoeconomics of cholinesterase inhibitors in the treatment of Alzheimer's disease.

    PubMed

    Jönsson, Linus

    2003-01-01

    Cholinesterase inhibitors constitute one of few treatment options available for Alzheimer's disease, the most common cause of dementia. The modest effects and relatively high acquisition costs of these drugs make the health economics of dementia an important subject of study. Simulation models can be used to bring together existing data and make predictions of the long-term cost effectiveness of treatment. Most models have been built around cognitive function as a key parameter based on the observed relationship between cognitive function and costs of care. Patients with more severe disease attain higher total costs of care. Also, these patients have a higher share of formal care costs than do patients with mild disease, who are usually looked after by informal caregivers. The valuation of unpaid care is controversial, and the choice of method may affect results considerably. Another important issue is the measurement of health-related QOL in patients with Alzheimer's disease. The few existing studies have used proxy respondents to elicit utility weights in different disease states; however, this methodology has not been validated. It is likely that the increased drug costs incurred by the use of cholinesterase inhibitors will be offset (at least partly) by savings in other healthcare costs. However, these results should be viewed as preliminary, since we are still awaiting data from long-term follow-up studies. Also, the value of treatment for patients and caregivers in terms of QOL improvements has yet to be established. PMID:13129415

  15. Disulfide bonds of acetylcholinesterase

    SciTech Connect

    MacPhee-Quigley, K.; Vedvick, T.; Taylor, P.; Taylor, S.

    1986-05-01

    The positions of the inter- and intrasubunit disulfide bridges were established for the 11S form of acetylcholinesterase (AChE) isolated from Torpedo californica. A major form of AChE localized within the basal lamina of the synapse is a dimensionally asymmetric molecule which contains either two (13S) or three (17S) sets of catalytic subunits linked to collagenous and non-collagenous structural subunits. Limited proteolysis yields a tetramer of catalytic subunits which sediments at 11S. Each catalytic subunit contains 8 cysteine residues. Initially, these Cys residues were identified following trypsin digestion of the reduced protein alkylated with (/sup 14/C)-iodoacetate. Peptides were resolved by gel filtration followed by reverse phase HPLC. To determine the disulfide bonding profile, native non-reduced 11S AChE was treated with a fluorescent, sulfhydryl-specific reagent, monobromobimane, prior to proteolytic digestion. One fluorescent Cys peptide was identified indicating that a single sulfhydryl residue was present in its reduced form. Three pairs of disulfide bonded peptides were identified, sequenced, and localized in the polypeptide chain. The Cys residue that is located in the C-terminal tryptic peptide was disulfide bonded to an identical peptide and thus forms the intersubunit crosslink. Finally, the cysteine positions have been compared with the sequence of the homologous protein, thyroglobulin. Both likely share a common pattern of folding.

  16. Model-based treatment optimization of a novel VEGFR inhibitor

    PubMed Central

    Keizer, Ron J.; Gupta, Anubha; Shumaker, Robert; Beijnen, Jos H.; Schellens, Jan H. M.; Huitema, Alwin D. R.

    2012-01-01

    AIM To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK–PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment. METHODS A previously developed PK–PD model for lenvatinib (E7080) was updated and parameters were re-estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de-escalation. Additionally, a within-patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred. RESULTS Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day−1. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day−1, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%). CONCLUSIONS The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE-guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome. PMID:22295876

  17. Treatment of young patients with lupus nephritis using calcineurin inhibitors

    PubMed Central

    Tanaka, Hiroshi; Tsuruga, Kazushi; Aizawa-Yashiro, Tomomi; Watanabe, Shojiro; Imaizumi, Tadaatsu

    2012-01-01

    Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contributed to a favorable outcome in children and adolescents with systemic lupus erythematosus (SLE). Nevertheless, we believe that a more effective and less toxic treatment is needed to attain an optimal control of the activity of lupus nephritis. Recent published papers and our experiences regarding treatment of young patients with lupus nephritis using calcineurin inhibitors are reviewed. Although it has been reported that intermittent monthly pulses of intravenous cyclophosphamide (IVCY) are effective for preserving renal function in adult patients, CPA is a potent immunosuppressive agent that induces severe toxicity, including myelo- and gonadal toxicity, and increases the risk of secondary malignancy. Thus, treatment for controlling lupus nephritis activity, especially in children and adolescents, remains challenging. Cyclosporine A (CsA) and tacrolimus (Tac) are T-cell-specific calcineurin inhibitors that prevent the activation of helper T cells, thereby inhibiting the transcription of the early activation genes of interleukin (IL)-2 and suppressing T cell-induced activation of tumor necrosis factor-α, IL-1β and IL-6. Therefore, both drugs, which we believe may be less cytotoxic, are attractive therapeutic options for young patients with lupus nephritis. Recently, a multidrug regimen of prednisolone (PDN), Tac, and mycophenolate mofetile (MMF) has been found effective and relatively safe in adult lupus nephritis. Since the mechanisms of action of MMF and Tac are probably complementary, multidrug therapy for lupus nephritis may be useful. We propose as an alternative to IVCY, a multidrug therapy with mizoribine, which acts very similarly to MMF, and Tac, which has a different mode of action, combined with PDN for pediatric-onset lupus nephritis. We also believe that a multidrug therapy including CsA and

  18. Potential role of aromatase inhibitors in the treatment of endometriosis.

    PubMed

    Abu Hashim, Hatem

    2014-01-01

    Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5%-10% of reproductive-age women, with a prevalence of 5%-50% in infertile women and >33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs) are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol. Thereby, AIs represent an appealing medical option for the management of different aspects of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, mainly pain and infertility. Notably, several studies have demonstrated that the combination of AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing hormone analogs can be used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory to other medical or surgical treatment. Some case reports have shown promising results in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. However, few studies are available regarding the use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosis-associated infertility are needed to clarify its effect. The safety of AIs for ovulation induction or superovulation has generated a lively discussion

  19. [Arteriosclerosis obliterans. Treatment with angiotensin-converting enzyme inhibitors].

    PubMed

    Orea, A; Valdés, R; Niebla, L; Rivas, R; Camacho, B

    1990-01-01

    We compare the effects of two of the main angiotensin convertase enzyme inhibitors, captopril and enalapril, aiming to evaluate their effects in the arterial circulation performance, micro-circulation, and changes in regional blood flow, assuming their property of lowering the angiotensin II blood levels, a very strong peripheral vasoconstrictor. We studied 22 patients: all of them with hypertension and/or skin ulcerations, dropping out those who had venous. They were evaluated periodically, clinically and with photoelectric plethysmography of lower extremities. To interpret the traces we designed an ideogram which gathered the plethysmographic behavior before and after the treatment. Nearly 80% showed considerable improvement in pain, functional capacity and plethysmographic traces patterns. healing of the ulcerations was achieved in all case. We propose some hypothesis to explain the good effect that we have observed.

  20. Characterization of acetylcholinesterases, and their genes, from the hemipteran species Myzus persicae (Sulzer), Aphis gossypii (Glover), Bemisia tabaci (Gennadius) and Trialeurodes vaporariorum (Westwood).

    PubMed

    Javed, N; Viner, R; Williamson, M S; Field, L M; Devonshire, A L; Moores, G D

    2003-12-01

    Gene sequences encoding putative acetylcholinesterases have been reported for four hemipteran insect species. Although acetylcholinesterase insensitivity occurs in insecticide-resistant populations of each of these species, no mutations were detected in the gene sequences from the resistant insects. This, coupled with a series of experiments using novel reversible inhibitors to compare the biochemical characteristics of acetylcholinesterase from a range of insect species, showed that the cloned cDNA fragments are unlikely to encode the hemipteran synaptic acetylcholinesterases, and there is likely to be a second ace locus.

  1. Chronic monoamine oxidase-B inhibitor treatment blocks monoamine oxidase-A enzyme activity.

    PubMed

    Bartl, Jasmin; Müller, Thomas; Grünblatt, Edna; Gerlach, Manfred; Riederer, Peter

    2014-04-01

    Patients with Parkinson's disease receive selective irreversible monoamine oxidase (MAO)-B inhibitors, but their effects on MAO-A activity are not known during long-term application. We determined MAO-A inhibition in plasma samples from patients with MAO-B inhibitor intake or without MAO-B inhibitor treatment and from healthy controls. We detected a 70 % reduction of MAO-A activity in patients with MAO-B inhibitor therapy in comparison to the other groups. Our results suggest that treatment with MAO-B inhibitor may also influence MAO-A activity in vivo, when administered daily.

  2. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  3. A Selenium Containing Inhibitor for the Treatment of Hepatocellular Cancer

    PubMed Central

    Tagaram, Hephzibah Rani S.; Desai, Dhimant; Li, Guangfu; Liu, Dai; Rountree, C. Bart; Gowda, Kavitha; Berg, Arthur; Amin, Shantu; Staveley-O’Carroll, Kevin F.; Kimchi, Eric T.

    2016-01-01

    Hepatocellular carcinoma (HCC) is the third most deadly cancer in the world. New treatment strategies are desperately needed due to limited standard therapies. Activation of the Erk, Akt, and STAT3pathways is implicated in the prognosis of HCC. The Se,Se′-1,4-phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe), is a selenium-containing MAPK and PI3 kinase inhibitor, effectively inhibit tumorigenesis in a variety of experimental models. The aim of our study is to demonstrate the potential role of PBISe in the treatment of HCC. The anti-proliferative and pro-apoptotic ability of PBISe is studied in vitro in four human HCC cell lines and in vivo in a spontaneous murine HCC model. Inhibition of cancer growth was performed by cell viability assay and apoptosis by caspase 3/7, PARP cleavage, annexin-V, and TUNEL assays. Role of PBISe on PI3 kinase, MAPK and STAT3 signaling is determined by Western blotting. In vivo effects of PBISe on tumor sizes were monitored using MRI in a spontaneous murine HCC. Liver tissues from the PBISe-treated mice are analyzed for angiogenesis, proliferation, and signaling pathway markers. Overall, PBISe activated caspase-3/7 and increased DNA fragmentation, which is positively correlated with the increased PARP cleavage. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling with significant reduction in the tumor sizes (p < 0.007). PBISe-treated tumors reduced survival marker PCNA, and angiogenesis markers Vegf-A, Vegf-R3 and CD34. These results demonstrate the chemotherapeutic effects of PBISe, by inhibiting tumor growth and facilitating tumor apoptosis for HCC treatment. PMID:27023566

  4. The Effect of Parathion on Red Blood Cell Acetylcholinesterase in the Wistar Rat

    PubMed Central

    Bunya, Naofumi; Sawamoto, Keigo; Benoit, Hanif

    2016-01-01

    Organophosphorus (OP) pesticide poisoning is a significant problem worldwide. Research into new antidotes for these acetylcholinesterase inhibitors, and even optimal doses for current therapies, is hindered by a lack of standardized animal models. In this study, we sought to characterize the effects of the OP pesticide parathion on acetylcholinesterase in a Wistar rat model that included comprehensive medical care. Methods. Male Wistar rats were intubated and mechanically ventilated and then poisoned with between 20 mg/kg and 60 mg/kg of intravenous parathion. Upon developing signs of poisoning, the rats were treated with standard critical care, including atropine, pralidoxime chloride, and midazolam, for up to 48 hours. Acetylcholinesterase activity was determined serially for up to 8 days after poisoning. Results. At all doses of parathion, maximal depression of acetylcholinesterase occurred at 3 hours after poisoning. Acetylcholinesterase recovered to nearly 50% of baseline activity by day 4 in the 20 mg/kg cohort and by day 5 in the 40 and 60 mg/kg cohorts. At day 8, most rats' acetylcholinesterase had recovered to roughly 70% of baseline. These data should be useful in developing rodent models of acute OP pesticide poisoning. PMID:27418928

  5. The Effect of Parathion on Red Blood Cell Acetylcholinesterase in the Wistar Rat.

    PubMed

    Bunya, Naofumi; Sawamoto, Keigo; Benoit, Hanif; Bird, Steven B

    2016-01-01

    Organophosphorus (OP) pesticide poisoning is a significant problem worldwide. Research into new antidotes for these acetylcholinesterase inhibitors, and even optimal doses for current therapies, is hindered by a lack of standardized animal models. In this study, we sought to characterize the effects of the OP pesticide parathion on acetylcholinesterase in a Wistar rat model that included comprehensive medical care. Methods. Male Wistar rats were intubated and mechanically ventilated and then poisoned with between 20 mg/kg and 60 mg/kg of intravenous parathion. Upon developing signs of poisoning, the rats were treated with standard critical care, including atropine, pralidoxime chloride, and midazolam, for up to 48 hours. Acetylcholinesterase activity was determined serially for up to 8 days after poisoning. Results. At all doses of parathion, maximal depression of acetylcholinesterase occurred at 3 hours after poisoning. Acetylcholinesterase recovered to nearly 50% of baseline activity by day 4 in the 20 mg/kg cohort and by day 5 in the 40 and 60 mg/kg cohorts. At day 8, most rats' acetylcholinesterase had recovered to roughly 70% of baseline. These data should be useful in developing rodent models of acute OP pesticide poisoning. PMID:27418928

  6. Treatment of Alzheimer disease.

    PubMed

    Winslow, Bradford T; Onysko, Mary K; Stob, Christian M; Hazlewood, Kathleen A

    2011-06-15

    Alzheimer disease is the most common form of dementia, affecting nearly one-half [corrected] of Americans older than 85 years. It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neurofibrillary tau tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer disease. Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3 fatty acid supplementation, physical activity, and cognitive engagement demonstrate modest potential. Acetylcholinesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with mild improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these effects is unclear. The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, confusion, and cardiac arrhythmias. Short-term use of the N-methyl-D-aspartate receptor antagonist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with moderate to severe Alzheimer disease. Memantine can also be used in combination with acetylcholinesterase inhibitors. Memantine is generally well tolerated, but whether its benefits produce clinically meaningful improvement is controversial. Although N-methyl-D-aspartate receptor antagonists and acetylcholinesterase inhibitors can slow the progression of Alzheimer disease, no pharmacologic agents can reverse the progression. Atypical antipsychotics can improve some behavioral symptoms, but have been associated with increased mortality rates in older patients with dementia. There is conflicting evidence about the benefit of selegiline, testosterone, and ginkgo for the treatment of Alzheimer disease. There is no evidence supporting the beneficial effects of vitamin E, estrogen, or nonsteroidal anti-inflammatory drug therapy.

  7. Angiogenesis Inhibitors in the treatment of Prostate Cancer

    PubMed Central

    Kluetz, Paul G.; Figg, William D.; Dahut, William L.

    2009-01-01

    Importance of the Field Prostate carcinoma is the most common non-cutaneous malignancy in American men. The efficacy of docetaxel and prednisone in metastatic castrate-resistant prostate cancer (mCRPC) has been shown to improve overall survival however its effect is not durable highlighting the need for new therapies. Areas covered in this Review We will review the development of some of the leading compounds with direct and indirect anti-angiogenic activity in prostate cancer including antibodies to vascular endothelial growth factor and its receptors, small molecule inhibitors of downstream signaling, immunomodulatory drugs with anti-angiogenic activity, and compounds thought to directly inhibit or destroy vascular endothelial cells. What the reader will gain The reader will gain a basic understanding of the role of angiogenesis in prostate cancer growth and metastasis. Current and potential targets of angiogenesis and their corresponding drugs under development for prostate cancer are discussed. Take Home Message There are now multiple early phase clinical trials of anti-angiogenic agents alone or in combination in prostate cancer. Several of these are now in phase III development. Combined therapy with two or more anti-angiogenic compounds may improve the activity of either compound alone. Multiple targets in the angiogenesis pathway continue to be elucidated and should remain an active area of investigation for the treatment of prostate cancer. PMID:20088745

  8. Acetylcholinesterase-Inhibition and Antibacterial Activity of Mondia whitei Adventitious Roots and Ex vitro-Grown Somatic Embryogenic-Biomass

    PubMed Central

    Baskaran, Ponnusamy; Kumari, Aloka; Ncube, Bhekumthetho; Van Staden, Johannes

    2016-01-01

    Mondia whitei (Hook.f.) Skeels is an important endangered medicinal and commercial plant in South Africa. In vitro propagation systems are required for biomass production and bioactivity analysis to supplement wild resources/stocks. Adventitious roots from somatic embryogenic explants using suspension culture and ex vitro-grown plants produced via somatic embryogenesis were established using different plant growth regulator treatments. The adventitious root biomass and different parts of ex vitro-grown and mother plants were used to investigate the potential for acetylcholinesterase (AChE) and antibacterial activities. Adventitious roots derived from 2.5 μM indole-3-acetic acid (IAA) treatments and ex vitro-grown plants derived from meta-topolin riboside and IAA treatments gave the best AChE and antibacterial activities. The in vitro-established M. whitei and ex vitro biomass have comparable ability to function as inhibitors of acetylcholinesterase and antibacterial agents, and can be used as potent bioresources in traditional medicine. PMID:27752244

  9. Highly efficient, selective and sensitive molecular screening of acetylcholinesterase inhibitors of natural origin by solid-phase extraction-liquid chromatography/electrospray ionisation-octopole-orthogonal acceleration time-of-flight-mass spectrometry and novel thin-layer chromatography-based bioautography.

    PubMed

    Mroczek, Tomasz

    2009-03-20

    Highly efficient, selective and sensitive molecular screening of natural acetylcholinesterase (AChE) inhibitors was developed and comprised optimized pressurized liquid extraction (PLE) of plant materials followed by highly selective solid-phase extraction (SPE) using Oasis HLB cartridges. Pure alkaloidal fractions were analyzed by a newly developed high-performance liquid-chromatography (HPLC) on a 3 microm Atlantis HILIC silica stationary phase combined with recently introduced electrospray ionisation (ESI) octopole-orthogonal acceleration time-of-flight (oa TOF)-mass spectrometry (MS) with high mass accuracy (about 2 ppm) and high sensitivity (absolute limit of detection (LOD) for galanthamine was about 43 fg at signal-to-noise 13:1). Moreover, a newly developed and validated TLC-bioautography permit galanthamine sensitivities at pg levels. In this way, more potent than galanthamine AChE inhibitor namely 1,2-dihydrogalanthamine in Narcissus jonquilla 'Pipit' extract could be found (with IC(50) value 0.19 microM lower of about 42% than that of galanthamine).

  10. Screening the methanol extracts of some Iranian plants for acetylcholinesterase inhibitory activity

    PubMed Central

    Gholamhoseinian, A.; Moradi, M.N.; Sharifi-far, F.

    2009-01-01

    Acetylcholinesterase (AChE) is the main enzyme for the breakdown of acetylcholine. Nowadays, usage of the inhibitors of this enzyme is one of the most important types of treatment of mild to moderate neurodegenerative diseases such as Alzheimer’s disease. Herbal medicines can be a new source of inhibitors of this enzyme. In this study we examined around 100 different plants to evaluate their inhibitory properties for AChE enzyme. Plants were scientifically identified and their extracts were prepared by methanol percolation. Acetylcholinesterase activity was measured using a colorimetric method in the presence or absence of the extracts. Eserine was used as a positive control. Methanol extracts of the Levisticum officinale, Bergeris integrima and Rheum ribes showed more than 50% AChE inhibitory activity. The inhibition kinetics were studied in the presence of the most effective extracts. L. officinale and B. integrima inhibited AChE activity in a non-competitive manner, while R. ribes competitively inhibitied the enzyme as revealed by double-reciprocal Linweaver-Burk plot analysis. Under controlled condition, Km and Vmax values of the enzyme were found to be 9.4 mM and 0.238 mM/min, respectively. However, in the presence of L. officinale, B. integrima, and R. ribes extracts, Vmax values were 0.192, 0.074 and 0.238 mM/min, respectively. Due to the competitive inhibition of the enzyme by R. ribes extract, the Km value of 21.2 mM was obtained. The concentration required for 50% enzyme inhibition (IC50 value) was 0.5, 0.9, and 0.95 mg/ml for the L. officinale, B. integrima and R. ribes extracts, respectively. The IC50 of the eserine was determined to be 0.8 mg/ml. PMID:21589805

  11. Extracts from Traditional Chinese Medicinal Plants Inhibit Acetylcholinesterase, a Known Alzheimer's Disease Target.

    PubMed

    Kaufmann, Dorothea; Kaur Dogra, Anudeep; Tahrani, Ahmad; Herrmann, Florian; Wink, Michael

    2016-01-01

    Inhibition of acetylcholinesterase (AChE) is a common treatment for early stages of the most general form of dementia, Alzheimer's Disease (AD). In this study, methanol, dichloromethane and aqueous crude extracts from 80 Traditional Chinese Medical (TCM) plants were tested for their in vitro anti-acetylcholinesterase activity based on Ellman's colorimetric assay. All three extracts of Berberis bealei (formerly Mahonia bealei), Coptis chinensis and Phellodendron chinense, which contain numerous isoquinoline alkaloids, substantially inhibited AChE. The methanol and aqueous extracts of Coptis chinensis showed IC50 values of 0.031 µg/mL and 2.5 µg/mL, therefore having an up to 100-fold stronger AChE inhibitory activity than the already known AChE inhibitor galantamine (IC50 = 4.33 µg/mL). Combinations of individual alkaloids berberine, coptisine and palmatine resulted in a synergistic enhancement of ACh inhibition. Therefore, the mode of AChE inhibition of crude extracts of Coptis chinensis, Berberis bealei and Phellodendron chinense is probably due to of this synergism of isoquinoline alkaloids. All extracts were also tested for their cytotoxicity in COS7 cells and none of the most active extracts was cytotoxic at the concentrations which inhibit AChE. Based on these results it can be stated that some TCM plants inhibit AChE via synergistic interaction of their secondary metabolites. The possibility to isolate pure lead compounds from the crude extracts or to administer these as nutraceuticals or as cheap alternative to drugs in third world countries make TCM plants a versatile source of natural inhibitors of AChE. PMID:27589716

  12. Galantamine derivatives with indole moiety: Docking, design, synthesis and acetylcholinesterase inhibitory activity.

    PubMed

    Atanasova, Mariyana; Stavrakov, Georgi; Philipova, Irena; Zheleva, Dimitrina; Yordanov, Nikola; Doytchinova, Irini

    2015-09-01

    The inhibitors of acetylcholinesterase are the main therapy against Alzheimer's disease. Among them, galantamine is the best tolerated and the most prescribed drug. In the present study, 41 galantamine derivatives with known acetylcholinesterase inhibitory activities expressed as IC50 were selected from the literature and docked into a recombinant human acetylcholinesterase by GOLD. A linear relationship between GoldScores and pIC50 values was found and used to design and predict novel galantamine derivatives with indole moiety in the side chain. The four best predicted compounds were synthesized and tested for inhibitory activity. All of them were between 11 and 95 times more active than galantamine. The novel galantamine derivatives with indole moiety have dual site binding to the enzyme--the galantamine moiety binds to the catalytic anionic site and the indole moiety binds to peripheral anionic site. Additionally, the indole moiety of one of the novel inhibitors binds in a region, close to the peripheral anionic site of the enzyme, where the Ω-loop of amyloid beta peptide adheres to acetylcholinesterase. This compound emerges as a promising lead compound for multi-target anti-Alzheimer therapy not only because of the strong inhibitory activity, but also because it is able to block the amyloid beta deposition on acetylcholinesterase. PMID:26260334

  13. Ligand exclusion on acetylcholinesterase.

    PubMed

    Berman, H A; Leonard, K

    1990-11-27

    This paper examines covalent reactivity of AchE with respect to cationic and uncharged methylphosphonates and substrates in the absence and presence of cationic ligands selective for the active center and the peripheral anionic site. The organophosphorus inhibitors are enantiomeric alkyl methylphosphonothioates (1-5) containing cycloheptyl and isopropyl phosphono ester groups and S-methyl, S-n-pentyl, and S-[beta-(trimethylammonio)ethyl] leaving groups; these agents differ in their configuration about phosphorus and their steric, hydrophobic, and electrostatic characteristics. The synthetic substrates examined are acetylthiocholine, p-nitrophenyl acetate, and 7-acetoxy-4-methylcoumarin (7AMC). Antagonism of the methylphosphonothioate reaction by cationic ligands is strongly dependent on the nature of both the cation and the methylphosphonate but independent of the configuration about phosphorus. While all cations cause linear mixed inhibition of acetylthiocholine hydrolysis, there are observed a variety of inhibition patterns of 7AMC and p-nitrophenyl acetate hydrolysis that are distinctly nonlinear, as well as patterns in which the reciprocal plots intersect in the upper right quadrant. Strong antagonism of cationic (methylphosphonyl)thiocholines correlates very well with linear inhibition of acetylthiocholine. Ligands that cause only negligible antagonism of the uncharged methylphosphonates display nonlinear inhibition of uncharged substrates. These relationships, since they are most pronounced for peripheral site ligands and are strongly dependent on the charge carried by the reactant, suggest that the peripheral anionic site alters enzyme reactivity through an electrostatic interaction with the net negative active center. Such behavior indicates a potential role for the peripheral anionic site in conserving AchE catalytic efficiency within a narrow range of values. PMID:2271673

  14. 7-Methoxytacrine-adamantylamine heterodimers as cholinesterase inhibitors in Alzheimer's disease treatment--synthesis, biological evaluation and molecular modeling studies.

    PubMed

    Spilovska, Katarina; Korabecny, Jan; Kral, Jan; Horova, Anna; Musilek, Kamil; Soukup, Ondrej; Drtinova, Lucie; Gazova, Zuzana; Siposova, Katarina; Kuca, Kamil

    2013-02-20

    A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC₅₀ value of 0.47 µM for hAChE and an IC₅₀ value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.

  15. Clinical Use of Proteasome Inhibitors in the Treatment of Multiple Myeloma

    PubMed Central

    Merin, Noah M.; Kelly, Kevin R.

    2014-01-01

    Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of neoplastic plasma cells. The use of proteasome inhibitors in the treatment of MM has led to significant improvements in outcomes. This article reviews data on the use of the two approved proteasome inhibitors (bortezomib and carlfilzomib), as well as newer agents under development. Emphasis is placed on the clinical use of proteasome inhibitors, including management of side effects and combination with other agents. PMID:25545164

  16. Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution.

    PubMed

    Greenblatt, H M; Kryger, G; Lewis, T; Silman, I; Sussman, J L

    1999-12-17

    (-)-Galanthamine (GAL), an alkaloid from the flower, the common snowdrop (Galanthus nivalis), shows anticholinesterase activity. This property has made GAL the target of research as to its effectiveness in the treatment of Alzheimer's disease. We have solved the X-ray crystal structure of GAL bound in the active site of Torpedo californica acetylcholinesterase (TcAChE) to 2.3 A resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp-84) and the acyl-binding pocket (Phe-288, Phe-290). The tertiary amine group of GAL does not interact closely with Trp-84; rather, the double bond of its cyclohexene ring stacks against the indole ring. The tertiary amine appears to make a non-conventional hydrogen bond, via its N-methyl group, to Asp-72, near the top of the gorge. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 A) with Glu-199. The relatively tight binding of GAL to TcAChE appears to arise from a number of moderate to weak interactions with the protein, coupled to a low entropy cost for binding due to the rigid nature of the inhibitor.

  17. [Insect cholinesterases and irreversible inhibitors. Statistical treatment of the data].

    PubMed

    Moralev, S N

    2010-01-01

    The data on sensitivity of cholinesterases (ChE) of different insects to reversible inhibitors, as well as the data on physico-chemical parameters of amino acids constituting their active centers, were treated by factor analysis and juxtaposed. It is shown that both these characteristics are related to taxonomical belonging of insects. It is revealed the "material substrate" of the factors determining inhibitor action specificity, which are specific sites in ChE active center.

  18. Tissue distribution of human acetylcholinesterase and butyrylcholinesterase messenger RNA

    SciTech Connect

    Jbilo, O.; Barteles, C.F.; Chatonnet, A.; Toutant, J.P.; Lockridge, O.

    1994-12-31

    Tissue distribution of human acetyicholinesterase and butyryicholinesterase messenger RNA. 1 Cholinesterase inhibitors occur naturally in the calabar bean (eserine), green potatoes (solanine), insect-resistant crab apples, the coca plant (cocaine) and snake venom (fasciculin). There are also synthetic cholinesterase inhibitors, for example man-made insecticides. These inhibitors inactivate acetyicholinesterase and butyrylcholinesterase as well as other targets. From a study of the tissue distribution of acetylcholinesterase and butyrylcholinesterase mRNA by Northern blot analysis, we have found the highest levels of butyrylcholinesterase mRNA in the liver and lungs, tissues known as the principal detoxication sites of the human body. These results indicate that butyrylcholinesterase may be a first line of defense against poisons that are eaten or inhaled.

  19. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression

    ERIC Educational Resources Information Center

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

  20. Diabetic nephropathy: Treatment with phosphodiesterase type 5 inhibitors.

    PubMed

    Thompson, Cecil Stanley

    2013-08-15

    The importance of nitric oxide (NO) in vascular physiology is irrefutable; it stimulates the intracellular production of cyclic guanosine monophosphate (cGMP), initiating vascular smooth muscle relaxation. This biochemical process increases the diameter of small arteries, regulating blood flow distribution between arterioles and the microvasculature. The kidney is no exception, since NO predominantly dilates the glomerular afferent arterioles. It is now evident that the vascular production of cGMP can be augmented by inhibitors of phosphodiesterase type 5 (PDE 5), the enzyme which breakdowns this cyclic nucleotide. This has clinical relevance, since diabetic nephropathy (DN) a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease, increases intraglomerular capillary pressure, leading to glomerular hypertension. PDE 5 inhibitors may have, therefore, the potential to reduce glomerular hypertension. This review describes the use of PDE 5 inhibitors to improve the metabolic, haemodynamic and inflammatory pathways/responses, all of which are dysfunctional in DN. PMID:23961322

  1. PCSK9 inhibitors: monoclonal antibodies for the treatment of hypercholesterolemia.

    PubMed

    Paton, D M

    2016-03-01

    In 2015 the U.S. Food and Drug Administration approved the first two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab (Praluent®; Sanofi/ Regeneron) and evolocumab (Repatha®; Amgen), for use in patients with heterozygous and homozygous familial hypercholesterolemia and for patients intolerant of statins or those with a major risk of cardiovascular disease (CVD) but unable to lower their LDL cholesterol (LDL-C) to optimal levels with statins and ezetimibe. Numerous randomized clinical trials have demonstrated that these inhibitors cause a fall in LDL-C levels of 50-60% as well as causing a decline in lipoprotein(a) and an increase in HDL cholesterol. They are effective in reducing levels of LDL-C to 1.8 mmol/L or less in almost all patients in the groups listed above except for those with homozygous familial hypercholesterolemia. In the latter case, many patients will still have LDL-C levels well above optimal levels despite the use of statins and a PCSK9 inhibitor. To date these inhibitors have not caused major adverse effects. However, the results of ongoing long-term randomized clinical trials are needed to determine whether they cause a significant reduction in CVD events including deaths from CVD. These studies will also demonstrate whether the PCSK9 inhibitors have any unexpected adverse effects and/or effects resulting from the loss of PCSK9 functions at other sites in the body, in particular regarding neurocognition. A further major concern is the high cost of PCSK9 inhibitors and their effect on healthcare costs and health insurance premiums.

  2. PCSK9 inhibitors: monoclonal antibodies for the treatment of hypercholesterolemia.

    PubMed

    Paton, D M

    2016-03-01

    In 2015 the U.S. Food and Drug Administration approved the first two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab (Praluent®; Sanofi/ Regeneron) and evolocumab (Repatha®; Amgen), for use in patients with heterozygous and homozygous familial hypercholesterolemia and for patients intolerant of statins or those with a major risk of cardiovascular disease (CVD) but unable to lower their LDL cholesterol (LDL-C) to optimal levels with statins and ezetimibe. Numerous randomized clinical trials have demonstrated that these inhibitors cause a fall in LDL-C levels of 50-60% as well as causing a decline in lipoprotein(a) and an increase in HDL cholesterol. They are effective in reducing levels of LDL-C to 1.8 mmol/L or less in almost all patients in the groups listed above except for those with homozygous familial hypercholesterolemia. In the latter case, many patients will still have LDL-C levels well above optimal levels despite the use of statins and a PCSK9 inhibitor. To date these inhibitors have not caused major adverse effects. However, the results of ongoing long-term randomized clinical trials are needed to determine whether they cause a significant reduction in CVD events including deaths from CVD. These studies will also demonstrate whether the PCSK9 inhibitors have any unexpected adverse effects and/or effects resulting from the loss of PCSK9 functions at other sites in the body, in particular regarding neurocognition. A further major concern is the high cost of PCSK9 inhibitors and their effect on healthcare costs and health insurance premiums. PMID:27186592

  3. [BACE1 inhibitors for the treatment of Alzheimer disease].

    PubMed

    Tomita, Taisuke

    2016-03-01

    β-Site amyloid precursor protein cleaving enzyme 1 (BACEl) is the enzyme required for the production of the amyloid-β peptide(Aβ), which is associated with Alzheimer disease (AD). BACEl has emerged as a prime molecular target for reducing the brain Aβ levels. Recently, several BACEl inhibitors have been developed in clinical trials to test the efficacy in AD patients and individuals with prodromal AD. However, identification of BACE1 substrates and phenotypes of Bace1 knockout mice have raised concerns regarding potential mechanism-based adverse effects. This review summarizes the current status of the development of BACE1 inhibitors and the evaluation of their therapeutic potential against AD.

  4. Cinnamomum loureirii Extract Inhibits Acetylcholinesterase Activity and Ameliorates Trimethyltin-Induced Cognitive Dysfunction in Mice.

    PubMed

    Kim, Cho Rong; Choi, Soo Jung; Kwon, Yoon Kyung; Kim, Jae Kyeom; Kim, Youn-Jung; Park, Gwi Gun; Shin, Dong-Hoon

    2016-01-01

    The pathogenesis of Alzheimer's disease (AD) has been linked to the deficiency of neurotransmitter acetylcholine (ACh) in the brain, and the main treatment strategy for improving AD symptoms is the inhibition of acetylcholinesterase (AChE) activity. In the present study, we aimed to identify potent AChE inhibitors from Cinnamomum loureirii extract via bioassay-guided fractionation. We demonstrated that the most potent AChE inhibitor present in the C. loureirii extract was 2,4-bis(1,1-dimethylethyl)phenol. To confirm the antiamnesic effects of the ethanol extract of C. loureirii, mice were intraperitoneally injected with the neurotoxin trimethyltin (2.5 mg/kg) to induce cognitive dysfunction, and performance in the Y-maze and passive avoidance tests was assessed. Treatment with C. loureirii extract significantly improved performance in both behavioral tests, suggesting that this extract may be neuroprotective and therefore beneficial in preventing or ameliorating the degenerative processes of AD, potentially by restoring cholinergic function. PMID:27374288

  5. Acetylcholinesterase Inhibitory Activity of Pigment Echinochrome A from Sea Urchin Scaphechinus mirabilis

    PubMed Central

    Lee, Sung Ryul; Pronto, Julius Ryan D.; Sarankhuu, Bolor-Erdene; Ko, Kyung Soo; Rhee, Byoung Doo; Kim, Nari; Mishchenko, Natalia P.; Fedoreyev, Sergey A.; Stonik, Valentin A.; Han, Jin

    2014-01-01

    Echinochrome A (EchA) is a dark-red pigment of the polyhydroxynaphthoquinone class isolated from sea urchin Scaphechinus mirabilis. Acetylcholinesterase (AChE) inhibitors are used in the treatment of various neuromuscular disorders, and are considered as strong therapeutic agents for the treatment of Alzheimer’s disease (AD). Although EchA is clinically used to treat ophthalmic diseases and limit infarct formation during ischemia/reperfusion injury, anti-AChE effect of EchA is still unknown. In this study, we investigated the anti-AChE effect of EchA in vitro. EchA and its exhausted form which lost anti-oxidant capacity did not show any significant cytotoxicy on the H9c2 and A7r5 cells. EchA inhibited AChE with an irreversible and uncompetitive mode. In addition, EchA showed reactive oxygen species scavenging activity, particularly with nitric oxide. These findings indicate new therapeutic potential for EchA in treating reduced acetylcholine-related diseases including AD and provide an insight into developing new AChE inhibitors. PMID:24918454

  6. A novel biosensor method for surfactant determination based on acetylcholinesterase inhibition

    NASA Astrophysics Data System (ADS)

    Kucherenko, I. S.; Soldatkin, O. O.; Arkhypova, V. M.; Dzyadevych, S. V.; Soldatkin, A. P.

    2012-06-01

    A novel enzyme biosensor based on acetylcholinesterase inhibition for the determination of surfactants in aqueous solutions is described. Acetylcholinesterase-based bioselective element was deposited via glutaraldehyde on the surface of conductometric transducers. Different variants of inhibitory analysis of surfactants were tested, and finally surfactant's concentration was evaluated by measuring initial rate of acetylcholinesterase inhibition. Besides, we studied the effect of solution characteristics on working parameters of the biosensor for direct measurement of acetylcholine and for inhibitory determination of surfactants. The biosensor's sensitivity to anionic and cationic surfactants (0.35 mg l-1) was tested. The high operational stability of the biosensor during determination of acetylcholine (RSD 2%) and surfactants (RSD 11%) was shown. Finally, we discussed the selectivity of the biosensor toward surfactants and other AChE inhibitors. The proposed biosensor can be used as a component of the multibiosensor for ecological monitoring of toxicants.

  7. [PCSK9 inhibitors: new treatment to lower cholesterol].

    PubMed

    Gencer, Baris; Rodondi, Nicolas; Mach, François

    2016-03-01

    The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors appear to represent an important development in the management of hypercholesterolemia. US Food and Drug Administration and European Medicines Agency approved alirocumab and evolocumab, injected drugs administered subcutaneously every 2 or 4 weeks, for patients with hypercholesterolemia, such as those who not reached the cholesterol targets or those with intolerance to statin, especially in secondary prevention or familial hypercholesterolemia. This decision is based on several clinical trials suggesting that these drugs have a powerful effect on levels of LDL-cholesterol with an acceptable safety compared to placebo. Large clinical studies are currently performed to assess the impact of PCSK9 inhibitors on major adverse cardiovascular events in secondary prevention.

  8. [PCSK9 inhibitors: new treatment to lower cholesterol].

    PubMed

    Gencer, Baris; Rodondi, Nicolas; Mach, François

    2016-03-01

    The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors appear to represent an important development in the management of hypercholesterolemia. US Food and Drug Administration and European Medicines Agency approved alirocumab and evolocumab, injected drugs administered subcutaneously every 2 or 4 weeks, for patients with hypercholesterolemia, such as those who not reached the cholesterol targets or those with intolerance to statin, especially in secondary prevention or familial hypercholesterolemia. This decision is based on several clinical trials suggesting that these drugs have a powerful effect on levels of LDL-cholesterol with an acceptable safety compared to placebo. Large clinical studies are currently performed to assess the impact of PCSK9 inhibitors on major adverse cardiovascular events in secondary prevention. PMID:27089600

  9. Cost effective design of scale inhibitor squeeze treatments using a mathematical model

    SciTech Connect

    Kokal, S.L.; Raju, K.U.; Bayona, H.

    1995-11-01

    Scale formation and deposition in production facilities is a challenging problem faced by the oil industry. Their deposition leads to operational problems, safety hazards and an overall decrease in production efficiency. Downhole scale inhibitor squeeze treatments provide the most common and effective means of preventing the formation of oilfield scale deposits. This paper presents an analysis and design study of field inhibitor squeeze treatments. A mathematical model was used to simulate inhibitor squeeze return data from several Saudi Aramco wells. A wide range of sensitivities in squeeze treatments were investigated including inhibitor concentration, inhibitor volume, overflush size, shut-in time, etc. An optimization of the squeeze injection parameters was carried out using the numerical simulator. This optimization was based on squeeze performance as well as on economic criteria. The results indicate that the optimized treatment strategy is very well specific and depends on the water production rates, and operational parameters like the scale inhibitor concentration and volume and the amount of overflush. Recommendations are made for optimizing (in terms of cost effectiveness) the squeeze treatment design.

  10. Cost-effective design of scale-inhibitor squeeze treatments using a mathematical model

    SciTech Connect

    Kokal, S.L.; Raju, K.U.; Bayona, H.

    1996-05-01

    Scale formation and deposition in production facilities is a challenging problem faced by the oil industry. Their deposition leads to operational problems, safety hazards, and an overall decrease in production efficiency. Downhole scale-inhibitor squeeze treatments provide the most common and effective means of preventing the formation of oilfield scale deposits. This paper presents an analysis and design study of field-inhibitor squeeze treatments. A mathematical model was used to simulate inhibitor-squeeze return data from several Saudi Aramco wells. A wide range of sensitivities in squeeze treatments were investigated, including inhibitor concentration, inhibitor volume, overflush size, and shut-in time. An optimization of the squeeze injection parameters was carried out with the numerical simulator. This optimization was based on squeeze performance as well as on economic criteria. The results indicate that the optimized treatment strategy is very well-specific and depends on the water production rates and operational parameters, like the scale-inhibitor concentration and volume and the amount of overflush. Recommendations are made for optimizing (in terms of cost effectiveness) the squeeze-treatment design.

  11. COX-2 inhibitors are contraindicated for treatment of combined injury.

    PubMed

    Jiao, W; Kiang, J G; Cary, L; Elliott, T B; Pellmar, T C; Ledney, G D

    2009-12-01

    Casualties of radiation dispersal devices, nuclear detonation or major ionizing radiation accidents, in addition to radiation exposure, may sustain physical and/or thermal trauma. Radiation exposure plus additional tissue trauma is known as combined injury. There are no definitive therapeutic agents. Cyclooxygenase-2 (COX-2), an inducible enzyme expressed in pathological disorders and radiation injury, plays an important role in inflammation and the production of cytokines and prostaglandin E(2) (PGE(2)) and could therefore affect the outcome for victims of combined injury. The COX-2 inhibitors celecoxib and meloxicam were evaluated for their therapeutic value against combined injury in mice. In survival studies, the COX-2 inhibitors had no beneficial effect on 30-day survival, wound healing or body weight gain after radiation injury alone or after combined injury. Meloxicam accelerated death in both wounded and combined injury mice. These drugs also induced severe hepatic toxicity, exaggerated inflammatory processes, and did not enhance hematopoietic cell regeneration. This study points to potential contraindications for use of COX-2 inhibitors in patients undergoing therapy for radiation injury and combined injury. PMID:19929415

  12. Acetylcholinesterase inhibitory activity and molecular docking study of 1-nitro-2-phenylethane, the main constituent of Aniba canelilla essential oil.

    PubMed

    Silva, Nayla N S; Silva, José R A; Alves, Claudio N; Andrade, Eloisa H A; da Silva, Joyce K R; Maia, José G S

    2014-08-01

    The odoriferous principle of Aniba canelilla (H.B.K.) Mez is due 1-nitro-2-phenylethane, the main constituent of its essential oil and also responsible for the plant's cinnamon scent. This nitroderivative was previously reported by their antioxidant, antinociception, cardiovascular, and vasorelaxant properties, and now it was tested as the inhibitor of acetylcholinesterase using bioautography on TLC plates. The oil and a purified fraction containing 1-nitro-2-phenylethane were analyzed by GC and GC-MS. The percentage content of 1-nitro-2-phenylethane in the oil and after fractionation was 70.2% and 98.0%, respectively. The results showed that the oil and 1-nitro-2-phenylethane are strong acetylcholinesterase inhibitors with the detection limit of 0.01 ng, equivalent to physostigmine used as the positive control. A molecular docking study was used to determine the position and conformation of the 1-nitro-2-phenylethane inhibitor in the receptor-binding pocket of the acetylcholinesterase enzyme. The nitrogroup of 1-nitro-2-phenylethane was positioned near of the catalytic serine residue of acetylcholinesterase, forming strong hydrogen bond with its hydroxyl group. Therefore, the electronegative character of 1-nitro-2-phenylethane may explain the interaction that occurs with the catalytic serine residue and its significant inhibitory activity of acetylcholinesterase.

  13. Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease and type 2 diabetes mellitus.

    PubMed

    Mushtaq, Gohar; Greig, Nigel H; Khan, Jalaluddin A; Kamal, Mohammad A

    2014-01-01

    Both Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) share the presence of systemic and neuro-inflammation, enhanced production and accumulation of β -amyloid peptide and abnormal levels of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Altered levels of AChE and BuChE both in AD as well as in T2DM imply that those two enzymes may be playing a pivotal role in the pathogenesis of the two disorders. AD and T2DM are both characterized by elevated levels of AChE and BuChE in the plasma. On the other hand, in AD the brain levels of AChE go down while those of BuChE go up, resulting in deregulation in balance between AChE and BuChE. This imbalance and change in the AChE/BuChE ratio causes cholinergic deficit in the brain, i.e. deficiency in the brain neurotransmitter acetylcholine. With better understanding of the inter-relationship of AChE and BuChE levels in normality as well as abnormality, AD and T2DM can be effectively treated. Thus, general cholinesterase inhibitors that inhibit both AChE and BuChE as well as highly selective BuChE inhibitors may have potential therapeutic benefits in the treatment of AD and other related dementias.

  14. Carbon-11 labeling of CP-126,998*: A radiotracer for in vivo studies of acetylcholinesterase

    SciTech Connect

    Musachio, J.L.; Flesher, J.E.; Scheffel, U.

    1996-05-01

    The study of acetylcholinesterase (AChE) via PET is of interest as reduced activity of this enzyme has been observed in Alzheimer`s disease. Our efforts to develop a radiotracer for mapping of AChE have focused on the N-benzylpiperidine benzisoxazole, CP-126,998, a highly potent (IC{sub 50}=0.48 nm) and selective inhibitor of AChE. High specific activity [C-11] CP-126,998 was synthesized (14 - 24% radiochemical yield, non-decay corrected) by treatment of the desmethyl precursor, CP-118,954, with [C-11] methyl iodide and tetrabutylammonium hydroxide in DMF. In vivo studies with [C-11] CP-126,998 in mice show that this radiotracer displays highest uptake in striatum (6.2 %ID/g), a brain region known to be rich in AChE. The (striatum-cerebellum)/cerebellar radioactivity ratio reached a maximum of 4.3 at 30 min postinjection, and this ratio decreased to 2.4 at 120 min. .Radiotracer binding was saturable in vivo by pretreatment with CP-118,954. Pretreatment of mice with diisopropylfluorophosphate (4 mg/kg i.p.), a known AChE inhibitor, significantly inhibited binding in striatum in a dose-dependent manner. Initial results suggest that [C-11] CP-126,998 may prove useful as a marker for the study of AChE in humans via PET.

  15. Magnus scale inhibitor squeeze treatments - a case history

    SciTech Connect

    Ravenscroft, P.D.; Cowie, L.G.; Smith, P.S.

    1996-12-31

    The Magnus oilfield lies approximately 160 km NE of the Shetland Islands in the UK sector of North Sea. Areal sweep and pressure support is achieved via sea water injection into the reservoir. Due to the layered nature of the reservoir, formation water and sea water are often co-produced and are commingled in the production wellbore. This has often resulted in downhole deposition of barium sulphate scale and an appreciable reduction in well productivity. A combination of scale inhibitor chemistry and its deployment into the reservoir using novel diverting agents has significantly reduced the problems and are described in detail in this paper.

  16. Treatment of type 2 diabetes, lifestyle, GLP1 agonists and DPP4 inhibitors.

    PubMed

    Tomkin, Gerald H

    2014-10-15

    In recent years the treatment focus for type 2 diabetes has shifted to prevention by lifestyle change and to more aggressive reduction of blood sugars during the early stage of treatment. Weight reduction is an important goal for many people with type 2 diabetes. Bariatric surgery is no longer considered a last resort treatment. Glucagon-like peptide-1 agonists given by injection are emerging as a useful treatment since they not only lower blood sugar but are associated with a modest weight reduction. The role of the oral dipeptidyl peptidase 4 inhibitors is emerging as second line treatment ahead of sulphonylureas due to a possible beneficial effect on the beta cell and weight neutrality. Drugs which inhibit glucose re-absorption in the kidney, sodium/glucose co-transport 2 inhibitors, may have a role in the treatment of diabetes. Insulin treatment still remains the cornerstone of treatment in many patients with type 2 diabetes.

  17. Treatment of type 2 diabetes, lifestyle, GLP1 agonists and DPP4 inhibitors

    PubMed Central

    Tomkin, Gerald H

    2014-01-01

    In recent years the treatment focus for type 2 diabetes has shifted to prevention by lifestyle change and to more aggressive reduction of blood sugars during the early stage of treatment. Weight reduction is an important goal for many people with type 2 diabetes. Bariatric surgery is no longer considered a last resort treatment. Glucagon-like peptide-1 agonists given by injection are emerging as a useful treatment since they not only lower blood sugar but are associated with a modest weight reduction. The role of the oral dipeptidyl peptidase 4 inhibitors is emerging as second line treatment ahead of sulphonylureas due to a possible beneficial effect on the beta cell and weight neutrality. Drugs which inhibit glucose re-absorption in the kidney, sodium/glucose co-transport 2 inhibitors, may have a role in the treatment of diabetes. Insulin treatment still remains the cornerstone of treatment in many patients with type 2 diabetes. PMID:25317241

  18. Hypomagnesemia Induced by Long-Term Treatment with Proton-Pump Inhibitors

    PubMed Central

    Janett, Simone; Camozzi, Pietro; Peeters, Gabriëlla G. A. M.; Lava, Sebastiano A. G.; Simonetti, Giacomo D.; Goeggel Simonetti, Barbara; Bianchetti, Mario G.; Milani, Gregorio P.

    2015-01-01

    In 2006, hypomagnesemia was first described as a complication of proton-pump inhibitors. To address this issue, we systematically reviewed the literature. Hypomagnesemia, mostly associated with hypocalcemic hypoparathyroidism and hypokalemia, was reported in 64 individuals on long-term proton-pump inhibitors. Hypomagnesemia recurred following replacement of one proton-pump inhibitor with another but not with a histamine type-2 receptor antagonist. The association between proton-pump inhibitors and magnesium metabolism was addressed in 14 case-control, cross-sectional studies. An association was found in 11 of them: 6 reports found that the use of proton-pump inhibitors is associated per se with a tendency towards hypomagnesemia, 2 found that this tendency is more pronounced in patients concurrently treated with diuretics, carboplatin, or cisplatin, and 2 found a relevant tendency to hypomagnesemia in patients with poor renal function. Finally, findings likely reflecting decreased intestinal magnesium uptake were observed on treatment with proton-pump inhibitors. Three studies did not disclose any relationship between magnesium metabolism and treatment with histamine type-2 receptor antagonists. In conclusion, proton-pump inhibitors may cause hypomagnesemia. In these cases, switching to a histamine type-2 receptor antagonist is advised. PMID:26064102

  19. [A Case of Life-Threatening Angioedema Occurred During Prolonged Angiotensin-Converting Enzyme Inhibitor Treatment].

    PubMed

    Nakamura, Rintaro; Nihei, Shun-Ichi; Arai, Hideaki; Nagata, Keiji; Isa, Yasuki; Harayama, Nobuya; Aibara, Keiji; Kamochi, Msayuki

    2016-03-01

    Although angiotensin-converting enzyme (ACE) inhibitors are widely used as the first choice drug for treating hypertension, we have only a superficial understanding of their relationship to angioedema. We report a case of life-threatening angioedema. The case was a 60-year-old man who had been taking an ACE inhibitor for hypertension for 11 years. He visited his home doctor for dyspnea, and tongue and neck swelling. He was transported to our hospital because of the possibility of airway obstruction. On admission, his tongue and neck swelling became more severe. We performed an intubation using an endoscope and started airway management. We also stopped his ACE inhibitor. The severe tongue and neck swelling improved gradually and he was extubated on day 3. On the fifth day he was discharged. We diagnosed angioedema caused by an ACE inhibitor. Although the risk of airway obstruction with ACE inhibitors is acknowledged, we have only a superficial understanding of how prolonged ACE inhibitor treatment induces angioedema. So we should consider angioedema in cases of taking ACE inhibitors, especially in cases of prolonged treatment. PMID:26972946

  20. Monoamine Transporter Inhibitors and Substrates as Treatments for Stimulant Abuse

    PubMed Central

    Howell, Leonard L.; Negus, S. Stevens

    2015-01-01

    The acute and chronic effects of abused psychostimulants on monoamine transporters and associated neurobiology have encouraged development of candidate medications that target these transporters. Monoamine transporters in general, and dopamine transporters in particular, are critical molecular targets that mediate abuse-related effects of psychostimulants such as cocaine and amphetamine. Moreover, chronic administration of psychostimulants can cause enduring changes in neurobiology reflected in dysregulation of monoamine neurochemistry and behavior. The current review will evaluate evidence for the efficacy of monoamine transporter inhibitors and substrates to reduce abuse-related effects of stimulants in preclinical assays of stimulant self-administration, drug discrimination and reinstatement. In considering deployment of monoamine transport inhibitors and substrates as agonist-type medications to treat stimulant abuse, the safety and abuse liability of the medications are an obvious concern, and this will also be addressed. Future directions in drug discovery should identify novel medications that retain efficacy to decrease stimulant use but possess lower abuse liability, and evaluate the degree to which efficacious medications can attenuate or reverse neurobiological effects of chronic stimulant use. PMID:24484977

  1. Monoamine transporter inhibitors and substrates as treatments for stimulant abuse.

    PubMed

    Howell, Leonard L; Negus, S Stevens

    2014-01-01

    The acute and chronic effects of abused psychostimulants on monoamine transporters and associated neurobiology have encouraged development of candidate medications that target these transporters. Monoamine transporters, in general, and dopamine transporters, in particular, are critical molecular targets that mediate abuse-related effects of psychostimulants such as cocaine and amphetamine. Moreover, chronic administration of psychostimulants can cause enduring changes in neurobiology reflected in dysregulation of monoamine neurochemistry and behavior. The current review will evaluate evidence for the efficacy of monoamine transporter inhibitors and substrates to reduce abuse-related effects of stimulants in preclinical assays of stimulant self-administration, drug discrimination, and reinstatement. In considering deployment of monoamine transport inhibitors and substrates as agonist-type medications to treat stimulant abuse, the safety and abuse liability of the medications are an obvious concern, and this will also be addressed. Future directions in drug discovery should identify novel medications that retain efficacy to decrease stimulant use but possess lower abuse liability and evaluate the degree to which efficacious medications can attenuate or reverse neurobiological effects of chronic stimulant use. PMID:24484977

  2. Targeting PTPs with small molecule inhibitors in cancer treatment

    PubMed Central

    Jiang, Zhong-Xing; Zhang, Zhong-Yin

    2009-01-01

    Protein tyrosine phosphorylation plays a major role in cellular signaling. The level of tyrosine phosphorylation is controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Disturbance of the normal balance between PTK and PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. A number of PTPs have been implicated in oncogenesis and tumor progression and therefore are potential drug targets for cancer chemotherapy. These include PTP1B, which may augment signaling downstream of HER2/Neu; SHP2, which is the first oncogene in the PTP superfamily and is essential for growth factor-mediated signaling; the Cdc25 phosphatases, which are positive regulators of cell cycle progression; and the PRL phosphatases, which promote tumor metastases. As PTPs have emerged as drug targets for cancer, a number of strategies are currently been explored for the identification of various classes of PTP inhibitors. These efforts have resulted many potent, and in some cases selective, inhibitors for PTP1B, SHP2, Cdc25 and PRL phosphatases. Structural information derived from these compounds serves as a solid foundation upon which novel anti-cancer agents targeted to these PTPs can be developed. PMID:18259840

  3. Angiogenesis inhibitors under study for the treatment of lung cancer.

    PubMed

    Shepherd, Frances A; Sridhar, Srikala S

    2003-08-01

    Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat. Trials of this class of agents have all been negative to date. Drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190 are all in earlier stages of clinical trial. Drugs that are similar to endogenous inhibitors of angiogenesis including interferons have also been evaluated without success. Endostatin has been shown to have an acceptable toxicity profile, but clinical evidence of activity has not yet been demonstrated. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies. PMID:12867064

  4. Poly (ADP-ribose) polymerase inhibitor: an evolving paradigm in the treatment of prostate cancer.

    PubMed

    Zhang, Jingsong

    2014-01-01

    Recent phase I studies have reported single-agent activities of poly (ADP-ribose) polymerase (PARP) inhibitor in sporadic and in BRCA-mutant prostate cancers. Two of the most common genetic alterations in prostate cancer, ETS gene rearrangement and loss of PTEN, have been linked to increased sensitivity to PARP inhibitor in preclinical models. Emerging evidence also suggests that PARP1 plays an important role in mediating the transcriptional activities of androgen receptor (AR) and ETS gene rearrangement. In this article, the preclinical work and early-phase clinical trials in developing PARP inhibitor-based therapy as a new treatment paradigm for metastatic prostate cancer are reviewed.

  5. Acetylcholinesterase is associated with apoptosis in β cells and contributes to insulin-dependent diabetes mellitus pathogenesis.

    PubMed

    Zhang, Bao; Yang, Lei; Yu, Luyang; Lin, Bo; Hou, Yanan; Wu, Jun; Huang, Qin; Han, Yifan; Guo, Lihe; Ouyang, Qi; Zhang, Bo; Lu, Lu; Zhang, Xuejun

    2012-03-01

    Acetylcholinesterase (AChE) expression is pivotal during apoptosis. Indeed, AChE inhibitors partially protect cells from apoptosis. Insulin-dependent diabetes mellitus (IDDM) is characterized in part by pancreatic β-cell apoptosis. Here, we investigated the role of AChE in the development of IDDM and analyzed protective effects of AChE inhibitors. Multiple low-dose streptozotocin (MLD-STZ) administration resulted in IDDM in a mouse model. Western blot analysis, cytochemical staining, and immunofluorescence staining were used to detect AChE expression in MIN6 cells, primary β cells, and apoptotic pancreatic β cells of MLD-STZ-treated mice. AChE inhibitors were administered intraperitoneally to the MLD-STZ mice for 30 days. Blood glucose, plasma insulin, and creatine levels were measured, and glucose tolerance tests were performed. The effects of AChE inhibitors on MIN6 cells were also evaluated. AChE expression was induced in the apoptotic MIN6 cells and primary β cells in vitro and pancreatic islets in vivo when treated with STZ. Induction and progressive accumulation of AChE in the pancreatic islets were associated with apoptotic β cells during IDDM development. The administration of AChE inhibitors effectively decreased hyperglycemia and incidence of diabetes, and restored plasma insulin levels and plasma creatine clearance in the MLD-STZ mice. AChE inhibitors partially protected MIN6 cells from the damage caused by STZ treatment. Induction and accumulation of AChE in pancreatic islets and the protective effects of AChE inhibitors on the onset and development of IDDM indicate a close relationship between AChE and IDDM.

  6. Targeting Acetylcholinesterase: Identification of Chemical Leads by High Throughput Screening, Structure Determination and Molecular Modeling

    PubMed Central

    Berg, Lotta; Andersson, C. David; Artursson, Elisabet; Hörnberg, Andreas; Tunemalm, Anna-Karin; Linusson, Anna; Ekström, Fredrik

    2011-01-01

    Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine. Compounds inhibiting this enzyme can be used (inter alia) to treat cholinergic deficiencies (e.g. in Alzheimer's disease), but may also act as dangerous toxins (e.g. nerve agents such as sarin). Treatment of nerve agent poisoning involves use of antidotes, small molecules capable of reactivating AChE. We have screened a collection of organic molecules to assess their ability to inhibit the enzymatic activity of AChE, aiming to find lead compounds for further optimization leading to drugs with increased efficacy and/or decreased side effects. 124 inhibitors were discovered, with considerable chemical diversity regarding size, polarity, flexibility and charge distribution. An extensive structure determination campaign resulted in a set of crystal structures of protein-ligand complexes. Overall, the ligands have substantial interactions with the peripheral anionic site of AChE, and the majority form additional interactions with the catalytic site (CAS). Reproduction of the bioactive conformation of six of the ligands using molecular docking simulations required modification of the default parameter settings of the docking software. The results show that docking-assisted structure-based design of AChE inhibitors is challenging and requires crystallographic support to obtain reliable results, at least with currently available software. The complex formed between C5685 and Mus musculus AChE (C5685•mAChE) is a representative structure for the general binding mode of the determined structures. The CAS binding part of C5685 could not be structurally determined due to a disordered electron density map and the developed docking protocol was used to predict the binding modes of this part of the molecule. We believe that chemical modifications of our discovered inhibitors, biochemical and biophysical characterization

  7. Strong topical steroid, NSAID, and carbonic anhydrase inhibitor cocktail for treatment of cystoid macular edema

    PubMed Central

    Asahi, Masumi G; Bobarnac Dogaru, Gabriela L; Onishi, Spencer M; Gallemore, Ron P

    2015-01-01

    Purpose To report the combination cocktail of strong steroid, non-steroidal anti-inflammatory drug (NSAID), and carbonic anhydrase inhibitor drops for treatment of cystoid macular edema. Methods This is a retrospective case series of patients with cystoid macular edema managed with a topical combination of strong steroid (difluprednate), NSAID, and carbonic anhydrase inhibitor drops. The patients were followed with optical coherence tomography and fluorescein angiography. Results In our six cases, resolution of the cystic edema with improvement in visual acuity was achieved with the use of a combination cocktail of drops. Leakage on fluorescein angiography and cystic edema on optical coherence tomography both responded to treatment with the topical cocktail of drops. Conclusion A topical cocktail of strong steroid, NSAID, and carbonic anhydrase inhibitor drops are effective for managing cystoid macular edema. Further studies comparing this combination with more invasive treatments should be undertaken to determine the efficacy of this cocktail over other treatment options. PMID:26664246

  8. A prospective study of frequency and characteristics of cough during ACE inhibitor treatment.

    PubMed

    Sato, Atsuhisa; Fukuda, Seiichi

    2015-01-01

    Angiotensin converting enzyme (ACE) inhibitors are reportedly effective, and positively indicated in patients with chronic heart failure with decreased contractility, after myocardial infarction, after cerebrovascular disorders, and in those with chronic kidney disease. However, the biggest challenge to continuous use of ACE inhibitors is the adverse reaction of cough. Accordingly, in the present study, we investigated the present state and characteristics of ACE inhibitor-induced cough in patients with essential hypertension currently being treated with an ACE inhibitor for an average of 18 months, who could be regularly checked for cough. Subjects in this study were 176 patients overall (mean age 67 ± 11 years old), 90 men and 86 women. The adverse reaction of cough was observed in 20% of patients, and more frequently in women than in men. However, in 26 of the patients with cough, the cough either resolved naturally or completely disappeared while the treatment continued, after which patients could continue taking the medication. Specifically, ACE inhibitor treatment was eventually discontinued due to cough in 5.1% of patients. Cough occurred less frequently with concomitant calcium antagonists or diuretics than with ACE inhibitor monotherapy. Cough as an adverse reaction occurred at a low frequency when medication was taken at bedtime. We considered a number of measures to counteract cough, then in addition to starting the ACE inhibitor treatment as early as possible, it is important to devise ways for the ACE inhibitor treatment to be continued for as long as possible, through the adept use of these measures.

  9. Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia.

    PubMed

    Longhurst, Hilary

    2008-03-01

    Pharming NV and Esteve are developing Rhucin, a recombinant human C1 esterase inhibitor. Rhucin is currently undergoing phase III clinical trials in North America and is awaiting regulatory approval in Western Europe for the treatment of prophylactic and acute hereditary angioedema. Pharming is also investigating Rhucin for the potential treatment of cerebral ischemic injury.

  10. Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia.

    PubMed

    Longhurst, Hilary

    2008-03-01

    Pharming NV and Esteve are developing Rhucin, a recombinant human C1 esterase inhibitor. Rhucin is currently undergoing phase III clinical trials in North America and is awaiting regulatory approval in Western Europe for the treatment of prophylactic and acute hereditary angioedema. Pharming is also investigating Rhucin for the potential treatment of cerebral ischemic injury. PMID:18311668

  11. Treatment discontinuation with selective serotonin reuptake inhibitors compared with tricyclic antidepressants: a meta-analysis.

    PubMed Central

    Anderson, I. M.; Tomenson, B. M.

    1995-01-01

    OBJECTIVE--To assess treatment discontinuation rates with selective serotonin reuptake inhibitors compared with tricyclic antidepressants. DESIGN--Meta-analysis of 62 randomised controlled trials. SUBJECTS--6029 patients with major unipolar depression. MAIN OUTCOME MEASURES--Pooled risk ratios for drop out rates with respect to all cases of discontinuation and those due to side effects and treatment failure. RESULTS--The total discontinuation rate was 10% lower with selective serotonin reuptake inhibitors than with tricyclic antidepressants (risk ratio 0.90; 95% confidence interval 0.84 to 0.97) and the drop out rate due to side effects was 25% lower (risk ratio 0.75; 0.66 to 0.84). There was no significant difference between drug classes in the drop out rates for treatment failure. The risk ratios for drop out did not differ significantly between individual selective serotonin reuptake inhibitors. CONCLUSIONS--Selective serotonin reuptake inhibitors are better tolerated than tricyclic antidepressants as measured by total numbers of drop outs. The definite advantage to selective serotonin reuptake inhibitors is explained by fewer drop outs due to side effects. The overall difference, however, is comparatively small and may not be clinically relevant. Analyses of cost effectiveness should not overestimate the advantage to selective serotonin reuptake inhibitors. PMID:7613276

  12. Evolving Therapies and FAK Inhibitors for the Treatment of Cancer

    PubMed Central

    Dunn, Kelli Bullard; Heffler, Melissa; Golubovskaya, Vita

    2012-01-01

    Despite advances in medical and surgical therapy, cancer kills more than half a million people in the United States annually, and the majority of these patients succumb to metastatic disease. The traditional approach to treating systemic disease has been the use of cytotoxic chemotherapy. However, chemotherapy is rarely curative and toxicity is often dose limiting. In addition, the effects of chemotherapy are nonspecific, targeting both malignant and normal tissues. As a result, recent efforts increasingly have focused on developing agents that target specific molecules in tumor cells in order to both improve efficacy and limit toxicity. This review summarizes the history and current use of targeted molecular therapy for cancer, with a special emphasis on recently developed inhibitors of Focal Adhesion Kinase (FAK). PMID:21291406

  13. [PCSK9 inhibitors. A new approach for treatment of hypercholesterolemia].

    PubMed

    Saußele, Tanja

    2015-07-01

    To date HMG-CoA-reductase inhibitors are the most effective drugs for reduction of LDL-cholesterol levels and for prevention of cardiovascular events. Inhibition of the enzyme PCSK9 (proprotein convertase subtilisin/kexin type 9), which is involved in depletion of the LDL-receptor, is a new pharmacologic approach. Inhibition of PCSK9 by monoclonal antibodies provokes an additional reduction of LDL-cholesterol levels by 50-60 % in addition to statins. Previous phase III studies indicate good compatibility. Ongoing long-term studies will answer questions of safety and influence on cardiovascular events. Although those results are not available yet, alirocumab and evolocumab have already been recommendd for approval. PMID:26364362

  14. Oral candidiasis in HIV+ patients under treatment with protease inhibitors.

    PubMed

    Witzel, Andréa Lusvarghi; Silveira, Fernando Ricardo Xavier da; Pires, Maria de Fátima Costa; Lotufo, Mônica Andrade

    2008-01-01

    The purpose of this work was to evaluate the influence of Protease Inhibitors (PI) on the occurrence of oral candidiasis in 111 HIV+ patients under PI therapy (Group A). The controls consisted of 56 patients that were not using PI drugs (Group B) and 26 patients that were not using any drugs for HIV therapy (Group C). The patient's cd4 cell counts were taken in account for the correlations. One hundred and ninety three patients were evaluated. The PI did not affect the prevalence of oral candidiasis (p = 0.158) or the frequency of C. albicans isolates (p = 0.133). Patients with lower cd4 cell counts showed a higher frequency of C. albicans isolates (p = 0.046) and a greater occurrence of oral candidiasis (p = 0.036).

  15. Caffeine inhibits acetylcholinesterase, but not butyrylcholinesterase.

    PubMed

    Pohanka, Miroslav; Dobes, Petr

    2013-05-08

    Caffeine is an alkaloid with a stimulant effect in the body. It can interfere in transmissions based on acetylcholine, epinephrine, norepinephrine, serotonin, dopamine and glutamate. Clinical studies indicate that it can be involved in the slowing of Alzheimer disease pathology and some other effects. The effects are not well understood. In the present work, we focused on the question whether caffeine can inhibit acetylcholinesterase (AChE) and/or, butyrylcholinesterase (BChE), the two enzymes participating in cholinergic neurotransmission. A standard Ellman test with human AChE and BChE was done for altering concentrations of caffeine. The test was supported by an in silico examination as well. Donepezil and tacrine were used as standards. In compliance with Dixon's plot, caffeine was proved to be a non-competitive inhibitor of AChE and BChE. However, inhibition of BChE was quite weak, as the inhibition constant, Ki, was 13.9 ± 7.4 mol/L. Inhibition of AChE was more relevant, as Ki was found to be 175 ± 9 µmol/L. The predicted free energy of binding was -6.7 kcal/mol. The proposed binding orientation of caffeine can interact with Trp86, and it can be stabilize by Tyr337 in comparison to the smaller Ala328 in the case of human BChE; thus, it can explain the lower binding affinity of caffeine for BChE with reference to AChE. The biological relevance of the findings is discussed.

  16. Altered Levels of Acetylcholinesterase in Alzheimer Plasma

    PubMed Central

    García-Ayllón, María-Salud; Riba-Llena, Iolanda; Serra-Basante, Carol; Alom, Jordi; Boopathy, Rathnam; Sáez-Valero, Javier

    2010-01-01

    Background Many studies have been conducted in an extensive effort to identify alterations in blood cholinesterase levels as a consequence of disease, including the analysis of acetylcholinesterase (AChE) in plasma. Conventional assays using selective cholinesterase inhibitors have not been particularly successful as excess amounts of butyrylcholinesterase (BuChE) pose a major problem. Principal Findings Here we have estimated the levels of AChE activity in human plasma by first immunoprecipitating BuChE and measuring AChE activity in the immunodepleted plasma. Human plasma AChE activity levels were ∼20 nmol/min/mL, about 160 times lower than BuChE. The majority of AChE species are the light G1+G2 forms and not G4 tetramers. The levels and pattern of the molecular forms are similar to that observed in individuals with silent BuChE. We have also compared plasma AChE with the enzyme pattern obtained from human liver, red blood cells, cerebrospinal fluid (CSF) and brain, by sedimentation analysis, Western blotting and lectin-binding analysis. Finally, a selective increase of AChE activity was detected in plasma from Alzheimer's disease (AD) patients compared to age and gender-matched controls. This increase correlates with an increase in the G1+G2 forms, the subset of AChE species which are increased in Alzheimer's brain. Western blot analysis demonstrated that a 78 kDa immunoreactive AChE protein band was also increased in Alzheimer's plasma, attributed in part to AChE-T subunits common in brain and CSF. Conclusion Plasma AChE might have potential as an indicator of disease progress and prognosis in AD and warrants further investigation. PMID:20090844

  17. Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment.

    PubMed

    Zeerleder, Sacha; Levi, Marcel

    2016-01-01

    Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. A decreased activity of C1-inhibitor is the hallmark of C1-INH-HAE (types 1 and 2) due to a mutation in the C1-inhibitor gene, whereas the deficiency in C1-inhibitor in C1-INH-AAE is the result of autoimmune phenomena. In HAE with normal C1-inhibitor, a significant percentage of patients have an increased activity of factor XIIa due to a FXII mutation (FXII-HAE). Treatment of C1-inhibitor-dependent angioedema focuses on restoring control of BK generation by inhibition of CP proteases by correcting the balance between CP inhibitors and BK breakdown or by inhibition of BK-mediated effects at the BKR2 on endothelial cells. This review will address the pathophysiology, clinical picture, diagnosis and available treatment in C1-inhibitor-dependent angioedema focusing on BK-release and its regulation. Key Messages Inadequate control of bradykinin formation results in the formation of characteristic subcutaneous and submucosal edemas of the skin, upper airways, facial structures, abdomen and extremities as seen in hereditary and acquired C1-inhibitor-dependent angioedema. Diagnosis of hereditary and acquired C1-inhibitor-dependent angioedema may be troublesome as illustrated by the fact that there is a significant delay in diagnosis; a certain grade of suspicion is therefore crucial for quick diagnosis. Submucosal edema formation in

  18. Small-Molecule Inhibitors of the MDM2–p53 Protein–Protein Interaction (MDM2 Inhibitors) in Clinical Trials for Cancer Treatment

    PubMed Central

    2015-01-01

    Design of small-molecule inhibitors (MDM2 inhibitors) to block the MDM2–p53 protein–protein interaction has been pursued as a new cancer therapeutic strategy. In recent years, potent, selective, and efficacious MDM2 inhibitors have been successfully obtained and seven such compounds have been advanced into early phase clinical trials for the treatment of human cancers. Here, we review the design, synthesis, properties, preclinical, and clinical studies of these clinical-stage MDM2 inhibitors. PMID:25396320

  19. Tailored therapy of ACE inhibitors in stable coronary artery disease: pharmacogenetic profiling of treatment benefit.

    PubMed

    Brugts, Jasper J; Boersma, Eric; Simoons, Maarten L

    2010-08-01

    Angiotensin-converting enzyme (ACE) inhibitors are among the most commonly used drugs in stable coronary artery disease as these agents have been proven to be effective for reducing the risk of cardiovascular morbidity and mortality. As with other drugs, individual variation in treatment benefit is likely. Such heterogeneity could be used to target ACE-inhibitor therapy to those patients most likely to benefit from treatment. However, prior attempts to target ACE-inhibitor therapy to those patients who are most likely to benefit of such prophylactic treatment in secondary prevention using clinical characteristics or the level of baseline risk appeared not to be useful. A new approach of 'tailored therapy' could be to integrate more patient-specific characteristics, such as the genetic information of patients. Pharmacogenetic research of ACE inhibitors in coronary artery disease patients is at a formative stage, and studies are limited. The Perindopril Genetic association (PERGENE) study is a large pharmacogenetic substudy of the randomized placebo-controlled European trial On Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery disease (EUROPA) trial, aimed to assess the feasibility of pharmacogenetic profiling of ACE-inhibitor therapy by perindopril. This article summarizes the recent findings of the PERGENE study and pharmacogenetic research of the treatment benefit of perindopril in stable coronary artery disease. PMID:20712529

  20. Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales

    PubMed Central

    El-Kenawi, Asmaa E; El-Remessy, Azza B

    2013-01-01

    Angiogenesis, a process of new blood vessel formation, is a prerequisite for tumour growth to supply the proliferating tumour with oxygen and nutrients. The angiogenic process may contribute to tumour progression, invasion and metastasis, and is generally accepted as an indicator of tumour prognosis. Therefore, targeting tumour angiogenesis has become of high clinical relevance. The current review aimed to highlight mechanistic details of anti-angiogenic therapies and how they relate to classification and treatment rationales. Angiogenesis inhibitors are classified into either direct inhibitors that target endothelial cells in the growing vasculature or indirect inhibitors that prevent the expression or block the activity of angiogenesis inducers. The latter class extends to include targeted therapy against oncogenes, conventional chemotherapeutic agents and drugs targeting other cells of the tumour micro-environment. Angiogenesis inhibitors may be used as either monotherapy or in combination with other anticancer drugs. In this context, many preclinical and clinical studies revealed higher therapeutic effectiveness of the combined treatments compared with individual treatments. The proper understanding of synergistic treatment modalities of angiogenesis inhibitors as well as their wide range of cellular targets could provide effective tools for future therapies of many types of cancer. PMID:23962094

  1. A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

    PubMed Central

    Guarnieri, Frank; Spencer, Jean L.; Lucey, Edgar C.; Nugent, Matthew A.; Stone, Phillip J.

    2010-01-01

    Two million Americans suffer from pulmonary emphysema, costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema is thought to result from an imbalance between elastase and endogenous inhibitors of elastase, leading to tissue destruction and a loss of alveoli. Decades of research have still not resulted in an effective treatment other than stopping cigarette smoking, a highly addictive behavior. On the basis of our previous work, we hypothesize that small molecule inhibitors of human neutrophil elastase are ineffective because of rapid clearance from the lungs. To develop a long-acting elastase inhibitor with a lung pharmacodynamic profile that has minimal immunogenicity, we covalently linked an elastase inhibitor, similar to a trifluoro inhibitor that was used in clinical trials, to a 25-amino-acid fragment of human surfactant peptide B. We used this construct to prevent human neutrophil elastase-induced emphysema in a rodent model. The elastase inhibitor alone, although in a 70-fold molar excess to elastase in a mixture with <0.6% residual elastase activity, provided no protection from elastase-induced emphysema. Covalently combining an endogenous peptide from the target organ with a synthetic small molecule inhibitor is a unique way of endowing an active compound with the pharmacodynamic profile needed to create in vivo efficacy. PMID:20534582

  2. The 3D-QSAR study of 110 diverse, dual binding, acetylcholinesterase inhibitors based on alignment independent descriptors (GRIND-2). The effects of conformation on predictive power and interpretability of the models.

    PubMed

    Vitorović-Todorović, Maja D; Cvijetić, Ilija N; Juranić, Ivan O; Drakulić, Branko J

    2012-09-01

    The 3D-QSAR analysis based on alignment independent descriptors (GRIND-2) was performed on the set of 110 structurally diverse, dual binding AChE reversible inhibitors. Three separate models were built, based on different conformations, generated following next criteria: (i) minimum energy conformations, (ii) conformation most similar to the co-crystalized ligand conformation, and (iii) docked conformation. We found that regardless on conformation used, all the three models had good statistic and predictivity. The models revealed the importance of protonated pyridine nitrogen of tacrine moiety for anti AChE activity, and recognized HBA and HBD interactions as highly important for the potency. This was revealed by the variables associated with protonated pyridinium nitrogen, and the two amino groups of the linker. MIFs calculated with the N1 (pyridinium nitrogen) and the DRY GRID probes in the AChE active site enabled us to establish the relationship between amino acid residues within AChE active site and the variables having high impact on models. External predictive power of the models was tested on the set of 40 AChE reversible inhibitors, most of them structurally different from the training set. Some of those compounds were tested on the different enzyme source. We found that external predictivity was highly sensitive on conformations used. Model based on docked conformations had superior predictive ability, emphasizing the need for the employment of conformations built by taking into account geometrical restrictions of AChE active site gorge.

  3. Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

    PubMed Central

    Li, Haoyu; Chen, Zhenghu; Hu, Ting; Wang, Long; Yu, Yang; Zhao, Yanling; Sun, Wenijing; Guan, Shan; Pang, Jonathan C.; Woodfield, Sarah E.; Liu, Qing; Yang, Jianhua

    2016-01-01

    Neuroblastoma (NB) is the most common extracranial malignant solid tumor seen in children and continues to lead to the death of many pediatric cancer patients. The poor outcome in high risk NB is largely attributed to the development of chemoresistant tumor cells. Doxorubicin (dox) has been widely employed as a potent anti-cancer agent in chemotherapeutic regimens; however, it also leads to chemoresistance in many cancer types including NB. Thus, developing novel small molecules that can overcome dox-induced chemoresistance is a promising strategy in cancer therapy. Here we show that the second generation proteasome inhibitor ixazomib (MLN9708) not only inhibits NB cell proliferation and induces apoptosis in vitro but also enhances dox-induced cytotoxicity in NB cells. Ixazomib inhibits dox-induced NF-κB activity and sensitizes NB cells to dox-induced apoptosis. More importantly, ixazomib demonstrated potent anti-tumor efficacy in vivo by enhancing dox-induced apoptosis in an orthotopic xenograft NB mouse model. Collectively, our study illustrates the anti-tumor efficacy of ixazomib in NB both alone and in combination with dox, suggesting that combination therapy including ixazomib with traditional therapeutic agents such as dox is a viable strategy that may achieve better outcomes for NB patients. PMID:27687684

  4. Interleukin-17 inhibitors. A new era in treatment of psoriasis and other skin diseases

    PubMed Central

    Wasilewska, Agnieszka; Winiarska, Marta; Olszewska, Małgorzata

    2016-01-01

    Psoriasis is a chronic skin disease caused by the excessive secretion of inflammatory cytokines. Available therapeutic options include biologic drugs such as tumor necrosis factor alpha inhibitors and interleukin 12/23 (IL-12/23) inhibitors. The recent discovery of IL-17, which contributes to development of psoriasis, opened new possibilities for further treatment modalities. Currently, one anti-IL17 biological agent is approved for the treatment – a fully human monoclonal antibody that targets IL-17A (secukinumab). Further clinical trials, including a humanized IgG4 specific for IL-17 (ixekizumab) and a fully human antibody that targets the IL-17 receptor A (brodalumab). PMID:27605893

  5. Sonidegib, a novel smoothened inhibitor for the treatment of advanced basal cell carcinoma

    PubMed Central

    Doan, Hung Q; Silapunt, Sirunya; Migden, Michael R

    2016-01-01

    Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer. If left untreated, BCCs can become locally aggressive or even metastasize. Currently available treatments include local destruction, surgery, and radiation. Systemic options for advanced disease are limited. The Hedgehog (Hh) pathway is aberrantly activated in a majority of BCCs and in other cancers. Hh pathway inhibitors are targeted agents that inhibit the aberrant activation of the Hh pathway, with smoothened being a targeted component. Sonidegib is a novel smoothened inhibitor that was recently approved by the US Food and Drug Administration. This review focuses on BCC pathogenesis and the clinical efficacy of sonidegib for the treatment of advanced BCC. PMID:27695345

  6. Interleukin-17 inhibitors. A new era in treatment of psoriasis and other skin diseases.

    PubMed

    Wasilewska, Agnieszka; Winiarska, Marta; Olszewska, Małgorzata; Rudnicka, Lidia

    2016-08-01

    Psoriasis is a chronic skin disease caused by the excessive secretion of inflammatory cytokines. Available therapeutic options include biologic drugs such as tumor necrosis factor alpha inhibitors and interleukin 12/23 (IL-12/23) inhibitors. The recent discovery of IL-17, which contributes to development of psoriasis, opened new possibilities for further treatment modalities. Currently, one anti-IL17 biological agent is approved for the treatment - a fully human monoclonal antibody that targets IL-17A (secukinumab). Further clinical trials, including a humanized IgG4 specific for IL-17 (ixekizumab) and a fully human antibody that targets the IL-17 receptor A (brodalumab). PMID:27605893

  7. NS3 protease inhibitors for treatment of chronic hepatitis C: Efficacy and safety

    PubMed Central

    Bakulin, Igor; Pasechnikov, Victor; Varlamicheva, Anna; Sannikova, Irina

    2014-01-01

    A new treatment paradigm for hepatitis C is that the treatment must include an existing direct-acting antiviral agent, namely, a protease inhibitor (PI) combined with PEGylated interferon-α and ribavirin. The currently marketed PIs and PIs in clinical trials have different mechanisms of action. The development of new PIs aims for an improved safety profile and higher effectiveness. This article reviews NS3/4A protease inhibitors, focusing on major criteria such as their effectiveness and safety. Specific attention is paid to dosing regimens and adverse event profiles of PIs administered in clinical settings. PMID:24868326

  8. Sonidegib, a novel smoothened inhibitor for the treatment of advanced basal cell carcinoma

    PubMed Central

    Doan, Hung Q; Silapunt, Sirunya; Migden, Michael R

    2016-01-01

    Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer. If left untreated, BCCs can become locally aggressive or even metastasize. Currently available treatments include local destruction, surgery, and radiation. Systemic options for advanced disease are limited. The Hedgehog (Hh) pathway is aberrantly activated in a majority of BCCs and in other cancers. Hh pathway inhibitors are targeted agents that inhibit the aberrant activation of the Hh pathway, with smoothened being a targeted component. Sonidegib is a novel smoothened inhibitor that was recently approved by the US Food and Drug Administration. This review focuses on BCC pathogenesis and the clinical efficacy of sonidegib for the treatment of advanced BCC.

  9. Interleukin-17 inhibitors. A new era in treatment of psoriasis and other skin diseases

    PubMed Central

    Wasilewska, Agnieszka; Winiarska, Marta; Olszewska, Małgorzata

    2016-01-01

    Psoriasis is a chronic skin disease caused by the excessive secretion of inflammatory cytokines. Available therapeutic options include biologic drugs such as tumor necrosis factor alpha inhibitors and interleukin 12/23 (IL-12/23) inhibitors. The recent discovery of IL-17, which contributes to development of psoriasis, opened new possibilities for further treatment modalities. Currently, one anti-IL17 biological agent is approved for the treatment – a fully human monoclonal antibody that targets IL-17A (secukinumab). Further clinical trials, including a humanized IgG4 specific for IL-17 (ixekizumab) and a fully human antibody that targets the IL-17 receptor A (brodalumab).

  10. Antihypertensive treatment in renal transplant patients--is there a role for ACE inhibitors?

    PubMed

    Hausberg, M; Kosch, M; Hohage, H; Suwelack, B; Barenbrock, M; Kisters, K; Rahn, K H

    2001-01-01

    During the past two decades great progress was achieved with regards to short-term kidney graft survival. However, long-term graft survival did not improve similarly. Many factors contribute to chronic graft nephropathy eventually resulting in late graft loss, among these arterial hypertension is of major importance. In patients with chronic renal disease of diabetic and non-diabetic origin, angiotensin converting enzyme inhibitors have been convincingly shown to slow the progression of renal failure. The achieved nephroprotection correlates with the reduction of proteinuria by ACE inhibitor treatment. Also in renal transplant patients, ACE inhibitors have been shown unequivocally to reduce urinary protein excretion. The prevention of hyperfiltration, particular in the context of a reduced number of functional nephrons in patients with chronic graft nephropathy, could be important to prolong graft survival after renal transplantation. Moreover, ACE inhibitors may exert beneficial effects on immunologic processes contributing to chronic graft nephropathy. Many studies published in the last decade show convincingly that ACE inhibitors are safe and effective for the treatment of hypertension in renal allograft recipients. However, no data exist so far showing that ACE inhibitors are superior to other antihypertensive drugs in renal transplant patients and that they prolong graft survival. Studies investigating this issue are warranted. Apart from effects on the graft, ACE inhibitors may improve alterations of the cardiovascular system generally observed in renal transplant patients, such as structural alterations of large arteries, left ventricular hypertrophy, disturbed mechanical vessel wall properties and endothelial dysfunction. Therefore, angiotensin converting enzyme inhibitors could reduce cardiovascular morbidity and mortality in kidney transplant patients.

  11. Compensatory Increase of Transglutaminase 2 Is Responsible for Resistance to mTOR Inhibitor Treatment

    PubMed Central

    Cao, Jingwen; Huang, Wenlong

    2016-01-01

    The mechanistic target of rapamycin complex 1 (mTORC1) plays a crucial role in controlling cell growth and homeostasis. Deregulation of mTOR signaling is frequently observed in some cancers, making it an attractive drug target for cancer therapy. Although mTORC1 inhibitor rapalog-based therapy has shown positive results in various pre-clinical animal cancer studies, tumors rebound upon treatment discontinuation. Moreover, several recent clinical trials showed that the mTORC1 inhibitors rapamycin and rapalog only reduce the capacity for cell proliferation without promoting cell death, consistent with the concept that rapamycin is cytostatic and reduces disease progression but is not cytotoxic. It is imperative that rapamycin-regulated events and additional targets for more effective drug combinations be identified. Here, we report that rapamycin treatment promotes a compensatory increase in transglutaminase 2 (TGM2) levels in mTORC1-driven tumors. TGM2 inhibition potently sensitizes mTORC1-hyperactive cancer cells to rapamycin treatment, and a rapamycin-induced autophagy blockade inhibits the compensatory TGM2 upregulation. More importantly, tumor regression was observed in MCF-7-xenograft tumor-bearing mice treated with both mTORC1 and TGM2 inhibitors compared with those treated with either a single inhibitor or the vehicle control. These results demonstrate a critical role for the compensatory increase in transglutaminase 2 levels in promoting mTORC1 inhibitor resistance and suggest that rational combination therapy may potentially suppress cancer therapy resistance. PMID:26872016

  12. Compensatory Increase of Transglutaminase 2 Is Responsible for Resistance to mTOR Inhibitor Treatment.

    PubMed

    Cao, Jingwen; Huang, Wenlong

    2016-01-01

    The mechanistic target of rapamycin complex 1 (mTORC1) plays a crucial role in controlling cell growth and homeostasis. Deregulation of mTOR signaling is frequently observed in some cancers, making it an attractive drug target for cancer therapy. Although mTORC1 inhibitor rapalog-based therapy has shown positive results in various pre-clinical animal cancer studies, tumors rebound upon treatment discontinuation. Moreover, several recent clinical trials showed that the mTORC1 inhibitors rapamycin and rapalog only reduce the capacity for cell proliferation without promoting cell death, consistent with the concept that rapamycin is cytostatic and reduces disease progression but is not cytotoxic. It is imperative that rapamycin-regulated events and additional targets for more effective drug combinations be identified. Here, we report that rapamycin treatment promotes a compensatory increase in transglutaminase 2 (TGM2) levels in mTORC1-driven tumors. TGM2 inhibition potently sensitizes mTORC1-hyperactive cancer cells to rapamycin treatment, and a rapamycin-induced autophagy blockade inhibits the compensatory TGM2 upregulation. More importantly, tumor regression was observed in MCF-7-xenograft tumor-bearing mice treated with both mTORC1 and TGM2 inhibitors compared with those treated with either a single inhibitor or the vehicle control. These results demonstrate a critical role for the compensatory increase in transglutaminase 2 levels in promoting mTORC1 inhibitor resistance and suggest that rational combination therapy may potentially suppress cancer therapy resistance. PMID:26872016

  13. [PCSK9 inhibitors : New treatment option in clinical practice].

    PubMed

    Müller-Wieland, D; Marx, N

    2016-06-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors leading to their degradation in the liver. Inhibition of PCSK9 leads to an increase in LDL receptors and as a result to a reduction of LDL cholesterol in blood. Currently, two antibodies against PCSK9 are available for clinical treatment in Germany, evolocumab (Repatha®) and alirocumab (Praluent®). Clinical studies have shown that treatment with these antibodies, which must be subcutaneously injected by patients every 2 or 4 weeks, in addition to an already existing lipid therapy can lower the LDL cholesterol level in blood by an average of 50-60 %. Data from previous study programs show that this treatment is safe although long-term data are still lacking. The results of currently running cardiovascular endpoint studies are not yet available, whereby a beneficial effect is to be expected after the preliminary analyses. These novel effective therapy approaches open up new perspectives for the treatment of patients whose LDL cholesterol values are still in excess of the corresponding target values despite previous maximum lipid-reducing therapy and suffer from a preexisting cardiovascular disease, statin intolerance, genetic forms of familiar hypercholesterolemia and patients on LDL apheresis. PMID:27215418

  14. Acetylcholinesterase inhibitory activity of Thai traditional nootropic remedy and its herbal ingredients.

    PubMed

    Tappayuthpijarn, Pimolvan; Itharat, Arunporn; Makchuchit, Sunita

    2011-12-01

    The incidence of Alzheimer disease (AD) is increasing every year in accordance with the increasing of elderly population and could pose significant health problems in the future. The use of medicinal plants as an alternative prevention or even for a possible treatment of the AD is, therefore, becoming an interesting research issue. Acetylcholinesterase (AChE) inhibitors are well-known drugs commonly used in the treatment of AD. The aim of the present study was to screen for AChE inhibitory activity of the Thai traditional nootropic recipe and its herbal ingredients. The results showed that ethanolic extracts of four out of twenty-five herbs i.e. Stephania pierrei Diels. Kaempfera parviflora Wall. ex Baker, Stephania venosa (Blume) Spreng, Piper nigrum L at 0.1 mg/mL showed % AChE inhibition of 89, 64, 59, 50; the IC50 were 6, 21, 29, 30 microg/mL respectively. The other herbs as well as combination of the whole recipe had no synergistic inhibitory effect on AChE activity. However some plants revealed antioxidant activity. More research should have be performed on this local wisdom remedy to verify the uses in scientific term. PMID:22619927

  15. Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

    PubMed Central

    2010-01-01

    Introduction Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. Methods In vitro assays monitoring inhibitor potencies at APP γ-site cleavage (equivalent to Aβ40), and Notch ε-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of Aβ production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain Aβ was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain Aβ reduction vs. Notch signaling endpoints in periphery. Results The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting Aβ production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain Aβ in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain Aβ was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post

  16. Synthesis of organophosphates with fluorine-containing leaving groups as serine esterase inhibitors with potential for Alzheimer disease therapeutics.

    PubMed

    Makhaeva, Galina F; Aksinenko, Alexey Y; Sokolov, Vladimir B; Serebryakova, Olga G; Richardson, Rudy J

    2009-10-01

    Acetylcholinesterase and butyrylcholinesterase inhibitors are potential cognition enhancers in Alzheimer disease. O,O-Dialkylphosphate inhibitors with 1-substituted 2,2,2-trifluoroethoxy leaving groups were synthesized by phosphonate-phosphate rearrangement. Substituents in the 1-position of the leaving group along with the O-alkyl groups modulated potency and selectivity against acetylcholinesterase, butyrylcholinesterase, and carboxylesterase.

  17. Treatment of Selective Serotonin Reuptake Inhibitor-Resistant Depression in Adolescents: Predictors and Moderators of Treatment Response

    ERIC Educational Resources Information Center

    Asarnow, Joan Rosenbaum; Emslie, Graham; Clarke, Greg; Wagner, Karen Dineen; Spirito, Anthony; Vitiello, Benedetto; Iyengar, Satish; Shamseddeen, Wael; Ritz, Louise; Birmaher, Boris; Ryan, Neal; Kennard, Betsy; Mayes, Taryn; DeBar, Lynn; McCracken, James; Strober, Michael; Suddath, Robert; Leonard, Henrietta; Porta, Giovanna; Keller, Martin; Brent, David

    2009-01-01

    Adolescents who did not improve with Selective Serotonin Reuptake Inhibitor (SSRI) were provided an alternative SSRI plus cognitive-behavioral therapy (CBT). The superiority of the CBT/combined treatment as compared to medication alone is more evident in youths who had more comorbid disorders, no abuse history, and lower hopelessness.

  18. BACE1 (β-Secretase) Inhibitors for the Treatment of Alzheimer's Disease

    PubMed Central

    Osswald, Heather L.

    2014-01-01

    BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's Disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's Disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials. PMID:24691405

  19. Combined cisplatin and aurora inhibitor treatment increase neuroblastoma cell death but surviving cells overproduce BDNF.

    PubMed

    Polacchini, Alessio; Albani, Clara; Baj, Gabriele; Colliva, Andrea; Carpinelli, Patrizia; Tongiorgi, Enrico

    2016-07-15

    Drug-resistance to chemotherapics in aggressive neuroblastoma (NB) is characterized by enhanced cell survival mediated by TrkB and its ligand, brain-derived neurotrophic factor (BDNF); thus reduction in BDNF levels represent a promising strategy to overcome drug-resistance, but how chemotherapics regulate BDNF is unknown. Here, cisplatin treatment in SK-N-BE neuroblastoma upregulated multiple BDNF transcripts, except exons 5 and 8 variants. Cisplatin increased BDNF mRNA and protein, and enhanced translation of a firefly reporter gene flanked by BDNF 5'UTR exons 1, 2c, 4 or 6 and 3'UTR-long. To block BDNF translation we focused on aurora kinases inhibitors which are proposed as new chemotherapeutics. NB cell survival after 24 h treatment was 43% with cisplatin, and 22% by cisplatin+aurora kinase inhibitor PHA-680632, while the aurora kinases inhibitor alone was less effective; however the combined treatment induced a paradoxical increase of BDNF in surviving cells with strong translational activation of exon6-3'UTR-long transcript, while translation of BDNF transcripts 1, 2C and 4 was suppressed. In conclusion, combined cisplatin and aurora kinase inhibitor treatment increases cell death, but induces BDNF overproduction in surviving cells through an aurora kinase-independent mechanism.

  20. Combined cisplatin and aurora inhibitor treatment increase neuroblastoma cell death but surviving cells overproduce BDNF.

    PubMed

    Polacchini, Alessio; Albani, Clara; Baj, Gabriele; Colliva, Andrea; Carpinelli, Patrizia; Tongiorgi, Enrico

    2016-01-01

    Drug-resistance to chemotherapics in aggressive neuroblastoma (NB) is characterized by enhanced cell survival mediated by TrkB and its ligand, brain-derived neurotrophic factor (BDNF); thus reduction in BDNF levels represent a promising strategy to overcome drug-resistance, but how chemotherapics regulate BDNF is unknown. Here, cisplatin treatment in SK-N-BE neuroblastoma upregulated multiple BDNF transcripts, except exons 5 and 8 variants. Cisplatin increased BDNF mRNA and protein, and enhanced translation of a firefly reporter gene flanked by BDNF 5'UTR exons 1, 2c, 4 or 6 and 3'UTR-long. To block BDNF translation we focused on aurora kinases inhibitors which are proposed as new chemotherapeutics. NB cell survival after 24 h treatment was 43% with cisplatin, and 22% by cisplatin+aurora kinase inhibitor PHA-680632, while the aurora kinases inhibitor alone was less effective; however the combined treatment induced a paradoxical increase of BDNF in surviving cells with strong translational activation of exon6-3'UTR-long transcript, while translation of BDNF transcripts 1, 2C and 4 was suppressed. In conclusion, combined cisplatin and aurora kinase inhibitor treatment increases cell death, but induces BDNF overproduction in surviving cells through an aurora kinase-independent mechanism. PMID:27256407

  1. Combined cisplatin and aurora inhibitor treatment increase neuroblastoma cell death but surviving cells overproduce BDNF

    PubMed Central

    Polacchini, Alessio; Albani, Clara; Baj, Gabriele; Colliva, Andrea; Carpinelli, Patrizia

    2016-01-01

    ABSTRACT Drug-resistance to chemotherapics in aggressive neuroblastoma (NB) is characterized by enhanced cell survival mediated by TrkB and its ligand, brain-derived neurotrophic factor (BDNF); thus reduction in BDNF levels represent a promising strategy to overcome drug-resistance, but how chemotherapics regulate BDNF is unknown. Here, cisplatin treatment in SK-N-BE neuroblastoma upregulated multiple BDNF transcripts, except exons 5 and 8 variants. Cisplatin increased BDNF mRNA and protein, and enhanced translation of a firefly reporter gene flanked by BDNF 5′UTR exons 1, 2c, 4 or 6 and 3′UTR-long. To block BDNF translation we focused on aurora kinases inhibitors which are proposed as new chemotherapeutics. NB cell survival after 24 h treatment was 43% with cisplatin, and 22% by cisplatin+aurora kinase inhibitor PHA-680632, while the aurora kinases inhibitor alone was less effective; however the combined treatment induced a paradoxical increase of BDNF in surviving cells with strong translational activation of exon6-3′UTR-long transcript, while translation of BDNF transcripts 1, 2C and 4 was suppressed. In conclusion, combined cisplatin and aurora kinase inhibitor treatment increases cell death, but induces BDNF overproduction in surviving cells through an aurora kinase-independent mechanism. PMID:27256407

  2. Individualization of bypassing agent treatment for haemophilic patients with inhibitors utilizing thromboelastography.

    PubMed

    Young, G; Blain, R; Nakagawa, P; Nugent, D J

    2006-11-01

    The treatment of bleeding for haemophilic patients with inhibitors relies on the use of the bypassing agents, recombinant factor VIIa and factor eight inhibitor bypass activity (FEIBA). While both therapies are effective in the majority of bleeding episodes, there is a significant amount of interindividual variability when it comes to the response to therapy. As of yet, there is no reliable laboratory parameter that can predict the response to therapy in the same manner that factor VIII and factor IX levels predict response in non-inhibitor patients. Developing such a laboratory parameter is vital in order to maximize the clinical efficacy of these agents. Thromboelastography (TEG) is a device, which assesses clot formation over time in whole blood and has several characteristics which suggest it may be an effective way to monitor bypass agent therapy. We studied the ability of TEG to individualize the treatment regimens of three patients with high titre inhibitors assessing the response to recombinant factor VIIa, FEIBA, and when both were used sequentially. The TEG allowed for individualization of treatment for each of the three patients and resulted in more effective, convenient and less expensive treatment regimens. We thus believe that TEG is a promising device for monitoring of bypass agent therapy and should be studied further.

  3. Treatment of hereditary angioedema with plasma-derived C1 inhibitor

    PubMed Central

    Prematta, Michael J; Prematta, Tracy; Craig, Timothy J

    2008-01-01

    Background: Plasma-derived C1 inhibitor (C1-INH) concentrate is a treatment option for acute hereditary angioedema (HAE) attacks and is considered the standard-of-care in many countries, although it is not yet available in the United States. Studies are still being conducted to establish its safety and efficacy as required by the FDA. Objective: To review the medical literature to determine if C1-INH concentrate is a safe and effective treatment for acute HAE attacks. Methods: The following keywords were searched in PubMed and OVID: C1 esterase inhibitor, C1-inhibitor, C1 inhibitor, and hereditary angioedema treatment. English-language articles were searched from 1966 to the present to look for studies demonstrating the efficacy and the safety of C1-INH concentrate. Results: The English-language literature search revealed several studies showing significantly improved relief of HAE symptoms with the administration of C1-INH concentrate – many studies demonstrated some improvement of symptoms within 30 minutes. Side effects have been similar to placebo, and no proven cases of viral transmission have occurred in over 20 years. Conclusion: C1-INH concentrate appears to be a very safe and effective treatment option for HAE. PMID:19209279

  4. DEPRESSION and SEROTONIN REUPTAKE INHIBITOR TREATMENT AS RISK FACTORS FOR PRETERM BIRTH

    PubMed Central

    Yonkers, Kimberly A.; Norwitz, Errol R.; Smith, Megan V.; Lockwood, Charles J.; Gotman, Nathan; Luchansky, Edward; Lin, Haiqun; Belanger, Kathleen

    2012-01-01

    Background Major depressive disorder as well as the use of serotonin reuptake inhibitors in pregnancy have been associated with preterm birth. Studies that have attempted to separate effects of illness from treatment have been inconclusive. We sought to explore the separate effects of serotonin reuptake inhibitor use and major depressive episodes in pregnancy on risk of preterm birth. Methods We conducted a prospective cohort study of 2793 pregnant women, oversampled for a recent episode of major depression or use of a serotonin reuptake inhibitor. We extracted data on birth outcomes from hospital charts and used binary logistic regression to model preterm birth (<37 weeks’ gestation). We used ordered logistic regression to model early (<34 weeks’ gestation) or late (34-36 weeks) preterm birth, and we used nominal logistic regression to model preterm birth antecedents (spontaneous preterm labor/preterm premature rupture of membranes/preterm for medical indications/term). Results Use of a serotonin reuptake inhibitor, both with (odds ratio=2.1 [95% confidence interval=1.0—4.6]) and without (1.6=[1.0—2.5]) a major depressive episode, was associated with preterm birth. A major depressive episode without serotonin reuptake inhibitor use (1.2; [0.68—2.1]) had no clear effect on preterm risk. None of these exposures was associated with early preterm birth. Use of serotonin reuptake inhibitors in pregnancy was associated with increases in spontaneous but not medically indicated preterm birth. Conclusions Serotonin reuptake inhibitor use increased risk of preterm birth. Although the effect of a major depressive episode alone was unclear, symptomatic women undergoing antidepressant treatment had elevated risk. PMID:22627901

  5. Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

    PubMed Central

    2015-01-01

    JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile. PMID:26288683

  6. Inhibitor-Based Therapeutics for Treatment of Viral Hepatitis

    PubMed Central

    Dey, Debajit; Banerjee, Manidipa

    2016-01-01

    Abstract Viral hepatitis remains a significant worldwide threat, in spite of the availability of several successful therapeutic and vaccination strategies. Complications associated with acute and chronic infections, such as liver failure, cirrhosis and hepatocellular carcinoma, are the cause of considerable morbidity and mortality. Given the significant burden on the healthcare system caused by viral hepatitis, it is essential that novel, more effective therapeutics be developed. The present review attempts to summarize the current treatments against viral hepatitis, and provides an outline for upcoming, promising new therapeutics. Development of novel therapeutics requires an understanding of the viral life cycles and viral effectors in molecular detail. As such, this review also discusses virally-encoded effectors, found to be essential for virus survival and replication in the host milieu, which may be utilized as potential candidates for development of alternative therapies in the future. PMID:27777893

  7. ENaC inhibitors for the treatment of cystic fibrosis.

    PubMed

    Butler, Rebecca; Hunt, Thomas; Smith, Nichola J

    2015-01-01

    The epithelial Na(+) channel, ENaC, is a key regulator of the volume of airway surface liquid in the human airway epithelium. In cystic fibrosis (CF), Na(+) hyperabsorption through ENaC in the absence of CFTR-mediated anion secretion results in the dehydration of respiratory secretions and the impairment of mucociliary clearance. The hypothesis of utilizing an ENaC-blocking molecule to facilitate restoration of the airway surface liquid volume sufficiently to allow normal mucociliary clearance is of interest in the management of lung disease in CF patients. This article summarizes the published patent applications from 2010 that claim approaches to inhibit the function of ENaC for utility in the treatment of CF. Patents were located though SciFinder(®), using "ENaC" as the keyword from 2010 onwards; documents not relevant to CF were then manually removed. PMID:25565157

  8. Acetylcholinesterase activity in Clytia hemisphaerica (Cnidaria).

    PubMed

    Denker, Elsa; Chatonnet, Arnaud; Rabet, Nicolas

    2008-09-25

    Cholinesterase activity is known in representatives of all living organisms phyla but the origin of the cholinergic system as known in bilaterian animals is still undeciphered. In particular the implication of cholinesterases in the nervous system of non-bilaterian Metazoa is not well known. We thus chose to investigate this activity in the Clytia hemisphaerica (Cnidaria) medusa. In toto histochemical staining revealed an acetylcholinesterase activity in the tentacle bulbs but not in the nervous system. Sequences homologous to acetylcholinesterase were searched within Clytia ESTs and compared to other sequences found in public databases.

  9. Role of acetylcholinesterase in lung cancer

    PubMed Central

    Xi, Hui-Jun; Wu, Ren-Pei; Liu, Jing-Jing; Zhang, Ling-Juan; Li, Zhao-Shen

    2015-01-01

    Acetylcholinesterase (AChE) plays a key role in catalytic hydrolysis of cholinergic neurotransmitters. Intensive research has proven the involvement of this protein in novel functions, such as cell adhesion, differentiation, and proliferation. In addition, several recent studies have indicated that acetylcholinesterase is potentially a marker and regulator of apoptosis. Importantly, AChE is also a promising tumor suppressor. In this review, we briefly summarize the involvement of AChE in apoptosis and cancer, focusing on the role of AChE in lung cancer, as well as the therapeutic consideration of AChE for cancer therapy. PMID:26273392

  10. [Research progresses of the PARP inhibitors for the treatment of cancer].

    PubMed

    He, Yu-Jun; Liu, Rui-Huan; Ning, Cheng-Qing; Yu, Nie-Fang

    2013-05-01

    The poly(ADP-ribose) polymerases (PARPs) is an important group of enzymes in DNA repair pathways, especially the base excision repair (BER) for DNA single-strand breaks (SSBs) repair. Inhibition of PARP in DNA repair-defective tumors (like those with BRAC1/2 mutations) can lead to cell death and genomic instability, what is so called "synthetic lethality". Currently, PARP inhibitors combined with cytotoxic chemotherapeutic agents in the treatment of BRCA-1/2 deficient cancers are in the clinical development. In this review, we will be focused on the development of combination application of PARP inhibitors with other anticancer agents in clinical trials.

  11. First Selective CYP11B1 Inhibitors for the Treatment of Cortisol-Dependent Diseases

    PubMed Central

    2010-01-01

    Outgoing from an etomidate-based design concept, we succeeded in the development of a series of highly active and selective inhibitors of CYP11B1, the key enzyme of cortisol biosynthesis, as potential drugs for the treatment of Cushing's syndrome and related diseases. Thus, compound 33 (IC50 = 152 nM) is the first CYP11B1 inhibitor showing a rather good selectivity toward the most important steroidogenic CYP enzymes aldosterone synthase (CYP11B2), the androgen-forming CYP17, and aromatase (estrogen synthase, CYP19). PMID:24900247

  12. Data on the utilization of treatment modalities for ED in Taiwan in the era of PDE5 inhibitors.

    PubMed

    Tsai, W-K; Jiann, B-P

    2014-01-01

    Oral PDE5 inhibitors, intracavernosal injection and penile implants are mainstay treatments for ED. Data on their utilization reflect economic aspects of ED, but are underreported. We report utilization data and user characteristics for these modalities in Taiwan between 1999 and 2011. Sales data on PDE5 inhibitors-sildenafil citrate, tadalafil and vardenafil and on alprostadil were retrieved from International Market Services Health, and on penile implants from the local importing company for them. Users' clinical characteristics were derived from one institution. Between 1999 and 2011, sales of PDE5 inhibitors increased 5.9-fold, whereas those of alprostadil and penile implants remained stable. Over 90% of PDE5 inhibitors were purchased in pharmacies without a prescription. Between 1999 and 2011, the number of patients who received PDE5 inhibitors (n=4715) exceeded those who underwent penile injection (n=333) and penile implantation (n=108). The mean age of patients with ED who first received PDE5 inhibitors tended to decrease over consecutive years. Discontinuation of treatment with PDE5 inhibitors or intracavernosal injection reached 90% within 3 years of treatment initiation. Our data on the increasing market for PDE5 inhibitors and the trend for first use of PDE5 inhibitors at younger ages highlight the growing burden of ED and the acceptance of PDE5 inhibitors as the primary treatment for ED. PMID:24451166

  13. Resistance to reverse transcriptase inhibitors used in the treatment and prevention of HIV-1 infection.

    PubMed

    Sluis-Cremer, Nicolas; Wainberg, Mark A; Schinazi, Raymond F

    2015-01-01

    Inhibitors that target the retroviral enzyme reverse transcriptase (RT) have played an indispensable role in the treatment and prevention of HIV-1 infection. They can be grouped into two distinct therapeutic groups, namely the nucleoside and nucleotide RT inhibitors (NRTIs), and the non-nucleoside RT inhibitors (NNRTIs). NRTIs form the backbones of most first- and second-line antiretroviral therapy (ART) regimens formulated for the treatment of HIV-1 infection. They are also used to prevent mother-to-child transmission, and as pre-exposure prophylaxis in individuals at risk of HIV-1 infection. The NNRTIs nevirapine (NVP), efavirenz and rilpivirine also used to form part of first-line ART regimens, although this is no longer recommended, while etravirine can be used in salvage ART regimens. A single-dose of NVP administered to both mother and child has routinely been used in resource-limited settings to reduce the rate of HIV-1 transmission. Unfortunately, the development of HIV-1 resistance to RT inhibitors can compromise the efficacy of these antiviral drugs in both the treatment and prevention arenas. Here, we provide an up-to-date review on drug-resistance mutations in HIV-1 RT, and discuss their cross-resistance profiles, molecular mechanisms and clinical significance. PMID:26517190

  14. Treatment with Dimethyl Fumarate attenuates calcineurin inhibitor-induced Nephrotoxicity

    PubMed Central

    Takasu, Chie; Vaziri, Nosratola D.; Li, Shiri; Robles, Lourdes; Vo, Kelly; Takasu, Mizuki; Pham, Christine; Liu, Shuman; Farzaneh, Seyed H.; Foster, Clarence E; Stamos, Michael J; Ichii, Hirohito

    2014-01-01

    Background Cyclosporine A (CsA) is an immunosuppressive drug which has been widely used to prevent rejection following organ transplantation. However, its therapeutic use is limited by nephrotoxicity, in part mediated by oxidative stress. The present study aims to investigate the protective effects of Dimethyl Fumarate (DMF) on CsA-induced nephrotoxicity by enhancing the antioxidant defense system. Methods Male Sprague-Dawley rats were treated with CsA (n=8, 20 mg/kg/day i.p.) orCsA + DMF (n=7, 50 mg/kg/day p.o.) for 28 days. Renal function, histopathology, malondialdehyde (MDA), myeloperoxidase (MPO) levels and anti-oxidant enzyme expression were determined. Results DMF co-treatment ameliorated CsA-induced renal dysfunction as evidenced by significant decrease in serum creatinine (CsA 0.79 ± 0.02 mg/dl vs. CsA + DMF 0.62 ± 0.04 mg/dl, P=0.001) and urea (CsA 66.9 ± 0.4 mg/dl vs. CsA + DMF 53.3 ± 2.6 mg/dl, P<0.0001) levels, as well as improvement of creatinine clearance. DMF also significantly decreased serum MDA and renal tissue MDA and MPO contents. The protein expression of NQO-1, a major cellular anti-oxidant and detoxifying enzyme was significantly enhanced by DMF administration in kidney. Conclusions Administration of DMF has a protective potential against CsA nephrotoxicity. The protection afforded by DMF is mediated in part through inhibiting oxidative stress and inflammation and enhancing the antioxidant capacity. PMID:25710612

  15. Synthesis of Novel 3-Aryl-N-Methyl-1,2,5,6-Tetrahydropyridine Derivatives by Suzuki coupling: As Acetyl Cholinesterase Inhibitors

    PubMed Central

    Prasad, S.B. Benaka; Kumar, Y.C. Sunil; Kumar, C.S. Ananda; Sadashiva, C.T; Vinaya, K; Rangappa, K.S

    2007-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder affecting the central nervous system, which is also associated with progressive loss of memory and cognition. The development of numerous structural classes of compounds with different pharmacological profile could be an evolving, promising therapeutic approach for the treatment of AD. Thus, providing a symptomatic treatment for this disease are cholinomimetics with the pharmacological profile of Acetylcholinesterase (AChE) inhibitors. In view of this, we have synthesized novel 3-aryl-N-methyl-1,2,5,6-tetrahydropyridine derivatives 5a-k by Suzuki coupling and screened the efficacy of these derivatives for their AChE inhibitor activity. PMID:19662135

  16. Role of 5α-reductase inhibitors in prostate cancer prevention and treatment.

    PubMed

    Azzouni, Faris; Mohler, James

    2012-06-01

    Although testosterone is the most abundant serum androgen, dihydrotestosterone is the main prostatic androgen. Testosterone is converted to dihydrotestosterone by the enzyme 5α-reductase (5α-R). Dihydrotestosterone plays an important role in several human diseases, including benign prostate enlargement and prostate cancer. The observation that males born with 5α-R 2 deficiency have never been reported to develop prostate cancer stimulated interest in development of 5α-R inhibitors. Thus far, 2 5α-R inhibitors are approved for clinical use. Several trials evaluated the use of 5α-R inhibitors in prostate cancer prevention and treatment and will be reviewed in this article. PMID:22446342

  17. Diagnosis and treatment of congenital hemophilia with inhibitors a Latin American perspective.

    PubMed

    Pérez Bianco, Raúl; Ozelo, Margareth Castro; Villaça, Paula Ribeiro; Solano, Maria Helena; Jimenez Cruze, Guillermo; Martinez Murillo, Carlos; Garcia Chavez, Jaime; Mendoza, Saul; Rodriguez Grecco, Ismael; Ruiz-Saez, Arlette

    2008-01-01

    The Committee of Latin America on the Therapeutics of Inhibitor Groups (CLOTTING) is composed of a number of hemophilia specialists from Latin America. The group aims to encourage the adoption of a good standard of care for Latin American patients with hemophilia. The occurrence of inhibitors in patients with hemophilia poses clinical challenges, and it is estimated that between 1000 and 3000 patients in Latin America are affected by hemophilia with inhibitors. There is an urgent need to establish a regional consensus and clinical guidelines for the diagnosis and treatment of these patients. We present an extensive review based on best current clinical practice and published literature, as seen from a Latin American perspective, taking into account the variable nature of hemophilia care available in the various countries in this Region.

  18. Cathepsin K inhibitors: a novel target but promising approach in the treatment of osteoporosis.

    PubMed

    Helali, Asadul Mazid; Iti, Farhana Matin; Mohamed, Isa Naina

    2013-12-01

    Osteoporosis is a pathologic process characterized by low bone mass with skeletal fragility and an increased risk of fracture. It occurs due to an imbalance between bone resorption and formation. Although current antiresorptive therapy halts bone loss, it does not cure the condition as it also inhibits bone formation. Recent preclinical and clinical trials suggest that the inhibition of resorption by cathepsin K inhibitors increases bone formation. Cathepsin K is a papainlike cysteine protease with high potent collagenase activity and predominantly expressed in osteoclasts. While allowing demineralization, cathepsin K inhibitors suppress the degradation of type I collagen (the major organic matrix of bone) and thus enhancing bone formation. Many of these inhibitors have passed preclinical studies and are presently in clinical trials at different stages of advancement. This review explores the promising role of cathepsin K as a novel antiresorptive for the treatment of osteoporosis.

  19. Future perspectives for mTOR inhibitors in renal cell cancer treatment.

    PubMed

    Czarnecka, Anna M; Kornakiewicz, Anna; Lian, Fei; Szczylik, Cezary

    2015-01-01

    Everolimus is a mTOR inhibitor that demonstrates antitumor and antiangiogenic activities. In a randomized Phase III trial, patients with metastatic renal cell carcinoma who progressed on sunitinib/sorafenib were treated with everolimus and showed significant improvement in progression-free survival compared with best supportive care. Novel approaches in treatment are expected to ensure less toxic therapies and increase efficacy of everolimus. To provide a new perspective for mTOR inhibitor research and therapy, we discuss renal cell carcinoma cancer stem cells as a potential target for mTOR inhibitors and present new concepts on emerging antiangiogenic therapies. Finally, we point why systems biology approach with reverse molecular engineering may also contribute to the field of drug discovery in renal cell carcinoma.

  20. Effects of aldose reductase inhibitor treatment in diabetic polyneuropathy - a clinical and neurophysiological study.

    PubMed Central

    Fagius, J; Jameson, S

    1981-01-01

    The efficacy of treatment with an aldose reductase inhibitor (1,3-dioxo-1 H-benz-de-isoquinoline-2(3H)-acetic acid, AY-22,284, Alrestatin) on peripheral nerve function in diabetic polyneuropathy was assessed. Thirty patients with long-standing diabetes and slight to moderate neuropathy participated in the double-blind placebo trial. Clinical examination, sensory threshold determinations for vibratory, tactile and thermal stimuli, conduction velocity measurements and studies of automatic function were performed to evaluate the treatment. Significant differences favouring Alrestatin over placebo were found for many of the measured variables, whereas no changes occurred on placebo. The apparent improvement of neuropathy occurred despite persisting hyperglycaemia. The results indicate that aldose reductase inhibitor treatment may be of value in diabetic polyneuropathy, and provide support for the sorbitol pathway hypothesis of diabetic polyneuropathy. PMID:6801211

  1. Acetylcholinesterase inhibitory, antioxidant and phytochemical properties of selected medicinal plants of the Lamiaceae family.

    PubMed

    Vladimir-Knežević, Sanda; Blažeković, Biljana; Kindl, Marija; Vladić, Jelena; Lower-Nedza, Agnieszka D; Brantner, Adelheid H

    2014-01-09

    The present study aimed to evaluate acetylcholinesterase (AChE) inhibitory and antioxidant activities of Lamiaceae medicinal plants growing wild in Croatia. Using Ellman's colorimetric assay all tested ethanolic extracts and their hydroxycinnamic acid constituents demonstrated in vitro AChE inhibitory properties in a dose dependent manner. The extracts of Mentha x piperita, M. longifolia, Salvia officinalis, Satureja montana, Teucrium arduini, T. chamaedrys, T. montanum, T. polium and Thymus vulgaris at 1 mg/mL showed strong inhibitory activity against AChE. The antioxidant potential of the investigated Lamiaceae species was assessed by DPPH• scavenging activity and total antioxidant capacity assays, in comparison with hydroxycinnamic acids and trolox. The extracts differed greatly in their total hydroxycinnamic derivatives content, determined spectrophotometrically. Rosmarinic acid was found to be the predominant constituent in most of the investigated medicinal plants (by RP-HPLC) and had a substantial influence on their AChE inhibitory and antioxidant properties, with the exception of Teucrium species. These findings indicate that Lamiaceae species are a rich source of various natural AChE inhibitors and antioxidants that could be useful in the prevention and treatment of Alzheimer's and other related diseases.

  2. Inhibitory effect of ebselen on cerebral acetylcholinesterase activity in vitro: kinetics and reversibility of inhibition.

    PubMed

    Martini, Franciele; Bruning, César Augusto; Soares, Suelen Mendonca; Nogueira, Cristina Wayne; Zeni, Gilson

    2015-01-01

    Ebselen is a synthetic organoselenium compound that has been considered a potential pharmacological agent with low toxicity, showing antioxidant, anti-inflammatory and neuroprotective effects. It is bioavailable, blood-brain barrier permeant and safe based on cellular toxicity and Phase I-III clinical trials. There is evidence that ebselen inhibits acetylcholinesterase (AChE) activity, an enzyme that plays a key role in the cholinergic system by hydrolyzing acetylcholine (ACh), in vitro and ex vivo. This system has a well-known relationship with cognitive process, and AChE inhibitors, such as donepezil and galantamine, have been used to treat cognitive deficits, mainly in the Alzheimer's Disease (AD). However, these drugs have poor bioavailability and a number of side effects, including gastrointestinal upsets and hepatotoxicity. In this way, this study aimed to evaluate the effect of ebselen on cerebral AChE activity in vitro and to determine the kinetic profile and the reversibility of inhibition by dialysis. Ebselen inhibited the cerebral AChE activity with an IC50 of 29 µM, similar to IC50 found with pure AChE from electric eel, demonstrating a mixed and reversible inhibition of AChE, since it increased Km and decreased Vmax. The AChE activity was recovered within 60 min of dialysis. Therefore, the use of ebselen as a therapeutic agent for treatment of AD should be considered, although memory behavior tasks are needed to support such hypothesis. PMID:25312723

  3. Inhibition of Growth by Combined Treatment with Inhibitors of Lactate Dehydrogenase and either Phenformin or Inhibitors of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase 3.

    PubMed

    Lea, Michael A; Guzman, Yolanda; Desbordes, Charles

    2016-04-01

    Enhanced glycolysis in cancer cells presents a target for chemotherapy. Previous studies have indicated that proliferation of cancer cells can be inhibited by treatment with phenformin and with an inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB) namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). In the present work, the action of two inhibitors that are effective at lower concentrations than 3PO, namely 1-(3-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PQP) and 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) were investigated. The inhibitors of lactate dehydrogenase (LDHA) studied in order of half-maximal inhibitory concentrations were methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2) < isosafrole < oxamate. In colonic and bladder cancer cells, additive growth inhibitory effects were seen with the LDHA inhibitors, of which NHI-2 was effective at the lowest concentrations. Growth inhibition was generally greater with PFK15 than with PQP. The increased acidification of the culture medium and glucose uptake caused by phenformin was blocked by combined treatment with PFKFB3 or LDHA inhibitors. The results suggest that combined treatment with phenformin and inhibitors of glycolysis can cause additive inhibition of cell proliferation and may mitigate lactic acidosis caused by phenformin when used as a single agent. PMID:27069123

  4. Characterisation of acetylcholinesterase release from neuronal cells.

    PubMed

    Hicks, David A; Makova, Natalia Z; Nalivaeva, Natalia N; Turner, Anthony J

    2013-03-25

    Although acetylcholinesterase (AChE) is primarily a hydrolytic enzyme, metabolising the neurotransmitter acetylcholine in cholinergic synapses, it also has some non-catalytic functions in the brain which are far less well characterised. AChE was shown to be secreted or shed from the neuronal cell surface like several other membrane proteins, such as the amyloid precursor protein (APP). Since AChE does not possess a transmembrane domain, its anchorage in the membrane is established via the Proline Rich Membrane Anchor (PRiMA), a transmembrane protein. Both the subunit oligomerisation and membrane anchor of AChE are shared by a related enzyme, butyrylcholinesterase (BChE), the physiological function of which in the brain is unclear. In this work, we have assayed the relative activities of AChE and BChE in membrane fractions and culture medium of three different neuronal cell lines, namely the neuroblastoma cell lines SH-SY5Y and NB7 and the mouse basal forebrain cell line SN56. In an effort to understand the shedding process of AChE, we have used several pharmacological treatments, which showed that it is likely to be mediated in part by an EDTA- and batimastat-sensitive, but GM6001-insensitive metalloprotease, with the possible additional involvement of a thiol isomerase. Cellular release of AChE by SH-SY5Y is significantly enhanced by the muscarinic acetylcholine receptor (mAChR) agonists carbachol or muscarine, with the effect of carbachol blocked by the mAChR antagonist atropine. AChE has been implicated in the pathogenesis of Alzheimer's disease and it has been shown that it accelerates formation and increases toxicity of amyloid fibrils, which have been closely linked to the pathology of AD. In light of this, greater understanding of AChE and BChE physiology may also benefit AD research.

  5. Rat brain acetylcholinesterase visualized with [11C]physostigmine.

    PubMed

    Planas, A M; Crouzel, C; Hinnen, F; Jobert, A; Né, F; DiGiamberardino, L; Tavitian, B

    1994-06-01

    Physostigmine, a powerful cholinesterase inhibitor, has recently been labelled with 11C in view of its potential application for in vivo imaging of cerebral acetylcholinesterase (AChE) using positron emission tomography. Here we carried out autoradiography of the rat brain using [11C]physostigmine in order to characterize the cerebral targets of this ligand. Autoradiograms were obtained using phosphor storage plates which, compared to autoradiographic films, greatly improved the quality of 11C images. Following autoradiography, brain sections were stained for AChE activity, allowing a direct comparison of autoradiographic and histoenzymatic localizations. The distributions of 11C label and of AChE activity were found to be essentially super-imposable, both after in vivo injection of and after in vitro incubation with [11C]physostigmine. Densitometric analysis showed that radioactivity and enzymatic activity distributions were regionally correlated. The fixation of [11C]physostigmine to cerebral tissue was abolished after incubation of the rat brain sections with BW 284C51, a specific AChE inhibitor, but not after incubation with iso-OMPA, a specific inhibitor of butyrylcholinesterase. Unilateral excitotoxic lesions of the striatum that eliminated local AChE expression concomitantly reduced the binding of the ligand in the lesioned area. These results indicate that autoradiographic images of the rat brain obtained with [11C]physostigmine reflect AChE distribution, thus supporting the use of this radioligand to trace cerebral AChE activity in humans with positron emission tomography.

  6. An evaluation of the inhibition of human butyrylcholinesterase and acetylcholinesterase by the organophosphate chlorpyrifos oxon

    SciTech Connect

    Shenouda, Josephine; Green, Paula; Sultatos, Lester

    2009-12-01

    Acetylcholinesterase (EC 3.1.1.7) and butyrylcholinesterase (EC 3.1.1.8) are enzymes that belong to the superfamily of alpha/beta-hydrolase fold proteins. While they share many characteristics, they also possess many important differences. For example, whereas they have about 54% amino acid sequence identity, the active site gorge of acetylcholinesterase is considerably smaller than that of butyrylcholinesterase. Moreover, both have been shown to display simple and complex kinetic mechanisms, depending on the particular substrate examined, the substrate concentration, and incubation conditions. In the current study, incubation of butyrylthiocholine in a concentration range of 0.005-3.0 mM, with 317 pM human butyrylcholinesterase in vitro, resulted in rates of production of thiocholine that were accurately described by simple Michaelis-Menten kinetics, with a K{sub m} of 0.10 mM. Similarly, the inhibition of butyrylcholinesterase in vitro by the organophosphate chlorpyrifos oxon was described by simple Michaelis-Menten kinetics, with a k{sub i} of 3048 nM{sup -1} h{sup -1}, and a K{sub D} of 2.02 nM. In contrast to inhibition of butyrylcholinesterase, inhibition of human acetylcholinesterase by chlorpyrifos oxon in vitro followed concentration-dependent inhibition kinetics, with the k{sub i} increasing as the inhibitor concentration decreased. Chlorpyrifos oxon concentrations of 10 and 0.3 nM gave k{sub i}s of 1.2 and 19.3 nM{sup -1} h{sup -1}, respectively. Although the mechanism of concentration-dependent inhibition kinetics is not known, the much smaller, more restrictive active site gorge of acetylcholinesterase almost certainly plays a role. Similarly, the much larger active site gorge of butyrylcholinesterase likely contributes to its much greater reactivity towards chlorpyrifos oxon, compared to acetylcholinesterase.

  7. Concentration-dependent interactions of the organophosphates chlorpyrifos oxon and methyl paraoxon with human recombinant acetylcholinesterase

    SciTech Connect

    Kaushik, R.; Rosenfeld, Clint A.; Sultatos, L.G. . E-mail: sultatle@umdnj.edu

    2007-06-01

    For many decades it has been thought that oxygen analogs (oxons) of organophosphorus insecticides phosphorylate the catalytic site of acetylcholinesterase by a mechanism that follows simple Michaelis-Menten kinetics. More recently, the interactions of at least some oxons have been shown to be far more complex and likely involve binding of oxons to a second site on acetylcholinesterase that modulates the inhibitory capacity of other oxon molecules at the catalytic site. The current study has investigated the interactions of chlorpyrifos oxon and methyl paraoxon with human recombinant acetylcholinesterase. Both chlorpyrifos oxon and methyl paraoxon were found to have k {sub i}'s that change as a function of oxon concentration. Furthermore, 10 nM chlorpyrifos oxon resulted in a transient increase in acetylthiocholine hydrolysis, followed by inhibition. Moreover, in the presence of 100 nM chlorpyrifos oxon, acetylthiocholine was found to influence both the K {sub d} (binding affinity) and k {sub 2} (phosphorylation constant) of this oxon. Collectively, these results demonstrate that the interactions of chlorpyrifos oxon and methyl paraoxon with acetylcholinesterase cannot be described by simple Michaelis-Menten kinetics but instead support the hypothesis that these oxons bind to a secondary site on acetylcholinesterase, leading to activation/inhibition of the catalytic site, depending on the nature of the substrate and inhibitor. Additionally, these data raise questions regarding the adequacy of estimating risk of low levels of insecticide exposure from direct extrapolation of insecticide dose-response curves since the capacity of individual oxon molecules at low oxon levels could be greater than individual oxon molecules in vivo associated with the dose-response curve.

  8. Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC

    PubMed Central

    Yamasaki, Toshinari; Tran, Tram Anh T.; Oz, Orhan K.; Raj, Ganesh V.; Schwarz, Roderich E.; DeBerardinis, Ralph J.; Zhang, Xuewu; Brugarolas, James

    2011-01-01

    Background A 24-year-old woman presented with a 45 cm complex cystic renal mass, which was resected. The tumor was a type-2 papillary renal cell carcinoma (pRCC-2), and several nodules remained. The patient was treated with mammalian target of rapamycin complex 1 (mTORC1) inhibitors, but after 5 months the tumor had progressed. Genetic testing of the patient revealed a novel heterozygous germline mutation in the gene encoding fumarate hydratase (FH), an enzyme of the tricarboxylic acid (TCA) cycle. As the tumor exhibited loss of heterozygosity for FH and markedly reduced FH activity, and in the absence of other established therapies, treatment with the glycolytic inhibitor 2DG (2-deoxy-d-glucose) was explored. Investigations CT, histology, immunohistochemistry, genetic studies, 2-deoxy-2-(18F)fluoro-d-glucose (18FDG)-PET/CT, FH enzymatic assays, reconstitution experiments and in vitro studies of the effects of 2DG on FH-deficient tumor cells. Diagnosis pRCC-2 arising in a patient with a novel germline FH mutation and de novo hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome progressing after mTORC1 inhibitor therapy. Management Surgical resection of the renal mass, treatment with mTORC1 inhibitors followed by 2DG. Unfortunately, 2DG was not effective, and the patient died several weeks later. PMID:21304509

  9. Pathophysiology of visual disorders induced by phosphodiesterase inhibitors in the treatment of erectile dysfunction

    PubMed Central

    Moschos, Marilita M; Nitoda, Eirini

    2016-01-01

    Aim The aim of this review was to summarize the ocular action of the most common phosphodiesterase (PDE) inhibitors used for the treatment of erectile dysfunction and the subsequent visual disorders. Method This is a literature review of several important articles focusing on the pathophysiology of visual disorders induced by PDE inhibitors. Results PDE inhibitors have been associated with ocular side effects, including changes in color vision and light perception, blurred vision, transient alterations in electroretinogram (ERG), conjunctival hyperemia, ocular pain, and photophobia. Sildenafil and tadalafil may induce reversible increase in intraocular pressure and be involved in the development of non-arteritic ischemic optic neuropathy. Reversible idiopathic serous macular detachment, central serous chorioretinopathy, and ERG disturbances have been related to the significant impact of sildenafil and tadalafil on retinal perfusion. Discussion So far, PDE inhibitors do not seem to cause permanent toxic effects on chorioretinal tissue and photoreceptors. However, physicians should write down any visual symptom observed during PDE treatment and refer the patients to ophthalmologists. PMID:27799745

  10. Properties of bovine erythrocyte acetylcholinesterase solubilized by phosphatidylinositol-specific phospholipase C1.

    PubMed

    Taguchi, R; Ikezawa, H

    1987-10-01

    The properties of acetylcholinesterase solubilized from bovine erythrocyte membrane by phosphatidylinositol (PI)-specific phospholipase C of Bacillus thuringiensis or with a detergent, Lubrol-PX, were studied. The activity of Lubrol-PX-solubilized acetylcholinesterase was broadly distributed in the fractions having Ve/Vo = 1.0-2.0 in gel filtration on a Sepharose 6B column. The intermediary fractions (Ve/Vo = 1.3-1.7) were collected as "the middle active Sepharose 6B eluate" and characterized on the basis of enzymology and protein chemistry. When this eluate was treated with PI-specific phospholipase C, the major activity peak was obtained in the later fractions with Ve/Vo = 1.75-2.0 on the same column chromatography. Lubrol-solubilized and phospholipase C-treated acetylcholinesterase preparations were different in the thermostability, the elution profiles of chromatography on Mono Q, butyl-Toyopearl and phenyl-Sepharose columns, and the affinity to phospholipid micelles. On treatment with PI-specific phospholipase C, Lubrol-solubilized acetylcholinesterase became more thermostable. The phospholipase C-treated enzyme was eluted at lower NaCl concentration from the Mono Q column than the Lubrol-solubilized enzyme. The most important difference was observed in the hydrophobicity of these two enzyme preparations. The Lubrol-solubilized enzyme shows high affinity to phospholipid micelles and hydrophobic adsorbents such as butyl-Toyopearl and phenyl-Sepharose. However, this hydrophobicity was lost when acetylcholinesterase was solubilized from bovine erythrocyte membrane by PI-specific phospholipase C. The presence of myo-inositol was confirmed in the purified preparation of acetylcholinesterase by gas chromatography (GC)-mass spectrometry (MS).(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Synthesis, Biological Evaluation, and Molecular Docking of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene Analogs: New Dual AChE Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease.

    PubMed

    Shaik, Jeelan Basha; Palaka, Bhagath Kumar; Penumala, Mohan; Eadlapalli, Siddhartha; Darla Mark, Manidhar; Ampasala, Dinakara Rao; Vadde, Ramakrishna; Amooru Gangaiah, Damu

    2016-07-01

    Alzheimer's disease onset and progression are associated with the dysregulation of multiple and complex physiological processes, and a successful therapeutic approach should therefore address more than one target. In line with this modern paradigm, a series of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene analogs (4a-q) were synthesized and evaluated for their multitarget-directed activity on acetylcholinesterase, butyrylcholinesterase (BuChE), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical, and amyloid-β peptide (Aβ) specific targets for Alzheimer's disease therapy. Most of the synthesized compounds showed remarkable acetylcholinesterase inhibitory activities in low nm concentrations and good ABTS radical scavenging activity, however, no evidence of BuChE inhibitory activity. Among them, 3-bromobenzylamide derivative 4m exhibited the best acetylcholinesterase inhibitory activity with IC50 value of 13 ± 1.4 nm which is 51-fold superior to galantamine, a reference drug. Kinetic and molecular docking studies indicated 4m as mixed-type inhibitor, binding simultaneously to catalytic active and peripheral anionic sites of acetylcholinesterase. Five compounds 4e, 4f, 4g, 4j, and 4k have shown 1.4- to 2.5-fold of higher antioxidant activities than trolox. Interestingly, the most active compound 4m demonstrated dosage-dependent acceleration of Aβ1-42 aggregation, which may reduce toxicity of oligomers. Overall, these results lead to discovery of fused tricyclic coumarins as promising dual binding site inhibitors of acetylcholinesterase and afford multifunctional compounds with potential impact for further pharmacological development in Alzheimer's therapy. PMID:26833890

  12. 5alpha-Reductase inhibitor treatment of prostatic diseases: background and practical implications.

    PubMed

    Dörsam, J; Altwein, J

    2009-01-01

    This literature review discusses the theoretical background of 5alpha-reductase inhibitor (5ARI) treatment and the resulting clinical implications. A Medline-based search for peer-reviewed articles addressing 5ARIs, benign prostatic hyperplasia and prostate cancer was performed. The 5ARIs Finasteride and Dutasteride, which specifically inhibit the production of dihydrotestosterone by acting as competitive inhibitors of 5alpha-reductase, are clinically well tolerated and represent an effective treatment option for benign prostatic obstruction. Finasteride is the first compound which has a proven efficacy in chemoprevention of prostate cancer. The aim of this review was to elucidate, if there are sufficient data available to point out clinically relevant differences between the drugs. Both compounds achieve a significant reduction of prostate volume, an improvement of symptoms and a lower risk of acute urinary retention. Whether the different pharmacokinetic and pharmacodynamic properties of Finasteride and Dutasteride are of clinical importance cannot be judged at this time. PMID:19030020

  13. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema

    PubMed Central

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette; Rasmussen, Eva Rye

    2016-01-01

    Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature. PMID:27123347

  14. Isolation, diversity and acetylcholinesterase inhibitory activity of the culturable endophytic fungi harboured in Huperzia serrata from Jinggang Mountain, China.

    PubMed

    Wang, Ya; Lai, Zheng; Li, Xi-Xi; Yan, Ri-Ming; Zhang, Zhi-Bin; Yang, Hui-Lin; Zhu, Du

    2016-02-01

    acetylcholinesterase inhibitors resources used for Alzheimer's disease treatment.

  15. Discovery of covalent inhibitors of glyceraldehyde-3-phosphate dehydrogenase, a target for the treatment of malaria.

    PubMed

    Bruno, Stefano; Pinto, Andrea; Paredi, Gianluca; Tamborini, Lucia; De Micheli, Carlo; La Pietra, Valeria; Marinelli, Luciana; Novellino, Ettore; Conti, Paola; Mozzarelli, Andrea

    2014-09-11

    We developed a new class of covalent inhibitors of Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase, a validated target for the treatment of malaria, by screening a small library of 3-bromo-isoxazoline derivatives that inactivate the enzyme through a covalent, selective bond to the catalytic cysteine, as demonstrated by mass spectrometry. Substituents on the isoxazolinic ring modulated the potency up to 20-fold, predominantly due to an electrostatic effect, as assessed by computational analysis. PMID:25137375

  16. In vitro inhibition of acetylcholinesterase from four marine species by organophosphates and carbamates

    SciTech Connect

    Galgani, F.; Bocquene, G. )

    1990-08-01

    The literature on the biological, physical, and pharmaceutical chemistry of cholinesterase is considerable and includes data on activators and inhibitors. Most of the work on specific anticholinesterasic agents has been concerned with carbamates and organophosphates. Because of the sensitivity of acetylcholinesterase to carbamates and organophosphates, the enzyme has been used as a biochemical indicator of pollution by these agents. However, the chemical reactivity of such chemicals has not been correlated with their effect on Ache and it is impossible to accurately predict biological effects based only on structure. The objectives of this study were to investigate the sensitivity of various marine animals to both organo-phosphates and carbamates. The study was conducted by assessing the in vitro effect of five organophosphates and three carbamates on acetylcholinesterase activity from the muscle of the shrimp Palaemon serratus, the fishes Scomber and Pleuronectes platessa, and from the whole mussels Mytilus edulis. All these species could be used for the monitoring of effect of pollutants.

  17. Spectrophotometry in vivo, a technique for local and direct enzymatic assays: application to brain acetylcholinesterase.

    PubMed Central

    Testylier, G; Gourmelon, P

    1987-01-01

    In vivo enzymology is not widely studied due to the lack of a well-adapted technology. We have developed a system that allows local and long-term spectrophotometric assays in brain tissue of live animals. It utilizes a miniaturized optical probe consisting of a multibarrel micropipette for reagent injections and optical fibers for light absorption measurements. We have applied this system to the colorimetric determination of brain acetylcholinesterase activity in rats. The reproducibility of the assay was demonstrated by repetitive assays over 24 hr, its specificity was established through the use of a highly specific organophosphorus inhibitor, and the activities measured in different brain areas agreed with the known distribution of acetylcholinesterase. No electroencephalographic abnormalities and no change in vigilance level were observed in the experimental animals. This methodology should prove to be useful for the colorimetric measurement of different enzymes or metabolites in various organs. PMID:3479782

  18. Some enzymatic properties of brain Acetylcholinesterase from bluegill and channel catfish

    USGS Publications Warehouse

    Hogan, James W.; Knowles, Charles O.

    1968-01-01

    Using a manometric technique an acetylcholinesterase (EC 3.1.1.7, acetylcholine acetyl-hydrolase) was demonstrated in brain tissue from the bluegill, Lepomis macrochirus Rafinesque, and the channel catfish, Ictalurus punctatus (Walbaum). The activities were 19 and 37 μmoles acetylcholine hydrolyzed/milligram protein per hour for the bluegill and channel catfish enzymes, respectively. The optimum substrate concentration for the hydrolysis of acetylcholine was 10 mMfor the enzymes from both species. Generally, the catfish acetylcholinesterase was somewhat more susceptible than the bluegill to the inhibitors tested; however, the bluegill enzyme was more susceptible to inhibition by malathion and malaoxon.

  19. Synthesis and acetylcholinesterase inhibitory activity of polyhydroxylated sulfated steroids: structure/activity studies.

    PubMed

    Richmond, Victoria; Murray, Ana P; Maier, Marta S

    2013-11-01

    Disulfated and trisulfated steroids have been synthesized from cholesterol and their acetylcholinesterase inhibitory activity has been evaluated. In our studies we have found that the activity was not only dependent on the location of the sulfate groups but on their configurations. 2β,3α,6α-trihydroxy-5α-cholestan-6-one trisulfate (18) was the most active steroid with an IC50 value of 15.48 μM comparable to that of 2β,3α-dihydroxy-5α-cholestan-6-one disulfate (1). Both compounds were found to be less active than the reference compound eserine. The butyrylcholinesterase activity of 1 and 18 was one magnitude lower than that against acetylcholinesterase revealing a selective inhibitor profile.

  20. Treatment and management of myelofibrosis in the era of JAK inhibitors

    PubMed Central

    Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

    2013-01-01

    Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment. PMID:23990704

  1. Treatment and management of myelofibrosis in the era of JAK inhibitors.

    PubMed

    Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

    2013-01-01

    Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment.

  2. Alkaloid metabolite profiles by GC/MS and acetylcholinesterase inhibitory activities with binding-mode predictions of five Amaryllidaceae plants.

    PubMed

    Cortes, Natalie; Alvarez, Rafael; Osorio, Edison H; Alzate, Fernando; Berkov, Strahil; Osorio, Edison

    2015-01-01

    Acetylcholinesterase (AChE) enzymatic inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the mainstay drugs for its treatment. In order to discover new sources of potent AChE inhibitors, a combined strategy is presented based on AChE-inhibitory activity and chemical profiles by GC/MS, together with in silico studies. The combined strategy was applied on alkaloid extracts of five Amaryllidaceae species that grow in Colombia. Fifty-seven alkaloids were detected using GC/MS, and 21 of them were identified by comparing their mass-spectral fragmentation patterns with standard reference spectra in commercial and private library databases. The alkaloid extracts of Zephyranthes carinata exhibited a high level of inhibitory activity (IC50 = 5.97 ± 0.24 μg/mL). Molecular modeling, which was performed using the structures of some of the alkaloids present in this extract and the three-dimensional crystal structures of AChE derived from Torpedo californica, disclosed their binding configuration in the active site of this AChE. The results suggested that the alkaloids 3-epimacronine and lycoramine might be of interest for AChE inhibition. Although the galanthamine group is known for its potential utility in treating AD, the tazettine-type alkaloids should be evaluated to find more selective compounds of potential benefit for AD. PMID:25305596

  3. C1 inhibitor treatment improves host defense in pneumococcal meningitis in rats and mice.

    PubMed

    Zwijnenburg, Petra J G; van der Poll, Tom; Florquin, Sandrine; Polfliet, Machteld M J; van den Berg, Timo K; Dijkstra, Christine D; Roord, John J; Hack, C Erik; van Furth, A Marceline

    2007-07-01

    In spite of antibiotic treatment, pneumococcal meningitis continues to be associated with significant morbidity and mortality. The complement system is a key component of innate immunity against invading pathogens. However, activation of complement is also involved in tissue damage, and complement inhibition by C1 inhibitor (C1-inh) is beneficial in animal models of endotoxemia and sepsis. In the present study, we demonstrate classical pathway complement activation during pneumococcal meningitis in rats. We also evaluate the effect of C1-inh treatment on clinical illness, bacterial clearance, and inflammatory responses in rats and mice with pneumococcal meningitis. C1-inh treatment was associated with reduced clinical illness, a less-pronounced inflammatory infiltrate around the meninges, and lower brain levels of proinflammatory cytokines and chemokines. C1-inh treatment increased bacterial clearance, possibly through an up-regulation of CR3. Hence, C1-inh may be a useful agent in the treatment of pneumococcal meningitis.

  4. Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease.

    PubMed

    Patterson, C E; Todd, S A; Passmore, A P

    2011-12-01

    Factors that influence response to drug treatment are of increasing importance. We report an analysis of genetic factors affecting response to cholinesterase inhibitor therapy in 165 subjects with Alzheimer's disease (AD). The presence of apolipoprotein E ε4 (APOE ε4) allele was associated with early and late cognitive response to cholinesterase inhibitor treatment in mild AD (Mini-Mental State Examination (MMSE) ≥21) (P<0.01). In moderate-to-severe AD (MMSE ≤15), presence of the BCHE-K variant was associated with late response to cholinesterase inhibitor treatment (P=0.02). Testing for APOE and BCHE genotypes may be useful in therapeutic decision making.

  5. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond.

    PubMed

    Maxwell, Patrick H; Eckardt, Kai-Uwe

    2016-03-01

    Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler - and potentially cheaper - production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial - for instance by reducing the need for parenteral iron - but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury. PMID:26656456

  6. Rituximab for the treatment of childhood chronic idiopathic thrombocytopenic purpura and hemophilia with inhibitors.

    PubMed

    Franchini, Massimo; Zaffanello, Marco; Veneri, Dino; Lippi, Giuseppe

    2007-07-01

    Rituximab, a monoclonal chimeric antibody to the CD20 antigen, is an effective treatment for non-Hodgkin lymphomas. Moreover, rituximab has also shown efficacy in various autoimmune disorders. In this review, we will focus on the use of rituximab in childhood disorders of hemostasis associated with inhibitor formation. Although the results presented suggest that rituximab can be useful in the treatment of this subset of pediatric patients, most of the data come from isolated case reports or descriptions of small, uncontrolled series. Therefore, large, prospective, and randomized trials are needed to confirm the positive, preliminary results.

  7. Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivo

    NASA Technical Reports Server (NTRS)

    Matsui, Jonathan I.; Haque, Asim; Huss, David; Messana, Elizabeth P.; Alosi, Julie A.; Roberson, David W.; Cotanche, Douglas A.; Dickman, J. David; Warchol, Mark E.

    2003-01-01

    The sensory hair cells of the inner ear undergo apoptosis after acoustic trauma or aminoglycoside antibiotic treatment, causing permanent auditory and vestibular deficits in humans. Previous studies have demonstrated a role for caspase activation in hair cell death and ototoxic injury that can be reduced by concurrent treatment with caspase inhibitors in vitro. In this study, we examined the protective effects of caspase inhibition on hair cell death in vivo after systemic injections of aminoglycosides. In one series of experiments, chickens were implanted with osmotic pumps that administrated the pan-caspase inhibitor z-Val-Ala-Asp(Ome)-fluoromethylketone (zVAD) into inner ear fluids. One day after the surgery, the animals received a 5 d course of treatment with streptomycin, a vestibulotoxic aminoglycoside. Direct infusion of zVAD into the vestibule significantly increased hair cell survival after streptomycin treatment. A second series of experiments determined whether rescued hair cells could function as sensory receptors. Animals treated with streptomycin displayed vestibular system impairment as measured by a greatly reduced vestibulo-ocular response (VOR). In contrast, animals that received concurrent systemic administration of zVAD with streptomycin had both significantly greater hair cell survival and significantly increased VOR responses, as compared with animals treated with streptomycin alone. These findings suggest that inhibiting the activation of caspases promotes the survival of hair cells and protects against vestibular function deficits after aminoglycoside treatment.

  8. 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

    PubMed Central

    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

  9. Hemicrania continua changed to chronic paroxysmal hemicrania after treatment with cyclooxygenase-2 inhibitor.

    PubMed

    Müller, Kai Ivar; Bekkelund, Svein Ivar

    2011-02-01

    Remission of hemicrania continua (HC) and transformation from HC to chronic paroxysmal hemicrania (CPH) are unusual. We report a patient with left-sided HC who, after a period of remission, presented as CPH. The continuous HC headache disappeared completely after initiating treatment with cyclooxygenase (COX)-2 inhibitor, but reappeared on the same side after 14 months remission with paroxysmal, frequent, intense and short-lasting headache attacks accompanied by ipsilateral cranial autonomic symptoms. This happened shortly after the treatment was discontinued because of withdrawal of the COX-2 inhibitor from the market. The response to indomethacin was prompt, and the patient became completely free from her paroxysmal headache with a dose of 50 mg 2 times daily. This case questions a possible modification effect on the course of HC by use of COX-2 inhibitor, as well as further supporting that some aspects of the pathophysiology of HC may resemble those of CPH, and may argue for common biological mechanisms in HC and CPH.

  10. Understanding physiological responses to pre-treatment inhibitors in ethanologenic fermentations.

    PubMed

    Taylor, Mark P; Mulako, Inonge; Tuffin, Marla; Cowan, Don

    2012-09-01

    Alcohol-based liquid fuels feature significantly in the political and social agendas of many countries, seeking energy sustainability. It is certain that ethanol will be the entry point for many sustainable processes. Conventional ethanol production using maize- and sugarcane-based carbohydrates with Saccharomyces cerevisiae is well established, while lignocellulose-based processes are receiving growing interest despite posing greater technical and scientific challenges. A significant challenge that arises from the chemical hydrolysis of lignocellulose is the generation of toxic compounds in parallel with the release of sugars. These compounds, collectively termed pre-treatment inhibitors, impair metabolic functionality and growth. Their removal, pre-fermentation or their abatement, via milder hydrolysis, are currently uneconomic options. It is widely acknowledged that a more cost effective strategy is to develop resistant process strains. Here we describe and classify common inhibitors and describe in detail the reported physiological responses that occur in second-generation strains, which include engineered yeast and mesophilic and thermophilic prokaryotes. It is suggested that a thorough understanding of tolerance to common pre-treatment inhibitors should be a major focus in ongoing strain engineering. This review is a useful resource for future metabolic engineering strategies. PMID:22331581

  11. Tacrine derivatives-acetylcholinesterase interaction: 1H NMR relaxation study.

    PubMed

    Delfini, Maurizio; Di Cocco, Maria Enrica; Piccioni, Fabiana; Porcelli, Fernando; Borioni, Anna; Rodomonte, Andrea; Del Giudice, Maria Rosaria

    2007-06-01

    Two acetylcholinesterase (AChE) inhibitors structurally related to Tacrine, 6-methoxytacrine (1a) and 9-heptylamino-6-methoxytacrine (1b), and their interaction with Electrophorus Electricus AChE were investigated. The complete assignment of the 1H and 13C NMR spectra of 1a and 1b was performed by mono-dimensional and homo- and hetero-correlated two-dimensional NMR experiments. This study was undertaken to elucidate the interaction modes between AChE and 1a and 1b in solution, using NMR. The interaction between the two inhibitors and AChE was studied by the analysis of the motional parameters non-selective and selective spin-lattice relaxation times, thereby allowing the motional state of 1a and 1b, both free and bound with AChE, to be defined. The relaxation data pointed out the ligands molecular moiety most involved in the binding with AChE. The relevant ligand/enzyme interaction constants were also evaluated for both compounds and resulted to be 859 and 5412M(-1) for 1a and1b, respectively.

  12. Dapoxetine, a novel selective serotonin transport inhibitor for the treatment of premature ejaculation

    PubMed Central

    Kendirci, Muammer; Salem, Emad; Hellstrom, Wayne JG

    2007-01-01

    Premature ejaculation (PE) is the most common male sexual disorder, estimated to affect up to 30% of men. Over the past one or two decades, clinical investigators have participated in an increasing number of studies that are helping in our understanding of PE, which will undoubtedly facilitate future treatments. Apart from a number of behavioral approaches, the treatment of PE consists of primarily off-label use of oral selective serotonin reuptake inhibitors (SSRIs) via either on-demand or daily delivery. However, various undesirable side-effects of these medications have led researchers to search for and develop new therapeutic approaches for PE. Dapoxetine is a short-acting SSRI developed specifically for the treatment of PE. Early trials with dapoxetine have documented successful outcomes without serious short- or long-term side-effects. This review addresses the definition, classification, diagnosis, physiology, and neurobiopathology of PE, and evaluates therapeutic strategies with novel treatments for PE. PMID:18360636

  13. [Hydrogen peroxide inhibits acetylcholinesterase of myometrium sarcolemma].

    PubMed

    Danylovych, Iu V

    2009-01-01

    The action of hydrogen peroxide on acetylcholinesterase enzymatic activity in myometrium sarcolemma fraction is investigated. Hydrogen peroxide (0.1-26 microM), depending on the concentration, suppressed the activity. Acetylcholinesterase proved to be highly sensitive to the action of H2O2, making Ki = 2.4 +/- 0.4 microM, nH = 0.65 +/- 0.08 (n = 4-5). It is established, that hydrogen peroxide in the range of 1.6 - 6.4 microM essentially reduce V(0,max) and K(M). In the presence of dithiothreitole (a reducer of SH-groups of the membrane surface) the investigated substance effect considerably decreased.

  14. Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?

    PubMed Central

    Mittica, Gloria; Genta, Sofia; Aglietta, Massimo; Valabrega, Giorgio

    2016-01-01

    Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the “turn off” signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC. PMID:27447625

  15. Gelatin-coated Gold Nanoparticles as Carriers of FLT3 Inhibitors for Acute Myeloid Leukemia Treatment.

    PubMed

    Suarasan, Sorina; Simon, Timea; Boca, Sanda; Tomuleasa, Ciprian; Astilean, Simion

    2016-06-01

    This study presents the design of a gold nanoparticle (AuNPs)-drug system with improved efficiency for the treatment of acute myeloid leukemia. The system is based on four different FLT3 inhibitors, namely midostaurin, sorafenib, lestaurtinib, and quizartinib, which were independently loaded onto gelatin-coated gold nanoparticles. Detailed investigation of the physicochemical properties of the formed complexes lead to the selection of quizartinib-loaded AuNPs for the in vitro evaluation of the biological effects of the formed complex against OCI-AML3 acute myeloid leukemia cells. Viability tests by MTT demonstrated that the proposed drug complex has improved efficacy when compared with the drug alone. The obtained results constitute a premise for further in vivo investigation of such drug vehicles based on AuNPs. To the best of our knowledge, this is the first study that investigates the delivery of the above-mentioned FLT3 inhibitors via gelatin-coated gold nanoparticles. PMID:26808072

  16. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma.

    PubMed

    Sturdivant, Jill M; Royalty, Susan M; Lin, Cheng-Wen; Moore, Lori A; Yingling, Jeffrey D; Laethem, Carmen L; Sherman, Bryan; Heintzelman, Geoffrey R; Kopczynski, Casey C; deLong, Mitchell A

    2016-05-15

    Inhibition of Rho kinase (ROCK) to improve fluid outflow through the trabecular meshwork and lower intraocular pressure is a strategy for the development of new anti-glaucoma agents. Alpha-aryl-beta-amino isoquinoline analogs were identified as potent ROCK inhibitors. Compounds that provided a longer duration of intraocular pressure reduction in Dutch Belted rabbits also inhibited norepinephrine transporter. Ester 60 improved bioavailability of its parent ROCK inhibitor, 29 (Ki=0.2nM) and demonstrated an effective and sustained IOP reduction for 24h after dosing. From these studies, netarsudil (a.k.a. AR-13324) was discovered and is currently in clinical trials for the treatment of glaucoma and ocular hypertension.

  17. Bioengineering and semisynthesis of an optimized cyclophilin inhibitor for treatment of chronic viral infection

    PubMed Central

    Hansson, Magnus Joakim; Moss, Steven James; Bobardt, Michael; Chatterji, Udayan; Coates, Nigel; Garcia-Rivera, Jose A; Elmér, Eskil; Kendrew, Steve; Leyssen, Pieter; Neyts, Johan; Nur-E-Alam, Mohammad; Warneck, Tony; Wilkinson, Barrie; Gallay, Philippe; Gregory, Matthew Alan

    2015-01-01

    Summary Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent, high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed non-ribosomal peptide/polyketide origin in order to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of HBV, HCV and HIV-1 replication, shows minimal inhibition of major drug transporters and has a high barrier to generation of both HCV and HIV-1 resistance. PMID:25619934

  18. Gelatin-coated Gold Nanoparticles as Carriers of FLT3 Inhibitors for Acute Myeloid Leukemia Treatment.

    PubMed

    Suarasan, Sorina; Simon, Timea; Boca, Sanda; Tomuleasa, Ciprian; Astilean, Simion

    2016-06-01

    This study presents the design of a gold nanoparticle (AuNPs)-drug system with improved efficiency for the treatment of acute myeloid leukemia. The system is based on four different FLT3 inhibitors, namely midostaurin, sorafenib, lestaurtinib, and quizartinib, which were independently loaded onto gelatin-coated gold nanoparticles. Detailed investigation of the physicochemical properties of the formed complexes lead to the selection of quizartinib-loaded AuNPs for the in vitro evaluation of the biological effects of the formed complex against OCI-AML3 acute myeloid leukemia cells. Viability tests by MTT demonstrated that the proposed drug complex has improved efficacy when compared with the drug alone. The obtained results constitute a premise for further in vivo investigation of such drug vehicles based on AuNPs. To the best of our knowledge, this is the first study that investigates the delivery of the above-mentioned FLT3 inhibitors via gelatin-coated gold nanoparticles.

  19. Discovery and SAR of orally efficacious tetrahydropyridopyridazinone PARP inhibitors for the treatment of cancer.

    PubMed

    Zhu, Gui-Dong; Gong, Jianchun; Gandhi, Viraj B; Liu, Xuesong; Shi, Yan; Johnson, Eric F; Donawho, Cherrie K; Ellis, Paul A; Bouska, Jennifer J; Osterling, Donald J; Olson, Amanda M; Park, Chang; Luo, Yan; Shoemaker, Alexander; Giranda, Vincent L; Penning, Thomas D

    2012-08-01

    PARP-1, the most abundant member of the PARP superfamily of nuclear enzymes, has emerged as a promising molecular target in the past decade particularly for the treatment of cancer. A number of PARP-1 inhibitors, including veliparab discovered at Abbott, have advanced into different stages of clinical trials. Herein we describe the development of a new tetrahydropyridopyridazinone series of PARP-1 inhibitors. Many compounds in this class, such as 20w, displayed excellent potency against the PARP-1 enzyme with a K(i) value of <1nM and an EC(50) value of 1nM in a C41 whole cell assay. The presence of the NH in the tetrahydropyridyl ring of the tetrahydropyridopyridazinone scaffold improved the pharmacokinetic properties over similar carbon based analogs. Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ).

  20. Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?

    PubMed

    Mittica, Gloria; Genta, Sofia; Aglietta, Massimo; Valabrega, Giorgio

    2016-01-01

    Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the "turn off" signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC. PMID:27447625

  1. Solubility and phase behavior of polyacrylate scale inhibitors and their implications for precipitation squeeze treatment

    SciTech Connect

    Rabaioli, M.R.; Lockhart, T.P.

    1995-11-01

    The phase behavior of a commercial phosphino-polyacrylate inhibitor (PPAA) in aqueous brine has been characterized as a function of temperature, pH, and the Ca{sup ++} and PPAA concentrations. The quantity of precipitate formed has been determined as a function of the same variables. Contrary to expectations, over a range of conditions the yield of phase-separated PPAA was found to be less than 50% and sometimes as low as 5%. Studies on a sample of isolated precipitate show that it has significant solubility even in brines with high Ca{sup ++} concentration. Ca{sup ++}-induced fractionation of the polymeric inhibitor by molecular weight has been identified as the mechanism responsible for both the observed precipitation and re-dissolution behavior. The implications of these results for the optimization of precipitation squeeze treatments are discussed.

  2. Isolation and characterization of acetylcholinesterase from Drosophila.

    PubMed

    Gnagey, A L; Forte, M; Rosenberry, T L

    1987-09-25

    The purification and characterization of acetylcholinesterase from heads of the fruit fly Drosophila are described. Sequential extraction procedures indicated that approximately 40% of the activity was soluble and 60% membrane-bound and that virtually none (less than 4%) corresponded to collagen-tailed forms. The membrane-bound enzyme was extracted with Triton X-100 and purified over 4000-fold by affinity chromatography on acridinium resin. Hydrodynamic analysis by both sucrose gradient centrifugation and chromatography on Sepharose CL-4B revealed an Mr of 165,000 similar to that observed for dimeric (G2) forms of the enzyme in mammalian tissues. In contrast, the purified enzyme gave predominant bands of about 100 kDa prior to disulfied reduction and 55 kDa after reduction on polyacrylamide gel electrophoresis in sodium dodecyl sulfate, values that are significantly lower than those reported for purified G2 enzymes from other species. However, the presence of a faint band at 70 kDa which could be labeled by [3H]diisopropyl fluorophosphate prior to denaturation suggested that the 55-kDa band as well as a 16-kDa species arose from proteolysis. This was confirmed by reductive radiomethylation and amine analysis of the 70-, 55-, and 16-kDa bands. All three contained ethanolamine and glucosamine residues that are characteristic of a C-terminal glycolipid anchor in other G2 acetylcholinesterases. The catalytic properties of the enzyme were examined by titration with a fluorogenic reagent which revealed a turnover number for acetylthiocholine that was 6-fold lower than eel and 3-fold lower than human erythrocyte acetylcholinesterase. Furthermore, the Drosophila enzyme hydrolyzed butyrylthiocholine much more efficiently than these eel or human enzymes, an indication that the fly head enzyme has a substrate specificity intermediate between mammalian acetylcholinesterases and butyrylcholinesterases.

  3. Protein-kinase inhibitors: A new treatment pathway for autoimmune and inflammatory diseases?

    PubMed

    Hernández-Flórez, Diana; Valor, Lara

    2016-01-01

    Although advances in biological medicine have seen significant progress in the treatment of autoimmune and inflammatory disease, many patients do not experience a satisfactory response. Hence, there are two challenges facing the medical research community. The first is to continue development in the field of existing biological therapies, such as monoclonal antibodies. The second is to open new frontiers of research and explore treatment alternatives for non-responders to other therapies. Attention has increasingly turned to the therapeutic potential of small molecule weight kinase inhibitors (SMKIs), currently used extensively in oncology and haematology. Initial research into the therapeutic value of SMKIs for autoimmune and inflammatory diseases has been encouraging. SMKIs are taken orally, which reduces cost for the health provider, and could increase compliance for the patient. This is why research is now focusing increasingly on SMKIs as a new generation line of treatment in these diseases. Tofacitinib, an inhibitor of Janus-kinase, is currently the only drug approved for the treatment of rheumatoid arthritis by FDA. However, much more needs to be done to understand the intracellular signalling pathways and how these might affect disease progression before solid conclusions can be drawn. PMID:26283525

  4. Protein-kinase inhibitors: A new treatment pathway for autoimmune and inflammatory diseases?

    PubMed

    Hernández-Flórez, Diana; Valor, Lara

    2016-01-01

    Although advances in biological medicine have seen significant progress in the treatment of autoimmune and inflammatory disease, many patients do not experience a satisfactory response. Hence, there are two challenges facing the medical research community. The first is to continue development in the field of existing biological therapies, such as monoclonal antibodies. The second is to open new frontiers of research and explore treatment alternatives for non-responders to other therapies. Attention has increasingly turned to the therapeutic potential of small molecule weight kinase inhibitors (SMKIs), currently used extensively in oncology and haematology. Initial research into the therapeutic value of SMKIs for autoimmune and inflammatory diseases has been encouraging. SMKIs are taken orally, which reduces cost for the health provider, and could increase compliance for the patient. This is why research is now focusing increasingly on SMKIs as a new generation line of treatment in these diseases. Tofacitinib, an inhibitor of Janus-kinase, is currently the only drug approved for the treatment of rheumatoid arthritis by FDA. However, much more needs to be done to understand the intracellular signalling pathways and how these might affect disease progression before solid conclusions can be drawn.

  5. How Clinically Relevant Are Treatment Comparisons of Topical Calcineurin Inhibitor Trials for Atopic Eczema?

    PubMed

    Wilkes, Sally R; Nankervis, Helen; Tavernier, Elsa; Maruani, Annabel; Williams, Hywel C

    2016-10-01

    We sought to explore the architecture of trials of calcineurin inhibitors for atopic eczema to document the extent to which comparisons with active treatments such as topical corticosteroids might have been included or avoided. We identified all eligible randomized controlled trials using the Global Resource for EczemA Trials (GREAT) database. Network plots were produced where the nodes represented a treatment type and the lines between the nodes represented the number of trials or participants involved in the various treatment comparisons. A total of 174 randomized controlled trials for atopic eczema treatments were identified in which pimecrolimus, tacrolimus, or topical corticosteroids were compared with another intervention or a vehicle/emollient. Of 39 trials involving pimecrolimus and 41 trials involving tacrolimus, 8 (20.5%) and 13 (31.7%), respectively, made comparisons with topical corticosteroids, and 25 (64.1%) and 15 (36.6%), respectively, were vehicle-controlled studies. The high rate of comparisons with vehicle controls in randomized controlled trials that assessed the efficacy of pimecrolimus or tacrolimus long after efficacy had been established is a matter of concern. Active comparators (mild topical corticosteroids for pimecrolimus and moderate to potent topical corticosteroids for tacrolimus) are best placed to determine how topical calcineurin inhibitors compare with established clinical practice.

  6. Treatment of erectile dysfunction and lower urinary tract symptoms by phosphodiesterase inhibitors.

    PubMed

    Uckert, Stefan; Stief, Christian G

    2011-01-01

    To date, it is widely accepted that several disorders of the male and female urogenital tract, such as erectile dysfunction, bladder overactivity, urinary stone disease, the benign prostatic syndrome, as well as symptoms of female sexual arousal and orgasmic dysfunctions, can be therapeutically approached by influencing the function of the smooth musculature of the respective organs. To achieve a pronounced drug effect without significant adverse events, a certain degree of tissue selectivity is mandatory. Selective intervention in intracellular pathways regulating smooth muscle tone has become the most promising strategy to modulate tissue and organ function. Since the concept of taking a pill to relieve symptoms of lower urinary tract dysfunction is now widely accepted following the successes of phosphodiesterase 5 (PDE5) inhibitor treatment of erectile dysfunction, the treatment of urological diseases has focused on orally available drugs acting via influencing intracellular signaling pathways, thereby combining a high response rate with the advantage of an on-demand intake. Specifically, the use of isoenzyme-selective PDE inhibitors offers great opportunities in the medical treatment of various genitourinary diseases. These agents are regarded to be safe and to be efficacious, i.e., having a fast onset of drug action and an improved effect-to-side-effect ratio. As experience with this class of compounds and their use in urology is rapidly growing, basic and clinical research in this field will most likely expand the pharmacological armamentarium of innovative treatment options in the next few years. The purpose of this review is to summarize current, as well as potential, upcoming indications for the use of PDE inhibitors in the pharmacotherapy of male erectile dysfunction and lower urinary tract symptoms. PMID:21695646

  7. A review on cholinesterase inhibitors for Alzheimer's disease.

    PubMed

    Anand, Preet; Singh, Baldev

    2013-04-01

    Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Aβ) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Aβ-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Aβ deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD.

  8. Structures of paraoxon-inhibited human acetylcholinesterase reveal perturbations of the acyl loop and the dimer interface.

    PubMed

    Franklin, Matthew C; Rudolph, Michael J; Ginter, Christopher; Cassidy, Michael S; Cheung, Jonah

    2016-09-01

    Irreversible inhibition of the essential nervous system enzyme acetylcholinesterase by organophosphate nerve agents and pesticides may quickly lead to death. Oxime reactivators currently used as antidotes are generally less effective against pesticide exposure than nerve agent exposure, and pesticide exposure constitutes the majority of cases of organophosphate poisoning in the world. The current lack of published structural data specific to human acetylcholinesterase organophosphate-inhibited and oxime-bound states hinders development of effective medical treatments. We have solved structures of human acetylcholinesterase in different states in complex with the organophosphate insecticide, paraoxon, and oximes. Reaction with paraoxon results in a highly perturbed acyl loop that causes a narrowing of the gorge in the peripheral site that may impede entry of reactivators. This appears characteristic of acetylcholinesterase inhibition by organophosphate insecticides but not nerve agents. Additional changes seen at the dimer interface are novel and provide further examples of the disruptive effect of paraoxon. Ternary structures of paraoxon-inhibited human acetylcholinesterase in complex with the oximes HI6 and 2-PAM reveals relatively poor positioning for reactivation. This study provides a structural foundation for improved reactivator design for the treatment of organophosphate intoxication. Proteins 2016; 84:1246-1256. © 2016 Wiley Periodicals, Inc. PMID:27191504

  9. Advances in treatment of chronic myelogenous leukemia – new treatment options with tyrosine kinase inhibitors

    PubMed Central

    SANTOS, FABIO P. S.; RAVANDI, FARHAD

    2014-01-01

    Imatinib is considered standard therapy for patients with chronic myelogenous leukemia (CML), inducing a high rate of hematologic and cytogenetic responses. Despite these excellent results, several patients develop resistance to imatinib. Mechanisms of resistance are varied and include BCR-ABL1 kinase domain mutations, decreased entry of imatinib into cells, acquisition of secondary genetic changes and activation of alternate signaling pathways. Second-generation tyrosine kinase inhibitors (TKI) (dasatinib, nilotinib) were developed as an alternative for patients that develop resistance or are intolerant to imatinib. Dasatinib is a dual Abl/Src kinase TKI that is structurally unrelated to imatinib and is approved for therapy of all phases of CML in patients who are resistant or intolerant to imatinib. Nilotinib is a compound related to imatinib that has greater specificity and improved binding characteristics, and has clinical activity in the setting of imatinib failure. Resistance to multiple TKIs does occur, particularly in patients with the T315I mutation. Several new agents are in development including new TKIs, aurora kinase inhibitors and homoharringtonine. PMID:20017607

  10. Targeting copper(II)-induced oxidative stress and the acetylcholinesterase system in Alzheimer's disease using multifunctional tacrine-coumarin hybrid molecules.

    PubMed

    Hamulakova, Slavka; Poprac, Patrik; Jomova, Klaudia; Brezova, Vlasta; Lauro, Peter; Drostinova, Lenka; Jun, Daniel; Sepsova, Vendula; Hrabinova, Martina; Soukup, Ondrej; Kristian, Pavol; Gazova, Zuzana; Bednarikova, Zuzana; Kuca, Kamil; Valko, Marian

    2016-08-01

    Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-β (A-β) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7-hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e-g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu-5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-β1-40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease. PMID:27230386

  11. Successful treatment of nocturnal eating/drinking syndrome with selective serotonin reuptake inhibitors.

    PubMed

    Miyaoka, Tsuyoshi; Yasukawa, Rei; Tsubouchi, Ken; Miura, Seiji; Shimizu, Yoshiko; Sukegawa, Tsuruhei; Maeda, Takahiro; Mizuno, Shoichi; Kameda, Atsuko; Uegaki, Jun; Inagaki, Takuji; Horiguchi, Jun

    2003-05-01

    Nocturnal eating/drinking disorder (NE/DS) is a rare syndrome that includes disorders of both eating and sleeping. It is characterized by awakening in the middle of the night, getting out of bed, and consuming large quantities of food quickly and uncontrollably, then returning to sleep. This may occur several times during the night. Some patients are fully conscious during their nocturnal eating, while some report total amnesia. The aetiology of NE/DS is still unclear, and there is no satisfactory treatment. Four patients with NE/DS are described. Treatment with a selective seroronin reuptake inhibitor (SSRI) was effective in controlling their episodes of nocturnal eating. To our knowledge, this is the first published case report of successful treatment with SSRIs in NE/DS.

  12. Proton pump inhibitors for the treatment of cancer in companion animals.

    PubMed

    Walsh, Megan; Fais, Stefano; Spugnini, Enrico Pierluigi; Harguindey, Salvador; Abu Izneid, Tareq; Scacco, Licia; Williams, Paula; Allegrucci, Cinzia; Rauch, Cyril; Omran, Ziad

    2015-09-04

    The treatment of cancer presents a clinical challenge both in human and veterinary medicine. Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects. A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell. The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis. Human clinical trials have prompted to consider this as a viable and safe option for the treatment of cancer in companion animals. Preliminary animal studies suggest that the same positive outcome could be achievable. The purpose of this review is to support investigations into the use of PPIs for cancer treatment cancer in companion animals by considering the evidence available in both human and veterinary medicine.

  13. Acetylcholinesterase inhibition by biofumigant (Coumaran) from leaves of Lantana camara in stored grain and household insect pests.

    PubMed

    Rajashekar, Yallappa; Raghavendra, Anjanappa; Bakthavatsalam, Nandagopal

    2014-01-01

    Recent studies proved that the biofumigants could be an alternative to chemical fumigants against stored grain insect pests. For this reason, it is necessary to understand the mode of action of biofumigants. In the present study the prospectus of utilising Lantana camara as a potent fumigant insecticide is being discussed. Inhibition of acetylcholinesterase (AChE) by Coumaran, an active ingredient extracted from the plant L. camara, was studied. The biofumigant was used as an enzyme inhibitor and acetylthiocholine iodide as a substrate along with Ellman's reagent to carry out the reactions. The in vivo inhibition was observed in both dose dependent and time dependent in case of housefly, and the nervous tissue (ganglion) and the whole insect homogenate of stored grain insect exposed to Coumaran. The possible mode of action of Coumaran as an acetylcholinesterase inhibitor is discussed.

  14. The development of MetAP-2 inhibitors in cancer treatment.

    PubMed

    Yin, S-Q; Wang, J-J; Zhang, C-M; Liu, Z-P

    2012-01-01

    Methionine aminopeptidases (MetAPs), which remove methionine residue from newly synthesized polypeptide chains, are a class of metalloproteases ubiquitously distributed in both eukaryotes and prokaryotes. MetAP-2 inhibition can induce G1 cell cycle arrest, cytostasis in tumor cells in vitro and inhibition of tumor growth in vivo. The discovery of fumagillin with potent antiangiogenic and antiproliferative activities promoted the development of fumagillin analogues as a novel class of anticancer agents. Early drug discovery efforts have focused on analogs of fumagillin, which irreversibly inhibit MetAP-2 through covalent modification of an epoxide. Several fumagillin analogs, like CKD-732, TNP-470 and PPI-2458, were found to be potent selective inhibitors of MetAP-2 (proteolytic activity) and endothelial cell proliferation. Further, they have entered in clinical trials for the treatment of different types of tumors. Recently, attention has been paid to reversible human MetAP-2 inhibitors, such as bengamides, 2-hydroxy-3-aminoamides, anthranilic acid sulfonamides and triazole analogs, which have demonstrated their potential to inhibit angiogenesis and tumor growth in vivo as well. This review article mainly discussed the development of MetAP-2 inhibitors in cancer therapy and also summarized their structure-activity relationships. PMID:22229417

  15. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment.

    PubMed

    El-Osta, Hazem; Shahid, Kamran; Mills, Glenn M; Peddi, Prakash

    2016-01-01

    Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. PMID:27574451

  16. [New potassium binders effective: treatment of hyperkalaemia secondary to RAAS inhibitors].

    PubMed

    Hoorn, Ewout J

    2015-01-01

    This commentary discusses two recent publications by Weir et al. and Packham et al. in The New England Journal of Medicine on the efficacy of two novel potassium binders, sodium zirconium cyclosilicate and patiromer. In a similar manner to existing potassium binders, these drugs exchange dietary potassium for either sodium or calcium in the gut, thereby preventing absorption of potassium. Both drugs were tested against placebo in patients with chronic kidney disease who developed hyperkalaemia because they were also using renin-angiotensin-aldosterone system (RAAS) inhibitors. Both drugs lowered serum potassium effectively and were tolerated reasonably well. A strong point in the trials is that the new potassium binders allow patients to continue using RAAS inhibitors. By doing so, these patients with high cardiovascular risk may continue to benefit from the protective effects of RAAS inhibitors. Limitations include the relatively short treatment period, the lack of a control group using existing potassium binders, and the exclusion of patients with severe or symptomatic hyperkalaemia.

  17. LRRK2 inhibitors and their potential in the treatment of Parkinson’s disease: current perspectives

    PubMed Central

    Atashrazm, Farzaneh; Dzamko, Nicolas

    2016-01-01

    Major advances in understanding how genetics underlies Parkinson’s disease (PD) have provided new opportunities for understanding disease pathogenesis and potential new targets for therapeutic intervention. One such target is leucine-rich repeat kinase 2 (LRRK2), an enigmatic enzyme implicated in both familial and idiopathic PD risk. Both academia and industry have promoted the development of potent and selective inhibitors of LRRK2, and these are currently being employed to assess the safety and efficacy of such compounds in preclinical models of PD. This review examines the evidence that LRRK2 kinase activity contributes to the pathogenesis of PD and outlines recent progress on inhibitor development and early results from preclinical safety and efficacy testing. This review also looks at some of the challenges remaining for translation of LRRK2 inhibitors to the clinic, if indeed this is ultimately warranted. As a disease with no current cure that is increasing in prevalence in line with an aging population, there is much need for developing new treatments for PD, and targeting LRRK2 is currently a promising option. PMID:27799832

  18. The efficacy of rituximab in the treatment of inhibitor-associated hemostatic disorders.

    PubMed

    Franchini, Massimo; Veneri, Dino; Lippi, Giuseppe; Stenner, Rachel

    2006-08-01

    Rituximab is a chimeric anti-CD20 monoclonal antibody active against normal and malignant B cells which has proven to be effective in the therapy of CD-20 positive lymphomas. Its B-cell cytotoxic action has also been exploited in many non-malignant autoimmune disorders in which it has been used with the aim of interfering with the production of pathologic antibodies. The present knowledge regarding the use of rituximab in antibody-associated disorders of hemostasis (i.e. idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, acquired hemophilia A, congenital hemophilia with inhibitors, acquired inhibitors against coagulation factors) is presented briefly in this review. The results suggest that rituximab can be useful in the treatment of disorders of hemostasis associated with inhibitor formation. Although collectively the number of patients treated is now quite substantial, most of the data are drawn from isolated case reports or descriptions of small, uncontrolled series. Large, prospective, randomized trials are, therefore, needed to confirm the positive, preliminary results.

  19. Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

    PubMed Central

    2012-01-01

    Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a well-established cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC50 = 3.38 ± 0.08 μM. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood–brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development. PMID:23421686

  20. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment.

    PubMed

    El-Osta, Hazem; Shahid, Kamran; Mills, Glenn M; Peddi, Prakash

    2016-01-01

    Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field.

  1. In Silico Analysis Guides Selection of BET Inhibitors for Triple-Negative Breast Cancer Treatment.

    PubMed

    Pérez-Peña, Javier; Serrano-Heras, Gemma; Montero, Juan Carlos; Corrales-Sánchez, Verónica; Pandiella, Atanasio; Ocaña, Alberto

    2016-08-01

    Triple-negative breast cancer (TNBC) is an incurable disease with poor prognosis. At this moment, therapeutic options are limited to chemotherapy, and no targeted agent has reached the clinical setting. Bromodomain and extraterminal (BET) inhibitors are a new family of compounds that inhibit bromodomain-containing proteins affecting the expression of transcription factors, therefore modifying the expression of relevant oncogenic genes. In the present article, by using an in silico approach, we have identified the expression of upregulated transcription factors in TNBC compared with normal breast. Treatment with JQ1, a well-characterized BET inhibitor, modified some transcription factors, including DEP domain containing 1 (DEPDC), Forkhead box M1 (FOXM1), and Lim domain only 4 (LM04). In cell line models, administration of JQ1 or OTX015, another BET inhibitor, produced a significant antiproliferative effect and synergized with chemotherapies. Biochemical evaluation demonstrated an arrest at G1 as the main mechanism of action with a clear increase of p27. Addition of these compounds to chemotherapy induced apoptosis compared to each agent given alone. Evaluation of JQ1 in xenografted tumors in nude mice showed a profound antitumoral effect with a reduction of DEPDC, FOXM1, and LM04, in addition to an increase of p27. Globally, our data demonstrate the antitumor effect of this new family of compounds in TNBC, paving the way for its future clinical development. Mol Cancer Ther; 15(8); 1823-33. ©2016 AACR. PMID:27256375

  2. [Tubulointerstitial nephritis associated with treatment with selective Cox-2 inhibitors, celecoxib and rofecoxib].

    PubMed

    Ortiz, M; Mon, C; Fernández, M J; Sánchez, R; Mampaso, F; Alvarez Ude, F

    2005-01-01

    The nephrotoxic effect of nonselective nonsteroidal anti-inflamatory drugs (NSAIDS) has been widely described. The main benefit of the Cox-2 inhibitors in relation to the NSAIDS is the production of a very similar analgesic effect, but with fewer gastrointestinal side effects. However, their effects on renal function are little known as yet and their long-term safety is still pending definition. The use of selective Cox-2 inhibitors as anti-inflamatory analgesic is becoming more and more common in our environment. We report two cases of tubulointersticial nephritis confirmed by renal biopsy, associated with administration of the two Cox-2 inhibitors currently available on the market, celecoxib and rofecoxib. In both cases, we were talking about elderly women, with deterioration of the general condition and acute renal failure. In the former case, renal biopsy showed an acute tubulo-intersticial nephritis (TIN) so highly "variegated" in its histologic expression. In the second case, was associated with strong indications of chronicity. Treatment with steroid was initiated in both patients and improvement of renal function was observed.

  3. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment

    PubMed Central

    El-Osta, Hazem; Shahid, Kamran; Mills, Glenn M; Peddi, Prakash

    2016-01-01

    Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. PMID:27574451

  4. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment

    PubMed Central

    Li, Jian; Zhou, Nan; Cai, Peiling; Bao, Jinku

    2016-01-01

    Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8) and amber score (−51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development. PMID:26907257

  5. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways

    PubMed Central

    Spring, Bryan Q.; Sears, R. Bryan; Zheng, Lei Zak; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

    2015-01-01

    Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivatable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with photo-initiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivatable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release whilst reducing systemic drug exposure and associated toxicities. PMID:26780659

  6. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

    PubMed Central

    Phillips, Margaret A.; Lotharius, Julie; Marsh, Kennan; White, John; Dayan, Anthony; White, Karen L.; Njoroge, Jacqueline W.; El Mazouni, Farah; Lao, Yanbin; Kokkonda, Sreekanth; Tomchick, Diana R.; Deng, Xiaoyi; Laird, Trevor; Bhatia, Sangeeta N.; March, Sandra; Ng, Caroline L.; Fidock, David A.; Wittlin, Sergio; Lafuente-Monasterio, Maria; Benito, Francisco Javier Gamo; Alonso, Laura Maria Sanz; Martinez, Maria Santos; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Haselden, John N.; Louttit, James; Cui, Yi; Sridhar, Arun; Zeeman, Anna-Marie; Kocken, Clemens; Sauerwein, Robert; Dechering, Koen; Avery, Vicky M.; Duffy, Sandra; Delves, Michael; Sinden, Robert; Ruecker, Andrea; Wickham, Kristina S.; Rochford, Rosemary; Gahagen, Janet; Iyer, Lalitha; Riccio, Ed; Mirsalis, Jon; Bathhurst, Ian; Rueckle, Thomas; Ding, Xavier; Campo, Brice; Leroy, Didier; Rogers, M. John; Rathod, Pradipsinh K.; Burrows, Jeremy N.; Charman, Susan A.

    2015-01-01

    Malaria is one of the most significant causes of childhood mortality but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective towards DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200–400 mg. DSM265 was well tolerated in repeat dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood and liver-stage activity, and predicted long human half-life position DSM265 as a new potential drug combination partner for either single-dose treatment or once weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive on the parasite liver-stage PMID:26180101

  7. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways

    NASA Astrophysics Data System (ADS)

    Spring, Bryan Q.; Bryan Sears, R.; Zheng, Lei Zak; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

    2016-04-01

    Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)—a multikinase inhibitor—encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities.

  8. In silico search of energy metabolism inhibitors for alternative leishmaniasis treatments.

    PubMed

    Silva, Lourival A; Vinaud, Marina C; Castro, Ana Maria; Cravo, Pedro Vítor L; Bezerra, José Clecildo B

    2015-01-01

    Leishmaniasis is a complex disease that affects mammals and is caused by approximately 20 distinct protozoa from the genus Leishmania. Leishmaniasis is an endemic disease that exerts a large socioeconomic impact on poor and developing countries. The current treatment for leishmaniasis is complex, expensive, and poorly efficacious. Thus, there is an urgent need to develop more selective, less expensive new drugs. The energy metabolism pathways of Leishmania include several interesting targets for specific inhibitors. In the present study, we sought to establish which energy metabolism enzymes in Leishmania could be targets for inhibitors that have already been approved for the treatment of other diseases. We were able to identify 94 genes and 93 Leishmania energy metabolism targets. Using each gene's designation as a search criterion in the TriTrypDB database, we located the predicted peptide sequences, which in turn were used to interrogate the DrugBank, Therapeutic Target Database (TTD), and PubChem databases. We identified 44 putative targets of which 11 are predicted to be amenable to inhibition by drugs which have already been approved for use in humans for 11 of these targets. We propose that these drugs should be experimentally tested and potentially used in the treatment of leishmaniasis.

  9. CDK4/6 Inhibitor PD0332991 in Glioblastoma Treatment: Does It Have a Future?

    PubMed Central

    Schröder, Lisette B. W.; McDonald, Kerrie L.

    2015-01-01

    Glioblastoma is aggressive, highly infiltrating, and the most frequent malignant form of brain cancer. With a median survival time of only 14.6 months, when treated with the standard of care, it is essential to find new therapeutic options. A specific CDK4/6 inhibitor, PD0332991, obtained accelerated approval from the Food and Drug Administration for the treatment of patients with advanced estrogen receptor-positive and HER2-negative breast cancer. Common alterations in the cyclin D1-cyclin-dependent kinase 4/6-retinoblastoma 1 pathway in glioblastoma make PD0332991 also an interesting drug for the treatment of glioblastoma. Promising results in in vitro studies, where patient derived glioblastoma cell lines showed sensitivity to PD0332991, gave motive to start in vivo studies. Outcomes of these studies have been contrasting in terms of PD0332991 efficacy within the brain: more research is necessary to conclude whether CDK4/6 inhibitor can be beneficial in the treatment of glioblastoma. PMID:26649278

  10. Advanced basal cell carcinoma, the hedgehog pathway, and treatment options – role of smoothened inhibitors

    PubMed Central

    Fecher, Leslie A; Sharfman, William H

    2015-01-01

    Cutaneous basal cell carcinoma (BCC) is the most common human cancer and its incidence is rising worldwide. Ultraviolet radiation exposure, including tanning bed use, as well as host factors play a role in its development. The majority of cases are treated and cured with local therapies including surgery. Yet, the health care costs of diagnosis and treatment of BCCs in the US is substantial. In the United States, the cost of nonmelanoma skin cancer care in the Medicare population is estimated to be US$426 million per year. While rare, locally advanced BCCs that can no longer be controlled with surgery and/or radiation, and metastatic BCCs do occur and can be associated with significant morbidity and mortality. Vismodegib (GDC-0449), a smoothened inhibitor targeted at the hedgehog pathway, is the first US Food and Drug Association (FDA)-approved agent in the treatment of locally advanced, unresectable, and metastatic BCCs. This class of agents appears to be changing the survival rates in advanced BCC patients, but appropriate patient selection and monitoring are important. Multidisciplinary assessments are essential for the optimal care and management of these patients. For some patients with locally advanced BCC, treatment with a hedgehog inhibitor may eliminate the need for an excessively disfiguring or morbid surgery. PMID:26604681

  11. Influence of acetylcholinesterase immobilization on the photoluminescence properties of mesoporous silicon surface

    NASA Astrophysics Data System (ADS)

    Saleem, Muhammad; Rafiq, Muhammad; Seo, Sung-Yum; Lee, Ki Hwan

    2014-07-01

    Acetylcholinesterase immobilized p-type porous silicon surface was prepared by covalent attachment. The immobilization procedure was based on support surface chemical oxidation, silanization, surface activation with cyanuric chloride and finally covalent attachment of free enzyme on the cyanuric chloride activated porous silicon surface. Different pore diameter of porous silicon samples were prepared by electrochemical etching in HF based electrolyte solution and appropriate sample was selected suitable for enzyme immobilization with maximum trapping ability. The surface modification was studied through field emission scanning electron microscope, EDS, FT-IR analysis, and photoluminescence measurement by utilizing the fluctuation in the photoluminescence of virgin and enzyme immobilized porous silicon surface. Porous silicon showed strong photoluminescence with maximum emission at 643 nm and immobilization of acetylcholinesterase on porous silicon surface cause considerable increment on the photoluminescence of porous silicon material while acetylcholinesterase free counterpart did not exhibit any fluorescence in the range of 635-670 nm. The activities of the free and immobilized enzymes were evaluated by spectrophotometric method by using neostigmine methylsulfate as standard enzyme inhibitor. The immobilized enzyme exhibited considerable response toward neostigmine methylsulfate in a dose dependent manner comparable with that of its free counterpart alongside enhanced stability, easy separation from the reaction media and significant saving of enzyme. It was believed that immobilized enzyme can be exploited in organic and biomolecule synthesis possessing technical and economical prestige over free enzyme and prominence of easy separation from the reaction mixture.

  12. Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects

    SciTech Connect

    Dufour, Marc; Dormond-Meuwly, Anne; Pythoud, Catherine; Demartines, Nicolas; Dormond, Olivier

    2013-08-16

    Highlights: •PI3K inhibitors inhibit AKT only transiently. •Re-activation of AKT limits the anti-cancer effect of PI3K inhibitors. •The results suggest to combine PI3K and AKT inhibitors in cancer therapy. -- Abstract: Targeting the phosphatidylinositol-3-kinase (PI3K) is a promising approach in cancer therapy. In particular, PI3K blockade leads to the inhibition of AKT, a major downstream effector responsible for the oncogenic activity of PI3K. However, we report here that small molecule inhibitors of PI3K only transiently block AKT signaling. Indeed, treatment of cancer cells with PI3K inhibitors results in a rapid inhibition of AKT phosphorylation and signaling which is followed by the reactivation of AKT signaling after 48 h as observed by Western blot. Reactivation of AKT signaling occurs despite effective inhibition of PI3K activity by PI3K inhibitors. In addition, wortmannin, a broad range PI3K inhibitor, did not block AKT reactivation suggesting that AKT signals independently of PI3K. In a therapeutical perspective, combining AKT and PI3K inhibitors exhibit stronger anti-proliferative and pro-apoptotic effects compared to AKT or PI3K inhibitors alone. Similarly, in a tumor xenograft mouse model, concomitant PI3K and AKT blockade results in stronger anti-cancer activity compared with either blockade alone. This study shows that PI3K inhibitors only transiently inhibit AKT which limits their antitumor activities. It also provides the proof of concept to combine PI3K inhibitors with AKT inhibitors in cancer therapy.

  13. DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice {beta} cells

    SciTech Connect

    Nagamatsu, Shinya; Ohara-Imaizumi, Mica; Nakamichi, Yoko; Aoyagi, Kyota; Nishiwaki, Chiyono

    2011-09-09

    Highlights: {yields} Anti-diabetic new drug, DPP-4 inhibitor, can affect the insulin exocytosis. {yields} DPP-4 inhibitor treatment altered syntaxin 1 expression. {yields} Treatment of db/db mice with DPP-4 inhibitor increased insulin release. -- Abstract: Incretin promotes insulin secretion acutely. Recently, orally-administered DPP-4 inhibitors represent a new class of anti-hyperglycemic agents. Indeed, inhibitors of dipeptidyl peptidase-IV (DPP-4), sitagliptin, has just begun to be widely used as therapeutics for type 2 diabetes. However, the effects of sitagliptin-treatment on insulin exocytosis from single {beta}-cells are yet unknown. We therefore investigated how sitagliptin-treatment in db/db mice affects insulin exocytosis by treating db/db mice with des-F-sitagliptin for 2 weeks. Perfusion studies showed that 2 weeks-sitagliptin treatment potentiated insulin secretion. We then analyzed insulin granule motion and SNARE protein, syntaxin 1, by TIRF imaging system. TIRF imaging of insulin exocytosis showed the increased number of docked insulin granules and increased fusion events from them during first-phase release. In accord with insulin exocytosis data, des-F-sitagliptin-treatment increased the number of syntaxin 1 clusters on the plasma membrane. Thus, our data demonstrated that 2-weeks des-F-sitagliptin-treatment increased the fusion events of insulin granules, probably via increased number of docked insulin granules and that of syntaxin 1 clusters.

  14. Preclinical and first-in-human evaluation of PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R

    SciTech Connect

    Atsmon, Jacob; Brill-Almon, Einat; Nadri-Shay, Carmit; Chertkoff, Raul; Alon, Sari; Shaikevich, Dimitri; Volokhov, Inna; Haim, Kirsten Y.; Bartfeld, Daniel; Shulman, Avidor; Ruderfer, Ilya; Ben-Moshe, Tehila; Shilovitzky, Orit; Soreq, Hermona; Shaaltiel, Yoseph

    2015-09-15

    PRX-105 is a plant-derived recombinant version of the human ‘read-through’ acetylcholinesterase splice variant (AChE-R). Its active site structure is similar to that of the synaptic variant, and it displays the same affinity towards organophosphorus (OP) compounds. As such, PRX-105 may serve as a bio-scavenger for OP pesticides and chemical warfare agents. To assess its potential use in prophylaxis and treatment of OP poisoning we conducted several preliminary tests, reported in this paper. Intravenous (IV) PRX-105 was administered to mice either before or after exposure to an OP toxin. All mice who received an IV dose of 50 nmol/kg PRX-105, 2 min before being exposed to 1.33 × LD{sub 50} and 1.5 × LD{sub 50} of toxin and 10 min after exposure to 1.5 × LD{sub 50} survived. The pharmacokinetic and toxicity profiles of PRX-105 were evaluated in mice and mini-pigs. Following single and multiple IV doses (50 to 200 mg/kg) no deaths occurred and no significant laboratory and histopathological changes were observed. The overall elimination half-life (t{sub ½}) in mice was 994 (± 173) min. Additionally, a first-in-human study, to assess the safety, tolerability and pharmacokinetics of the compound, was conducted in healthy volunteers. The t{sub ½} in humans was substantially longer than in mice (average 26.7 h). Despite the small number of animals and human subjects who were assessed, the fact that PRX-105 exerts a protective and therapeutic effect following exposure to lethal doses of OP, its favorable safety profile and its relatively long half-life, renders it a promising candidate for treatment and prophylaxis against OP poisoning and warrants further investigation. - Highlights: • PRX-105 is a PEGylated plant-derived recombinant human acetylcholinesterase-R. • PRX-105 is a promising bio-scavenger for organophosphorous toxins at lethal doses. • PRX-105 was shown to protect animals both prophylactically and post-poisoning. • First-in-human study

  15. Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells.

    PubMed

    Ha, Kyungsoo; Fiskus, Warren; Choi, Dong Soon; Bhaskara, Srividya; Cerchietti, Leandro; Devaraj, Santhana G T; Shah, Bhavin; Sharma, Sunil; Chang, Jenny C; Melnick, Ari M; Hiebert, Scott; Bhalla, Kapil N

    2014-07-30

    There is an unmet need to develop new, more effective and safe therapies for the aggressive forms of triple negative breast cancers (TNBCs). While up to 20% of women under 50 years of age with TNBC harbor germline mutations in BRCA1, and these tumors are sensitive to treatment with poly(ADP) ribose polymerase inhibitors, a majority of TNBCs lack BRCA1 mutations or loss of expression. Findings presented here demonstrate that by attenuating the levels of DNA damage response and homologous recombination proteins, pan-histone deacetylase inhibitor (HDI) treatment induces 'BRCAness' and sensitizes TNBC cells lacking BRCA1 to lethal effects of PARP inhibitor or cisplatin. Treatment with HDI also induced hyperacetylation of nuclear hsp90. Similar effects were observed following shRNA-mediated depletion of HDAC3, confirming its role as the deacetylase for nuclear HSP90. Furthermore, cotreatment with HDI and ABT-888 induced significantly more DNA strand breaks than either agent alone, and synergistically induced apoptosis of TNBC cells. Notably, co-treatment with HDI and ABT-888 significantly reduced in vivo tumor growth and markedly improved the survival of mice bearing TNBC cell xenografts. These findings support the rationale to interrogate the clinical activity of this novel combination against human TNBC, irrespective of its expression of mutant BRCA1.

  16. Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking.

    PubMed

    Imramovsky, Ales; Stepankova, Sarka; Vanco, Jan; Pauk, Karel; Monreal-Ferriz, Juana; Vinsova, Jarmila; Jampilek, Josef

    2012-08-24

    A series of twenty-five novel salicylanilide N-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.). Experimental lipophilicity was determined, and the structure-activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'(₃,₄) of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'(₄) exhibited slightly more effective AChE inhibitors than in C'(₃). Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the N-alkyl chain.

  17. Immunocytochemical localization of thyroid hormone nuclear receptors in cultured acetylcholinesterase-positive neurons: a correlation between the presence of thyroid hormone nuclear receptors and L-tri-iodothyronine morphological effects.

    PubMed

    Garza, R; Puymirat, J; Dussault, J H

    1990-01-01

    A monoclonal antibody against the rat liver L-tri-iodothyronine nuclear receptor and acetylcholinesterase cytochemistry were used for the localization of thyroid hormone nuclear receptors in acetylcholinesterase-positive cell nuclei in fetal rat cerebral hemisphere neuronal cultures. After 3 days in vitro, the ratio of acetylcholinesterase-positive cells that were immunoreactive for the thyroid hormone nuclear receptor to those not stained for this receptor (74-26%, respectively) remains unchanged despite an increase in the number of acetylcholinesterase-positive cells with time (from day 3 to day 21) in culture. Furthermore, the addition of 3 X 10(-8) L-tri-iodothyronine in culture did not modify this ratio or have an effect on the number of acetylcholinesterase-positive cells, but significantly increased the neurite density in those acetylcholinesterase-positive cells that were immunoreactive for the thyroid hormone receptor. Conversely, no difference in the neurite densities of those acetylcholinesterase-positive cells not stained for this receptor was observed when cultured in the presence or absence of thyroid hormone. In other experiments with the same fetal brain cultures, treatment of cultures for 8 days with L-tri-iodothyronine, beginning on culture day 20, demonstrated the presence of a critical period which occurs in vitro around day 20, since the stimulatory effect of L-tri-iodothyronine on immunoreactive acetylcholinesterase-positive cell neurite density is lost after 20 days in vitro. These results demonstrate, for the first time, the presence of L-tri-iodothyronine nuclear receptors in fetal rat acetylcholinesterase-positive neurons and the existence of a cellular heterogeneity in the distribution of the thyroid hormone receptor. The presence of these receptors in fetal brain acetylcholinesterase-positive neurons suggests that some effects of L-tri-iodothyronine on the maturation of a subpopulation of acetylcholinesterase-positive neurons may result

  18. Ethical assessment of hepatitis C virus treatment: The lesson from first generation protease inhibitors.

    PubMed

    Sacchini, Dario; Craxì, Lucia; Refolo, Pietro; Minacori, Roberta; Cicchetti, Americo; Gasbarrini, Antonio; Cammà, Calogero; Spagnolo, Antonio G

    2015-05-01

    Since chronic hepatitis C has mostly become curable, issues concerning choice and allocation of treatment are of major concern. We assessed the foremost ethical issues in hepatitis C virus therapy with 1st generation protease inhibitors using the personalist ethical framework within the health technology assessment methodology. Our aim was to identify values at stake/in conflict and to support both the physicians' choices in hepatitis C therapy and social (macro-) allocation decision-making. The ethical assessment indicates that: (1) safety/effectiveness profile of treatment is guaranteed if its use is restricted to the patients subgroups who may benefit from it; (2) patients should be carefully informed, particularly on treatment deferral, and widespread information on these therapies should be implemented; (3) since treatment was proven to be cost-effective, its use is acceptable respecting resource macro-allocation. Concerning individual (micro-) location criteria: (a) criteria for eligibility to treatment should be clearly identified and updated periodically; (b) information on criteria for eligibility/deferral to treatment for specific patients' subgroups should be made widely known. Interferon-based regimens will disappear from use within the next year, with the introduction of highly effective/tolerable combination regimens of direct-acting antivirals, thus profoundly changing social choices. Nonetheless, our model could support future ethical assessment since the evaluation pertaining ethical domains remains generally applicable.

  19. Rubus coreanus Miquel Inhibits Acetylcholinesterase Activity and Prevents Cognitive Impairment in a Mouse Model of Dementia

    PubMed Central

    Kim, Cho Rong; Choi, Soo Jung; Oh, Seung Sang; Kwon, Yoon Kyung; Lee, Na Young; Park, Gwi Gun; Kim, Youn-Jung; Heo, Ho Jin; Jun, Woo Jin; Park, Cheung-Seog; Shin, Dong-Hoon

    2013-01-01

    Abstract To find acetylcholinesterase (AChE) inhibitors for the prevention of neurological disorders, such as Alzheimer's disease, ethanol extracts of promising traditional edible Korean plants were tested. Among them, Rubus coreanus Miquel extract exhibited the most significant AChE inhibitory activity. The effect of R. coreanus extract on trimethyltin-induced memory impairment in mice was investigated using Y-maze and passive avoidance tests. Our results showed that administration of R. coreanus extract significantly improved alternation behavior and step-through latency. In addition, R. coreanus extract was sequentially fractionated, and the purified constituent was determined to be 3,4,5-trihydroxybenzoic acid. PMID:24044488

  20. Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm.

    PubMed

    Wilding, John P H; Rajeev, Surya Panicker; DeFronzo, Ralph A

    2016-08-01

    Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in β-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials. PMID:27440828

  1. Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm.

    PubMed

    Wilding, John P H; Rajeev, Surya Panicker; DeFronzo, Ralph A

    2016-08-01

    Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in β-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials.

  2. New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease.

    PubMed

    Kleymann, Gerald; Fischer, Rüdiger; Betz, Ulrich A K; Hendrix, Martin; Bender, Wolfgang; Schneider, Udo; Handke, Gabriele; Eckenberg, Peter; Hewlett, Guy; Pevzner, Veniamin; Baumeister, Judith; Weber, Olaf; Henninger, Kerstin; Keldenich, Jörg; Jensen, Axel; Kolb, Jörg; Bach, Ute; Popp, Andreas; Mäben, Jutta; Frappa, Isabelle; Haebich, Dieter; Lockhoff, Oswald; Rübsamen-Waigmann, Helga

    2002-04-01

    The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications. PMID:11927946

  3. Analgesic effects of p38 kinase inhibitor treatment on bone fracture healing.

    PubMed

    Cottrell, Jessica A; Meyenhofer, Markus; Medicherla, Satyanarayana; Higgins, Linda; O'Connor, J Patrick

    2009-03-01

    Traditional and COX-2 selective non-steroidal anti-inflammatory drug (NSAID) treatment inhibits fracture healing in animal models. This indicates that either the inflammatory phase following a bone fracture is necessary for efficient or sufficient bone regeneration to heal the fracture or COX-2 may have a specific function during bone regeneration unrelated to inflammation. These observations also indicate that NSAID use during fracture healing may be contra-indicated. Thus, identification of different analgesics for fracture pain or other orthopaedic surgical procedures would be of significant clinical benefit. Inhibitors of p38 kinase also have significant analgesic properties. However, p38 kinase is a critical regulator of inflammation. To assess the potential use of p38 kinase inhibition as a therapeutic strategy to manage fracture pain, the analgesic properties of SCIO-469, a p38alpha kinase inhibitor, were assessed in a rat fracture model and compared to other common analgesics. In addition, the effects of SCIO-469 treatment on ultimate fracture healing outcomes were measured by radiography and torsional mechanical testing. The data indicate that SCIO-469 was an effective analgesic. No adverse events related to fracture healing were observed in rats treated with SCIO-469. Immunohistochemistry showed that p38 kinase is activated primarily in the first days following a fracture. These observations suggest that p38alpha kinase inhibition may be an effective therapeutic strategy to manage orthopaedic-related pain. These observations also indicate that COX-2 has a specific function during bone regeneration other than promoting inflammation.

  4. The role of phosphodiesterase type-5 inhibitors in treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia.

    PubMed

    Umul, Mehmet; Serel, Tekin Ahmet

    2013-12-01

    Phosphodiesterase type-5 (PDE-5) inhibitors are approved as the first line of therapy for the treatment of erectile dysfunction. However, different studies have been performed to study the use of these agents in other areas of urology. There are many studies related to the use of PDE-5 inhibitors as a monotherapy or combination therapy with alpha-blockers for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). It has been shown that contractions induced by various agents or electrical field stimulation in organ bath models of prostatic tissue can be reversed by PDE-5 inhibitors. Age, body mass index and the severity of LUTS are important factors for the selection of patients suitable for this treatment. It has also been reported that the use of PDE-5 inhibitors can relieve the chronic pelvic ischemia and endothelial dysfunction associated with metabolic syndrome. Most of the side effects observed with PDE-5 inhibitors are minimal and tolerable. The use of PDE-5 inhibitors is absolutely contraindicated in patients taking nitrate preparations. A significant interaction has not been observed even when a patient is taking several antihypertensive agents concurrently. Co-administration of alpha-blockers and PDE-5 inhibitors may result in orthostatic hypotension; therefore, patients should be stable on α-blocker therapy before the initiation of the combination therapy, and the initial PDE-5 inhibitor dose should be the lowest possible. In this review, our aim was to evaluate the role of PDE-5 inhibitors in the treatment of LUTS associated with BPH by analyzing the current literature. PMID:26328121

  5. Induction of Female-to-Male Sex Change in Adult Zebrafish by Aromatase Inhibitor Treatment

    NASA Astrophysics Data System (ADS)

    Takatsu, Kanae; Miyaoku, Kaori; Roy, Shimi Rani; Murono, Yuki; Sago, Tomohiro; Itagaki, Hideyuki; Nakamura, Masaru; Tokumoto, Toshinobu

    2013-12-01

    This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared, and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks, and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species.

  6. Induction of Female-to-Male Sex Change in Adult Zebrafish by Aromatase Inhibitor Treatment

    PubMed Central

    Takatsu, Kanae; Miyaoku, Kaori; Roy, Shimi Rani; Murono, Yuki; Sago, Tomohiro; Itagaki, Hideyuki; Nakamura, Masaru; Tokumoto, Toshinobu

    2013-01-01

    This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared, and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks, and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species. PMID:24292399

  7. Peptide POP inhibitors for the treatment of the cognitive symptoms of schizophrenia.

    PubMed

    López, Abraham; Mendieta, Laura; Prades, Roger; Royo, Soledad; Tarragó, Teresa; Giralt, Ernest

    2013-09-01

    Schizophrenia is a serious life-long disease that affects a significant part of the adult population. Although there is considerably effective medication for the positive symptoms of the disease, none are available for the associated cognitive deficits. These deficits are a core feature of schizophrenia, and they severely impair the functionality and social integration of patients. POP is a promising target for the treatment of the cognitive deficits of schizophrenia. Inhibitors of this peptidase show cognition-enhancing properties, act through a complex mechanism and have suitable pharmacological properties. Nevertheless, several studies must be carried out in order to improve the design and clinical evaluation of these substances. Permeability to the brain, appropriate animal models and suitable indications are the main issues that must be addressed. However, current information supports the potential of POP as an interesting drug target for the treatment of the cognitive deficits related to schizophrenia.

  8. EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen.

    PubMed

    Scheipl, Susanne; Barnard, Michelle; Cottone, Lucia; Jorgensen, Mette; Drewry, David H; Zuercher, William J; Turlais, Fabrice; Ye, Hongtao; Leite, Ana P; Smith, James A; Leithner, Andreas; Möller, Peter; Brüderlein, Silke; Guppy, Naomi; Amary, Fernanda; Tirabosco, Roberto; Strauss, Sandra J; Pillay, Nischalan; Flanagan, Adrienne M

    2016-07-01

    Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016

  9. Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking.

    PubMed

    Simeon, Saw; Anuwongcharoen, Nuttapat; Shoombuatong, Watshara; Malik, Aijaz Ahmad; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin

    2016-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disease which leads to the gradual loss of neuronal cells. Several hypotheses for AD exists (e.g., cholinergic, amyloid, tau hypotheses, etc.). As per the cholinergic hypothesis, the deficiency of choline is responsible for AD; therefore, the inhibition of AChE is a lucrative therapeutic strategy for the treatment of AD. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine that is essential for cognition and memory. A large non-redundant data set of 2,570 compounds with reported IC50 values against AChE was obtained from ChEMBL and employed in quantitative structure-activity relationship (QSAR) study so as to gain insights on their origin of bioactivity. AChE inhibitors were described by a set of 12 fingerprint descriptors and predictive models were constructed from 100 different data splits using random forest. Generated models afforded R (2), [Formula: see text] and [Formula: see text] values in ranges of 0.66-0.93, 0.55-0.79 and 0.56-0.81 for the training set, 10-fold cross-validated set and external set, respectively. The best model built using the substructure count was selected according to the OECD guidelines and it afforded R (2), [Formula: see text] and [Formula: see text] values of 0.92 ± 0.01, 0.78 ± 0.06 and 0.78 ± 0.05, respectively. Furthermore, Y-scrambling was applied to evaluate the possibility of chance correlation of the predictive model. Subsequently, a thorough analysis of the substructure fingerprint count was conducted to provide informative insights on the inhibitory activity of AChE inhibitors. Moreover, Kennard-Stone sampling of the actives were applied to select 30 diverse compounds for further molecular docking studies in order to gain structural insights on the origin of AChE inhibition. Site-moiety mapping of compounds from the diversity set revealed three binding anchors encompassing both hydrogen bonding and van der Waals

  10. The interactions of azure B, a metabolite of methylene blue, with acetylcholinesterase and butyrylcholinesterase

    SciTech Connect

    Petzer, Anél; Harvey, Brian H.; Petzer, Jacobus P.

    2014-02-01

    Methylene blue (MB) is reported to possess diverse pharmacological actions and is attracting increasing attention for the treatment of neurodegenerative disorders such as Alzheimer's disease. Among the pharmacological actions of MB, is the significant inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These activities may, at least in part, underlie MB's beneficial effects in Alzheimer's disease. MB is metabolized to yield N-demethylated products of which azure B, the monodemethyl metabolite, is the predominant species. Azure B has been shown to be pharmacologically active and also possesses a variety of biological actions. Azure B therefore may contribute to the pharmacological profile of MB. Based on these considerations, the present study investigates the possibility that azure B may, similar to MB, act as an inhibitor of human AChE and BuChE. The results document that azure B inhibits AChE and BuChE with IC{sub 50} values of 0.486 μM and 1.99 μM, respectively. The results further show that azure B inhibits AChE and BuChE reversibly, and that the modes of inhibition are most likely competitive. Although the AChE and BuChE inhibitory activities of azure B are twofold and fivefold, respectively, less potent than those recorded for MB [IC{sub 50}(AChE) = 0.214 μM; IC{sub 50}(BuChE) = 0.389 μM] under identical conditions, azure B may be a contributor to MB's in vivo activation of the cholinergic system and beneficial effects in Alzheimer's disease. - Highlights: • Methylene blue (MB) is a known inhibitor of AChE and BuChE. • Azure B, the major metabolite of MB, also is an inhibitor of AChE and BuChE. • Azure B may be a contributor to MB's in vivo activation of the cholinergic system. • Azure B may contribute to MB's potential in Alzheimer's disease therapy.

  11. Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking.

    PubMed

    Simeon, Saw; Anuwongcharoen, Nuttapat; Shoombuatong, Watshara; Malik, Aijaz Ahmad; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin

    2016-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disease which leads to the gradual loss of neuronal cells. Several hypotheses for AD exists (e.g., cholinergic, amyloid, tau hypotheses, etc.). As per the cholinergic hypothesis, the deficiency of choline is responsible for AD; therefore, the inhibition of AChE is a lucrative therapeutic strategy for the treatment of AD. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine that is essential for cognition and memory. A large non-redundant data set of 2,570 compounds with reported IC50 values against AChE was obtained from ChEMBL and employed in quantitative structure-activity relationship (QSAR) study so as to gain insights on their origin of bioactivity. AChE inhibitors were described by a set of 12 fingerprint descriptors and predictive models were constructed from 100 different data splits using random forest. Generated models afforded R (2), [Formula: see text] and [Formula: see text] values in ranges of 0.66-0.93, 0.55-0.79 and 0.56-0.81 for the training set, 10-fold cross-validated set and external set, respectively. The best model built using the substructure count was selected according to the OECD guidelines and it afforded R (2), [Formula: see text] and [Formula: see text] values of 0.92 ± 0.01, 0.78 ± 0.06 and 0.78 ± 0.05, respectively. Furthermore, Y-scrambling was applied to evaluate the possibility of chance correlation of the predictive model. Subsequently, a thorough analysis of the substructure fingerprint count was conducted to provide informative insights on the inhibitory activity of AChE inhibitors. Moreover, Kennard-Stone sampling of the actives were applied to select 30 diverse compounds for further molecular docking studies in order to gain structural insights on the origin of AChE inhibition. Site-moiety mapping of compounds from the diversity set revealed three binding anchors encompassing both hydrogen bonding and van der Waals

  12. Interferences on microbial inhibitor tests related to ivermectin treatment in lactating dairy goats.

    PubMed

    Romero, Tamara; Moya, Vicente Javier; Fernández, Nemesio; Althaus, Rafael; Reybroeck, Wim; Molina, María Pilar

    2016-08-01

    This Research Communication reports interferences related to the administration of ivermectin in lactating dairy goats on the response of microbial tests for screening antibiotics in milk. Twenty-eight Murciano-Granadina goats, naturally infested with Sarcoptes scabiei var. caprae, were treated with a subcutaneous injection of ivermectin (200 µg/kg b.w.). To prevent re-infestation, a second dose was applied 7 d later. Individual milk samples were collected, daily, up to 15 d post-treatment. Milk samples were analysed by microbial inhibitor tests (BRT MRL, Delvotest SP-NT MCS and Eclipse 100) and ivermectin residues were quantified by HPLC. A large number of positive results were obtained for all microbial tests, especially on the first day after treatment (BRT MRL = 46·4%; Delvotest SP-NT MCS = 14·3%; and Eclipse 100 = 17·8%). However, the highest concentration of drug residues in milk (24·3 ng/ml) was detected on the tenth day after treatment, when positive outcomes were relatively lower (BRT MRL = 17·8%; Delvotest SP-NT MCS = 10·7%; and Eclipse 100 = 7·4%). Results herein suggest that factors related to the ivermectin treatment other than drug residues in milk, or alterations produced by the parasitic disease itself affecting the immune response of animals, could be the cause of false-positive results in microbial tests. It can be concluded that the application of ivermectin in dairy goats infested with sarcoptes mange during lactation produces persistent drug residues in milk, and could also cause false-positive results in microbial inhibitor tests for screening antibiotics.

  13. Interferences on microbial inhibitor tests related to ivermectin treatment in lactating dairy goats.

    PubMed

    Romero, Tamara; Moya, Vicente Javier; Fernández, Nemesio; Althaus, Rafael; Reybroeck, Wim; Molina, María Pilar

    2016-08-01

    This Research Communication reports interferences related to the administration of ivermectin in lactating dairy goats on the response of microbial tests for screening antibiotics in milk. Twenty-eight Murciano-Granadina goats, naturally infested with Sarcoptes scabiei var. caprae, were treated with a subcutaneous injection of ivermectin (200 µg/kg b.w.). To prevent re-infestation, a second dose was applied 7 d later. Individual milk samples were collected, daily, up to 15 d post-treatment. Milk samples were analysed by microbial inhibitor tests (BRT MRL, Delvotest SP-NT MCS and Eclipse 100) and ivermectin residues were quantified by HPLC. A large number of positive results were obtained for all microbial tests, especially on the first day after treatment (BRT MRL = 46·4%; Delvotest SP-NT MCS = 14·3%; and Eclipse 100 = 17·8%). However, the highest concentration of drug residues in milk (24·3 ng/ml) was detected on the tenth day after treatment, when positive outcomes were relatively lower (BRT MRL = 17·8%; Delvotest SP-NT MCS = 10·7%; and Eclipse 100 = 7·4%). Results herein suggest that factors related to the ivermectin treatment other than drug residues in milk, or alterations produced by the parasitic disease itself affecting the immune response of animals, could be the cause of false-positive results in microbial tests. It can be concluded that the application of ivermectin in dairy goats infested with sarcoptes mange during lactation produces persistent drug residues in milk, and could also cause false-positive results in microbial inhibitor tests for screening antibiotics. PMID:27600969

  14. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of Alzheimer's disease.

    PubMed

    Noetzli, Muriel; Eap, Chin B

    2013-04-01

    With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t(1/2)) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t(1/2) of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t(1/2) of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t(1/2) of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better

  15. Monitoring the Response to Tyrosine Kinase Inhibitor (TKI) Treatment in Chronic Myeloid Leukemia (CML)

    PubMed Central

    Haznedaroglu, Ibrahim C.

    2014-01-01

    The aim of oral tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) is to get ideal hematological, cytogenetic, molecular responses at the critical time points. The depth of the response obtained with TKI and the time to achieve this response are both important in predicting the prognosis in patients with CML. The high efficacy of the TKI treatment of CML has prompted the need for accurate methods to monitor response at levels below the landmark of CCyR. Quantification of BCR-ABL transcripts has proven to be the most sensitive method available and has shown prognostic impact with regard to progression-free survival. European LeukemiaNet (ELN) molecular program harmonized the reporting of results according to the IS (International harmonization of Scale) in Europe. The aim of this review is to outline monitoring the response to optimal TKI treatment based on the ELN CML 2013 recommendations from the clinical point of view as a physician. Careful cytogenetic and molecular monitoring could help to select the most convenient TKI drug and to optimize TKI treatment. Excessive monitoring may have an economic cost, but failure to optimize TKI treatment may result in CML disease acceleration and death. PMID:24455118

  16. A comparison of reactivating and therapeutic efficacy of bispyridinium acetylcholinesterase reactivator KR-22934 with the oxime K203 and commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice.

    PubMed

    Kassa, Jiri; Karasova, Jana Zdarova; Pavlikova, Ruzena; Musilek, Kamil; Kuca, Kamil; Bajgar, Jiri; Jung, Young-Sik

    2011-03-01

    The potency of bispyridinium acetylcholinesterase reactivator KR-22934 in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with the oxime K203 and commonly used oximes. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in rats showed that the reactivating efficacy of KR-22934 was slightly higher than the reactivating efficacy of K203 and roughly corresponded to the reactivating efficacy of obidoxime and trimedoxime in blood and diaphragm. On the other hand, the oxime KR-22934 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied approximately corresponded to their reactivating efficacy. Based on the results, one can conclude that the oxime KR-22934 is not suitable for the replacement of commonly used oximes for the antidotal treatment of tabun poisoning in spite of its potency to reactivate tabun-inhibited acetylcholinesterase in the peripheral compartment (blood, diaphragm).

  17. A novel role for synaptic acetylcholinesterase as an apoptotic deoxyribonuclease

    PubMed Central

    Du, Aiying; Xie, Jing; Guo, Kaijie; Yang, Lei; Wan, Yihan; OuYang, Qi; Zhang, Xuejin; Niu, Xin; Lu, Lu; Wu, Jun; Zhang, Xuejun

    2015-01-01

    In addition to terminating neurotransmission by hydrolyzing acetylcholine, synaptic acetylcholinesterase (AChES) has been found to have a pro-apoptotic role. However, the underlying mechanism has rarely been investigated. Here, we report a nuclear translocation-dependent role for AChES as an apoptotic deoxyribonuclease (DNase). AChES polypeptide binds to and cleaves naked DNA at physiological pH in a Ca2+–Mg2+-dependent manner. It also cleaves chromosomal DNA both in pre-fixed and in apoptotic cells. In the presence of a pan-caspase inhibitor, the cleavage still occurred after nuclear translocation of AChES, implying that AChES-DNase acts in a CAD- and EndoG-independent manner. AChE gene knockout impairs apoptotic DNA cleavage; this impairment is rescued by overexpression of the wild-type but not (aa 32–138)-deleted AChES. Furthermore, in comparison with the nuclear-localized wild-type AChES, (aa 32–138)-deleted AChES loses the capacity to initiate apoptosis. These observations confirm that AChES mediates apoptosis via its DNase activity. PMID:27462404

  18. Asymmetric distribution of acetylcholinesterase in gravistimulated maize seedlings.

    PubMed

    Momonoki, Y S

    1997-05-01

    Acetylcholinesterase (AChE) activity has previously been studied by this laboratory and shown to occur at the interface between the stele and cortex of the mesocotyl of maize (Zea mays L.) seedlings. In this work we studied the distribution of AChE activity in 5-d-old maize seedlings following a gravity stimulus. After the stimulus, we found an asymmetric distribution of the enzyme in the coleoptile, the coleoptile node, and the mesocotyl of the stimulated seedlings using both histochemical and colorimetric methods for measuring the hydrolysis of acetylthiocholine. The hydrolytic capability of the esterase was greater on the lower side of the horizontally placed seedlings. Using the histochemical method, we localized the hydrolytic capability in the cortical cells around the vascular stele of the tissues. The hydrolytic activity was inhibited 80 to 90% by neostigmine, an inhibitor of AChE. When neostigmine was applied to the corn kernel, the gravity response of the seedling was inhibited and no enzyme-positive spots appeared in the gravity-stimulated seedlings. We believe these results indicate a role for AChE in the gravity response of maize seedlings. PMID:11536808

  19. Molecular Dynamics of Mouse Acetylcholinesterase Complexed with Huperzine A

    SciTech Connect

    Tara, Sylvia; Helms, Volkhard H.; Straatsma, TP; Mccammon, J Andrew A.

    1999-03-16

    Two molecular dynamics simulations were performed for a modeled complex of mouse acetylcholinesterase liganded with huperzine A (HupA). Analysis of these simulations shows that HupA shifts in the active site toward Tyr 337 and Phe 338, and that several residues in the active site area reach out to make hydrogen bonds with the inhibitor. Rapid fluctuations of the gorge width are observed, ranging from widths that allow substrate access to the active site, to pinched structures that do not allow access of molecules as small as water. Additional openings or channels to the active site are found. One opening is formed in the side wall of the active site gorge by residues Val 73, Asp 74, Thr 83, Glu 84, and Asn 87. Another opening is formed at the base of the gorge by residues Trp 86, Val 132, Glu 202, Gly 448, and Ile 451. Both of these openings have been observed separately in the Torpedo californica form of the enzyme. These channels could allow transport of waters and ions to and from the bulk solution.

  20. Pyridine sulfonamide as a small key organic molecule for the potential treatment of type-II diabetes mellitus and Alzheimer's disease: In vitro studies against yeast α-glucosidase, acetylcholinesterase and butyrylcholinesterase.

    PubMed

    Riaz, Sadaf; Khan, Islam Ullah; Bajda, Marek; Ashraf, Muhammad; Qurat-Ul-Ain; Shaukat, Ayesha; Rehman, Tanzeel Ur; Mutahir, Sadaf; Hussain, Sajjad; Mustafa, Ghulam; Yar, Muhammad

    2015-12-01

    This paper presents the efficient high yield synthesis of novel pyridine 2,4,6-tricarbohydrazide derivatives (4a-4i) along with their α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition activities. The enzymes inhibition results showed the potential of synthesized compounds in controlling both type-II diabetes mellitus and Alzheimer's disease. In vitro biological investigations revealed that most of compounds were more active against yeast α-glucosidase than the reference compound acarbose (IC50 38.25±0.12μM). Among the tested series the compound 4c bearing 4-flouro benzyl group was noted to be the most active (IC50 25.6±0.2μM) against α-glucosidase, and it displayed weak inhibition activities against AChE and BChE. Compound 4a exhibited the most desired results against all three enzymes, as it was significantly active against all the three enzymes; α-glucosidase (IC50 32.2±0.3μM), AChE (IC50 50.2±0.8μM) and BChE (IC50 43.8±0.8μM). Due to the most favorable activity of 4a against the tested enzymes, for molecular modeling studies this compound was selected to investigate its pattern of interaction with α-glucosidase and AChE targets.

  1. Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment

    PubMed Central

    Oplustilova, Lenka; Wolanin, Kamila; Mistrik, Martin; Korinkova, Gabriela; Simkova, Dana; Bouchal, Jan; Lenobel, Rene; Bartkova, Jirina; Lau, Alan; O’Connor, Mark J.; Lukas, Jiri; Bartek, Jiri

    2012-01-01

    Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response to PARP-1i. Here we addressed these issues using PARP-1i on 20 human cell lines from carcinomas of the breast, prostate, colon, pancreas and ovary. Aberrations of the Mre11-Rad50-Nbs1 (MRN) complex sensitized cancer cells to PARP-1i, while p53 status was less predictive, even in response to PARP-1i combinations with camptothecin or ionizing radiation. Furthermore, monitoring PARsylation and Rad51 foci formation as surrogate markers for PARP activity and HR, respectively, supported their candidacy for biomarkers of PARP-1i responses. As to resistance mechanisms, we confirmed the role of the multidrug resistance efflux transporters and its reversibility. More importantly, we demonstrated that shRNA lentivirus-mediated depletion of 53BP1 in human BRCA1-mutant breast cancer cells increased their resistance to PARP-1i. Given the preferential loss of 53BP1 in BRCA-defective and triple-negative breast carcinomas, our findings warrant assessment of 53BP1 among candidate predictive biomarkers of response to PARPi. Overall, this study helps characterize genetic and functional determinants of cellular responses to PARP-1i and contributes to the search for biomarkers to exploit PARP inhibitors in cancer therapy. PMID:22983061

  2. Treatment of Experimental Candida Sepsis with a Janus Kinase Inhibitor Controls Inflammation and Prolongs Survival.

    PubMed

    Tsirigotis, P; Papanikolaou, N; Elefanti, A; Konstantinou, P; Gkirkas, K; Rontogianni, D; Siafakas, N; Karakitsos, P; Roilides, E; Dimitriadis, G; Zerva, L; Meletiadis, J

    2015-12-01

    Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) levels and IL-10/TNF-α ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-α ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.

  3. Treatment of Alzheimer's disease with the GSK-3 inhibitor tideglusib: a pilot study.

    PubMed

    del Ser, Teodoro; Steinwachs, Klaus C; Gertz, Hermann J; Andrés, María V; Gómez-Carrillo, Belén; Medina, Miguel; Vericat, Joan A; Redondo, Pilar; Fleet, David; León, Teresa

    2013-01-01

    This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 × ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD.

  4. Proteasome inhibitors.

    PubMed

    Teicher, Beverly A; Tomaszewski, Joseph E

    2015-07-01

    Proteasome inhibitors have a 20 year history in cancer therapy. The first proteasome inhibitor, bortezomib (Velcade, PS-341), a break-through multiple myeloma treatment, moved rapidly through development from bench in 1994 to first approval in 2003. Bortezomib is a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Next generation proteasome inhibitors include carfilzomib and oprozomib which are irreversible epoxyketone proteasome inhibitors; and ixazomib and delanzomib which are reversible boronic acid proteasome inhibitors. Two proteasome inhibitors, bortezomib and carfilzomib are FDA approved drugs and ixazomib and oprozomib are in late stage clinical trials. All of the agents are potent cytotoxics. The disease focus for all the proteasome inhibitors is multiple myeloma. This focus arose from clinical observations made in bortezomib early clinical trials. Later preclinical studies confirmed that multiple myeloma cells were indeed more sensitive to proteasome inhibitors than other tumor cell types. The discovery and development of the proteasome inhibitor class of anticancer agents has progressed through a classic route of serendipity and scientific investigation. These agents are continuing to have a major impact in their treatment of hematologic malignancies and are beginning to be explored as potential treatment agent for non-cancer indications. PMID:25935605

  5. Target prices for mass production of tyrosine kinase inhibitors for global cancer treatment

    PubMed Central

    Hill, Andrew; Gotham, Dzintars; Fortunak, Joseph; Meldrum, Jonathan; Erbacher, Isabelle; Martin, Manuel; Shoman, Haitham; Levi, Jacob; Powderly, William G; Bower, Mark

    2016-01-01

    Objective To calculate sustainable generic prices for 4 tyrosine kinase inhibitors (TKIs). Background TKIs have proven survival benefits in the treatment of several cancers, including chronic myeloid leukaemia, breast, liver, renal and lung cancer. However, current high prices are a barrier to treatment. Mass production of low-cost generic antiretrovirals has led to over 13 million people being on HIV/AIDS treatment worldwide. This analysis estimates target prices for generic TKIs, assuming similar methods of mass production. Methods Four TKIs with patent expiry dates in the next 5 years were selected for analysis: imatinib, erlotinib, lapatinib and sorafenib. Chemistry, dosing, published data on per-kilogram pricing for commercial transactions of active pharmaceutical ingredient (API), and quotes from manufacturers were used to estimate costs of production. Analysis included costs of excipients, formulation, packaging, shipping and a 50% profit margin. Target prices were compared with current prices. Global numbers of patients eligible for treatment with each TKI were estimated. Results API costs per kg were $347–$746 for imatinib, $2470 for erlotinib, $4671 for lapatinib, and $3000 for sorafenib. Basing on annual dose requirements, costs of formulation/packaging and a 50% profit margin, target generic prices per person-year were $128–$216 for imatinib, $240 for erlotinib, $1450 for sorafenib, and $4020 for lapatinib. Over 1 million people would be newly eligible to start treatment with these TKIs annually. Conclusions Mass generic production of several TKIs could achieve treatment prices in the range of $128–$4020 per person-year, versus current US prices of $75161–$139 138. Generic TKIs could allow significant savings and scaling-up of treatment globally, for over 1 million eligible patients. PMID:26817636

  6. Efficacy of C1 esterase inhibitor concentrate in treatment of cutaneous attacks of hereditary angioedema

    PubMed Central

    Bork, Konrad; Craig, Timothy J.; Bernstein, Jonathan A.; Feuersenger, Henrike; Machnig, Thomas

    2015-01-01

    Background: Although treatment with C1 esterase inhibitor (C1-INH) concentrate is well established for hereditary angioedema (HAE) attacks in general, data that assess its efficacy for cutaneous attack treatment are sparse. Objective: To assess efficacy of plasma-derived, nanofiltered C1-INH concentrate for cutaneous attack treatment by comparing treated attacks from the uncontrolled I.M.P.A.C.T.2 study with historical data for untreated attacks. Methods: Cutaneous attack data from patients with HAE who were treated for cutaneous edema with 20 IU/kg body weight C1-INH concentrate in the uncontrolled I.M.P.A.C.T.2 study (38 patients) were compared with data from untreated patients from an historical data base (46 patients) and included subset analyses for facial edema (treated group, 21 patients; untreated group, 33 patients) and peripheral edema (30 patients in each group). Average attack duration (AAD) per patient was the efficacy end point used to compare treated and untreated patients. Differences were assessed with a Wilcoxon test (primary analysis) and a log-rank test; AAD per patient was analyzed descriptively and graphically with Kaplan-Meier curves. Results: The AAD per patient of all cutaneous attacks or facial and peripheral cutaneous attack subsets was significantly faster with C1-INH treatment than without treatment (Wilcoxon and log-rank tests, both p < 0.0001 for all comparisons). Mean AADs per patient for all, facial, and peripheral attacks were 2.04, 1.45, and 2.16 days, respectively, in the C1-INH–treated group, and were 3.74, 4.45, and 2.98 days, respectively, in the untreated group. Kaplan-Meier curves corroborated the observed group differences. Conclusion: Treatment of cutaneous HAE attacks (all attacks or facial and peripheral attack subsets) with 20 IU/kg C1-INH concentrate provided faster attack resolution compared with no treatment. PMID:25803207

  7. Management of Chronic Myeloid Leukemia Patients Resistant to Tyrosine Kinase Inhibitors Treatment

    PubMed Central

    Wieczorek, Agnieszka; Uharek, Lutz

    2015-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with a characteristic chromosomal translocation called the Philadelphia chromosome. This oncogene is generated by the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus (ABL) genes and encodes a novel fusion gene translating into a protein with constitutive tyrosine kinase activity. The discovery and introduction of tyrosine kinase inhibitors (TKIs) irreversibly changed the landscape of CML treatment, leading to dramatic improvement in long-term survival rates. The majority of patients with CML in the chronic phase have a life expectancy comparable with that of healthy age-matched individuals. Although an enormous therapeutic improvement has been accomplished, there are still some unresolved issues in the treatment of patients with CML. One of the most important problems is based on the fact that TKIs can efficiently target proliferating mature cells but do not eradicate leukemic stem cells, allowing persistence of the malignant clone. Owing to the resistance mechanisms arising during the course of the disease, treatment with most of the approved BCR-ABL1 TKIs may become ineffective in a proportion of patients. This article highlights the different molecular mechanisms of acquired resistance being developed during treatment with TKIs as well as the pharmacological strategies to overcome it. Moreover, it gives an overview of novel drugs and therapies that are aiming in overcoming drug resistance, loss of response, and kinase domain mutations. PMID:26917943

  8. IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future.

    PubMed

    Kim, Go Woon; Lee, Na Ra; Pi, Ryo Han; Lim, Yee Seul; Lee, Yu Mi; Lee, Jong Min; Jeong, Hye Seung; Chung, Sung Hyun

    2015-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

  9. Treatment of functional decline in adults with Down syndrome using selective serotonin-reuptake inhibitor drugs.

    PubMed

    Geldmacher, D S; Lerner, A J; Voci, J M; Noelker, E A; Somple, L C; Whitehouse, P J

    1997-07-01

    Alzheimer's disease (AD) is a common cause of functional decline in Down syndrome (DS) adults. Acquired cognitive deficits may be difficult to evaluate in the context of baseline impairments. Behavioral symptoms are also common and may represent the effects of depression, AD, or both. Therefore, the objective of this study was to report a clinical case series of selected adults with DS and behavioral change who responded to treatment with selective serotonin-reuptake inhibitor (SSRI) medication. Six patients, aged 23 to 63 years, 5 women and 1 man, with the clinical diagnosis of DS presented for diagnosis and treatment of functional decline in adult life. Noncognitive symptoms were prominent and included aggression, social withdrawal, and compulsive behaviors. Memory dysfunction was reported in varying degrees. Treatment with SSRI antidepressants was instituted for depressive, apathetic, and compulsive behaviors. Treated patients showed improvement in behaviors as reported by caregivers, and on objective measures, such as workplace productivity. Noncognitive symptoms are a cardinal feature of functional decline in adults with DS and may represent either depression or AD. In some patients, the symptoms respond well to SSRI agents with concomitant improvement in daily function. Treatment trials with SSRIs may, therefore, be warranted in such cases.

  10. Treatment with the hyaluronic Acid synthesis inhibitor 4-methylumbelliferone suppresses LPS-induced lung inflammation.

    PubMed

    McKallip, Robert J; Ban, Hao; Uchakina, Olga N

    2015-01-01

    Exposure to bacterial endotoxins, such as lipopolysaccharide (LPS), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for LPS-induced inflammation. In the current study, we investigated the potential use of the hyaluronic acid (HA) synthesis inhibitor 4-methylumbelliferone (4-MU) on LPS-induced acute lung inflammation. Culturing LPS-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production, and an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from LPS-induced lung injury. Specifically, 4-MU treatment led to a reduction in LPS-induced hyaluronic acid synthase (HAS) messenger RNA (mRNA) levels, reduction in lung permeability, and reduction in proinflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target HA production may be an effective treatment for the inflammatory response following exposure to LPS.

  11. Inactivation of acetylcholinesterase by various fluorophores

    PubMed Central

    Guo, Lilu; Suarez, Alirica I.; Thompson, Charles M.

    2012-01-01

    The inhibition of recombinant mouse acetylcholinesterase (rMAChE) and electric eel acetylcholinesterase (EEAChE) by seven, structurally different chromophore-based (dansyl, pyrene, dabsyl, diethylamino- and methoxycoumarin, Lissamine rhodamine B, and Texas Red) propargyl carboxamides or sulfonamides was studied. Diethylaminocoumarin, Lissamine, and Texas Red amides inhibited rMAChE with IC50 values of 1.00 µM, 0.05 µM, and 0.70 µM, respectively. Lissamine and Texas Red amides inhibited EEAChE with IC50 values of 3.57 and 10.4 µM, respectively. The other chromophore amides did not inhibit either AChE. The surprising inhibitory potency of Lissamine was examined in further detail against EEAChE and revealed a mixed-type inhibition with Ki = 11.7 µM (competitive) and Ki′ = 24.9 µM (noncompetitive), suggesting that Lissamine binds to free enzyme and enzyme–substrate complex. PMID:19842944

  12. Mutagenesis of essential functional residues in acetylcholinesterase.

    PubMed Central

    Gibney, G; Camp, S; Dionne, M; MacPhee-Quigley, K; Taylor, P

    1990-01-01

    The cholinesterases are serine hydrolases that show no global similarities in sequence with either the trypsin or the subtilisin family of serine proteases. The cholinesterase superfamily includes several esterases with distinct functions and other proteins devoid of the catalytic serine and known esterase activity. To identify the residues involved in catalysis and conferring specificity on the enzyme, we have expressed wild-type Torpedo acetylcholinesterase (EC 3.1.1.7) and several site-directed mutants in a heterologous system. Mutation of serine-200 to cysteine results in diminished activity, while its mutation to valine abolishes detectable activity. Two conserved histidines can be identified at positions 425 and 440 in the cholinesterase family; glutamine replacement at position 440 eliminates activity whereas the mutation at 425 reduces activity only slightly. The assignment of the catalytic histidine to position 440 defines a rank ordering of catalytic residues in cholinesterases distinct from trypsin and subtilisin and suggests a convergence of a catalytic triad to form a third, distinct family of serine hydrolases. Mutation of glutamate-199 to glutamine yields an enzyme with a higher Km and without the substrate-inhibition behavior characteristic of acetylcholinesterase. Hence, modification of the acidic amino acid adjacent to the serine influences substrate association and the capacity of a second substrate molecule to affect catalysis. Images PMID:2217185

  13. Targets for AD treatment: conflicting messages from γ-secretase inhibitors

    PubMed Central

    Sambamurti, Kumar; Greig, Nigel H.; Utsuki, Tadanobu; Barnwell, Eliza L.; Sharma, Ekta; Mazell, Cheryl; Bhat, Narayan R.; Kindy, Mark S.; Lahiri, Debomoy K.; Pappolla, Miguel A

    2011-01-01

    Current evidence suggests that Alzheimer’s disease (AD) is a multi-factorial disease that starts with accumulation of multiple proteins. We have previously proposed that inhibition of γ-secretase may impair membrane recycling causing neurodegeneration starting at synapses (Sambamurti et al., 2006). We also proposed familal AD (FAD) mutations increase Aβ42 by inhibiting γ-secretase. Herein, we discuss the failure of Eli Lilly’s γ-secretase inhibitor, semagacestat, in clinical trials in the light of our hypothesis, which extends the problem beyond toxicity of Aβ aggregates. We elaborate that γ-secretase inhibitors lead to accumulation of amyloid precursor protein (APP) C-terminal fragments (CTFs) that can later be processed by γ-secretase to yields bursts of Aβ to facilitate aggregation. Although we do not exclude a role for toxic Aβ aggregates, inhibition of γ-secretase can affect numerous substrates other than APP to affect multiple pathways and the combined accumulation of multiple peptides in the membrane may impair its function and turnover. Taken together, protein processing and turnover pathways play an important role in maintaining cellular homeostasis and unless we clearly see consistent disease-related increase in their levels or activity, we need to focus on preserving their function rather than inhibiting them for treatment of AD and similar diseases. PMID:21320126

  14. Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer.

    PubMed

    Sridhar, Srikala S; Shepherd, Frances A

    2003-12-01

    It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently that anti-angiogenesis agents have entered the clinical setting. The search for novel therapies is particularly important in lung cancer, where the majority of patients succumb to their disease despite aggressive treatments. Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190. Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin, angiostatin and interferons. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies. PMID:14611919

  15. Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex.

    PubMed

    MacKeigan, Jeffrey P; Krueger, Darcy A

    2015-12-01

    Tuberous sclerosis complex (TSC) is a genetic autosomal dominant disorder characterized by benign tumor-like lesions, called hamartomas, in multiple organ systems, including the brain, skin, heart, kidneys, and lung. These hamartomas cause a diverse set of clinical problems based on their location and often result in epilepsy, learning difficulties, and behavioral problems. TSC is caused by mutations within the TSC1 or TSC2 genes that inactivate the genes' tumor-suppressive function and drive hamartomatous cell growth. In normal cells, TSC1 and TSC2 integrate growth signals and nutrient inputs to downregulate signaling to mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine kinase that controls cell growth and cell survival. The molecular connection between TSC and mTOR led to the clinical use of allosteric mTOR inhibitors (sirolimus and everolimus) for the treatment of TSC. Everolimus is approved for subependymal giant cell astrocytomas and renal angiomyolipomas in patients with TSC. Sirolimus, though not approved for TSC, has undergone considerable investigation to treat various aspects of the disease. Everolimus and sirolimus selectively inhibit mTOR signaling with similar molecular mechanisms, but with distinct clinical profiles. This review differentiates mTOR inhibitors in TSC while describing the molecular mechanisms, pathogenic mutations, and clinical trial outcomes for managing TSC. PMID:26289591

  16. Inhibitor treatment of peripheral mononuclear cells from Parkinson's disease patients further validates LRRK2 dephosphorylation as a pharmacodynamic biomarker.

    PubMed

    Perera, G; Ranola, M; Rowe, D B; Halliday, G M; Dzamko, N

    2016-01-01

    Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with increased risk of Parkinson's disease (PD). Thus, LRRK2 kinase inhibitors are in development as potential Parkinson's disease therapeutics. A reduction in the constitutive levels of phosphorylation on leucine-rich repeat kinase 2 (LRRK2) is currently used to measure target engagement of LRRK2 kinase inhibitors in cell and animal models. We aimed to determine if reduced phosphorylation of LRRK2 following inhibitor treatment is also a valid measure of target engagement in peripheral mononuclear cells from Parkinson's disease patients. Peripheral mononuclear cells from idiopathic Parkinson's disease patients and controls were treated ex vivo with two structurally distinct inhibitors of LRRK2, at four different doses, and immunoblotting was used to assess the reduction in LRRK2 phosphorylation at Ser910, Ser935, Ser955 and Ser973. Both inhibitors showed no acute toxicity in primary cells and both inhibitors reduced the constitutive phosphorylation of LRRK2 at all measured residues equally in both control and Parkinson's disease groups. Measuring the reduction in LRRK2 phosphorylation resulting from LRRK2 kinase inhibition, is thus a valid measure of acute peripheral target engagement in Parkinson's disease patients. This is important if LRRK2 kinase inhibitors are to be used in a clinical setting.

  17. Inhibitor treatment of peripheral mononuclear cells from Parkinson's disease patients further validates LRRK2 dephosphorylation as a pharmacodynamic biomarker.

    PubMed

    Perera, G; Ranola, M; Rowe, D B; Halliday, G M; Dzamko, N

    2016-01-01

    Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with increased risk of Parkinson's disease (PD). Thus, LRRK2 kinase inhibitors are in development as potential Parkinson's disease therapeutics. A reduction in the constitutive levels of phosphorylation on leucine-rich repeat kinase 2 (LRRK2) is currently used to measure target engagement of LRRK2 kinase inhibitors in cell and animal models. We aimed to determine if reduced phosphorylation of LRRK2 following inhibitor treatment is also a valid measure of target engagement in peripheral mononuclear cells from Parkinson's disease patients. Peripheral mononuclear cells from idiopathic Parkinson's disease patients and controls were treated ex vivo with two structurally distinct inhibitors of LRRK2, at four different doses, and immunoblotting was used to assess the reduction in LRRK2 phosphorylation at Ser910, Ser935, Ser955 and Ser973. Both inhibitors showed no acute toxicity in primary cells and both inhibitors reduced the constitutive phosphorylation of LRRK2 at all measured residues equally in both control and Parkinson's disease groups. Measuring the reduction in LRRK2 phosphorylation resulting from LRRK2 kinase inhibition, is thus a valid measure of acute peripheral target engagement in Parkinson's disease patients. This is important if LRRK2 kinase inhibitors are to be used in a clinical setting. PMID:27503089

  18. Cholinesterase inhibitors from botanicals

    PubMed Central

    Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P.; Ahmed, K. K. Mueen

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

  19. Cholinesterase inhibitors from botanicals.

    PubMed

    Ahmed, Faiyaz; Ghalib, Raza Murad; Sasikala, P; Ahmed, K K Mueen

    2013-07-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed. PMID:24347920

  20. C1-esterase inhibitor treatment: preclinical safety aspects on the potential prothrombotic risk.

    PubMed

    Schürmann, Daniel; Herzog, Eva; Raquet, Elmar; Nolte, Marc W; May, Frauke; Müller-Cohrs, Jochen; Björkqvist, Jenny; Dickneite, Gerhard; Pragst, Ingo

    2014-11-01

    Human plasma-derived C1-esterase inhibitor (C1-INH) is an efficacious and safe treatment for hereditary angioedema. However, thrombotic events in subjects treated with C1-INH at recommended or off-label, high doses have been reported. In this study, we addressed the potential prothrombotic risk of C1-INH treatment in high doses using a non-clinical rabbit model. Following intravenous infusion of C1-INH to rabbits at doses up to 800 IU/kg, the exposure and the pharmacodynamic efficacy of C1-INH in rabbits were confirmed by activity measurements of C1-esterase, and coagulation factors XIa and XIIa, respectively. Potential prothrombotic effects were assessed following induction of venous and arterial thrombosis using in vivo models of venous and arterial stasis, complemented by various in vitro assays of coagulation markers. Administration of C1-INH at doses up to 800 IU/kg did not potentiate thrombus formation during venous stasis. In contrast, inhibition of arterial occlusion was observed upon C1-INH administration when compared with isotonic saline treatment, indicating antithrombotic rather than prothrombotic activity of high dose C1-INH treatment in vivo. This was further confirmed in vitro by decreased thrombin generation, increased activated partial thromboplastin time, clotting time and clot formation time, and inhibition of platelet aggregation. No relevant changes in fibrinolysis or in the levels of thrombin-antithrombin complexes, and prothrombin fragment 1+2 were observed upon high dose C1-INH treatment. The data suggest that treatment of healthy rabbits with high doses of C1-INH could potentially inhibit coagulation and thrombus formation rather than induce a prothrombotic risk.

  1. Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

    PubMed Central

    Gupta, Shashank; Tyagi, Sandeep; Almeida, Deepak V.; Maiga, Mariama C.; Ammerman, Nicole C.

    2013-01-01

    Rationale: A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy. Objectives: Using mice, a mammalian model known to predict human treatment responses, and selecting conservative human bioequivalent doses, we tested verapamil as an adjunctive drug together with standard TB chemotherapy. As verapamil is a substrate for CYP3A4, which is induced by rifampin, we evaluated the pharmacokinetic/pharmacodynamic relationships of verapamil and rifampin coadministration in mice. Methods: Using doses that achieve human bioequivalent levels matched to those of standard verapamil, but lower than those of extended release verapamil, we evaluated the activity of verapamil added to standard chemotherapy in both C3HeB/FeJ (which produce necrotic granulomas) and the wild-type background C3H/HeJ mouse strains. Relapse rates were assessed after 16, 20, and 24 weeks of treatment in mice. Measurements and Main Results: We determined that a dose adjustment of verapamil by 1.5-fold is required to compensate for concurrent use of rifampin during TB treatment. We found that standard TB chemotherapy plus verapamil accelerates bacterial clearance in C3HeB/FeJ mice with near sterilization, and significantly lowers relapse rates in just 4 months of treatment when compared with mice receiving standard therapy alone. Conclusions: These data demonstrate treatment shortening by verapamil adjunctive therapy in mice, and strongly support further study of verapamil and other efflux pump inhibitors in human TB. PMID:23805786

  2. Goals for chronic myeloid leukemia TK inhibitor treatment: how little disease is too much?

    PubMed

    Mauro, Michael J

    2014-12-01

    Tyrosine kinase inhibitors, now numbering 5 for the treatment of Philadelphia chromosome-positive leukemia, have proven ability to reduce clonal disease burden rapidly, dramatically, and durably, especially in chronic myeloid leukemia in the chronic phase. Deep molecular remissions are likely in most chronic phase patients and expectations on timing of response have been developed, validated as best as possible, and evolved over time. Increasing attention has been given to the initial decline of Bcr-Abl1 transcripts and the ultimate depth of molecular remission, overshadowing but not displacing the traditional role of cytogenetic response. This chapter reviews the evolution of response milestones for chronic phase chronic myeloid leukemia and tries to answer the question of how little disease is too much.

  3. A novel CDPK1 inhibitor--a potential treatment for cryptosporidiosis in calves?

    PubMed

    Lendner, Matthias; Böttcher, Denny; Delling, Cora; Ojo, Kayode K; Van Voorhis, Wesley C; Daugschies, Arwid

    2015-01-01

    Cryptosporidium parvum is a zoonotic agent that infects humans and animals occasionally causing severe, watery diarrhoea. In immunocompetent hosts, cryptosporidiosis is self-limiting but can have a fatal outcome in immunocompromised individuals. Cryptosporidium is one of the most common causes of waterborne diseases (recreational water and drinking water) in humans, a leading cause of moderate to severe childhood diarrhoea, and a major agent of diarrhoea in calves leading to high economic losses and up to 10% lethality. So far, available treatment options are insufficient for both veterinary and human clinical disease cases. Here, we report for the first time that the novel bumped kinase inhibitor (BKI) 1294 targeting the calcium-dependent protein kinase 1 (CDPK1) of Cryptosporidium is able to reduce the oocyst shedding of C. parvum by calves--its natural host--without obvious side effects.

  4. PARP-inhibitor-induced synthetic lethality for acute myeloid leukemia treatment.

    PubMed

    Zhao, Lu; So, Chi Wai Eric

    2016-10-01

    Genomic instability is one of the most common and critical characteristics of cancer cells. The combined effect of replication stress and DNA damage repair defects associated with various oncogenic events drives genomic instability and disease progression. However, these DNA repair defects found in cancer cells can also provide unique therapeutic opportunities and form the basis of synthetic lethal targeting of solid tumors carrying BRCA mutations. Although the idea of utilizing synthetic lethality as a therapy strategy has been gaining momentum in various solid tumors, its application in leukemia still largely lags behind. In this article, we review recent advances in understanding the roles of the DNA damage response in acute myeloid leukemia and examine the potential therapeutic avenues of using poly (ADP-ribose) polymerase (PARP) inhibitors in AML treatment. PMID:27473567

  5. Long-Term Efficacy and Toxicity of Cholinesterase Inhibitors in the Treatment of Alzheimer Disease

    PubMed Central

    Hogan, David B

    2014-01-01

    Though the symptoms of Alzheimer disease go on for years, the phase 3 trials of the cholinesterase inhibitors (ChEIs), the current mainstay of symptomatic pharmacotherapy for this condition, were typically of only 3- to 6-months’ duration. We have limited data on long-term (that is, a year or more) therapy with these agents. In this review, we explore the available information on the biological and clinical effects of long-term ChEI therapy, what happens when these agents are discontinued, and examine what others have recommended. An individualized approach to deciding on whether to carry on with a ChEI should be taken. If continued, treatment goals should be clarified and patients monitored over time, for both drug-related benefits and adverse effects. PMID:25702360

  6. The effect of cyclin-dependent kinases inhibitor treatment on experimental herpes simplex encephalitis mice.

    PubMed

    Zhou, Yu; Zeng, Yan-Ping; Zhou, Qin; Guan, Jing-Xia; Lu, Zu-Neng

    2016-08-01

    Herpes simplex encephalitis(HSE) is the most common and serious viral encephalitis in humans. There is a lack of effective medication to date for HSE. A better understanding of the mediators of tissue damage is essential for finding new targets for therapeutic intervention. In this project, we explored the effect of cyclin-dependent kinases inhibitor olomoucine treatment on experimental HSE mice. The following results were obtained: (1) olomoucine increased survival in HSE mice; (2) olomoucine inhibited microglial activation and reduced HSV-1-induced cytokines release; (3) olomoucine prevented neural cells apoptosis and attenuated brain tissue pathological changes following HSV-1 infection; (4) olomoucine reduced brain edema and improved neurological function in HSE. Overall, olomoucine can induce a blunted inflammatory response, maintain the blood vessel wall intact, improve neurological function and increase survival in HSE mice.

  7. Targeting inhibitor of apoptosis proteins (IAPs) for diagnosis and treatment of human diseases.

    PubMed

    Fulda, Simone; Debatin, Klaus-Michael

    2006-01-01

    Since cell death by apoptosis plays a key role in the regulation of tissue homeostasis, any defect in this intrinsic death program may result in tumor formation. "Inhibitor of apoptosis proteins" (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases. Aberrant expression and/or function of IAPs have been implied to be involved in the pathogenesis and progression of various human diseases including cancer, autoimmune disorders or neurodegeneration. Recent insights into the regulation of IAPs have provided the basis for various exciting discoveries aimed at modulating expression or dysfunction of IAPs. Thus, targeting IAPs, e.g. by antisense approaches, RNA interference or small molecules, may proof to be a novel strategy for the diagnosis and treatment of human diseases.

  8. Histone Deacetylases Inhibitors in the Treatment of Retinal Degenerative Diseases: Overview and Perspectives

    PubMed Central

    Dai, Xufeng; Du, Wei; Pang, Ji-jing

    2015-01-01

    Retinal degenerative diseases are one of the important refractory ophthalmic diseases, featured with apoptosis of photoreceptor cells. Histone acetylation and deacetylation can regulate chromosome assembly, gene transcription, and posttranslational modification, which are regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. The histone deacetylase inhibitors (HDACis) have the ability to cause hyperacetylation of histone and nonhistone proteins, resulting in a variety of effects on cell proliferation, differentiation, anti-inflammation, and anti-apoptosis. Several HDACis have been approved for clinical trials to treat cancer. Studies have shown that HDACis have neuroprotective effects in nervous system damage. In this paper, we will summarize the neuroprotective effects of common HDACis in retinal degenerative diseases and make a prospect to the applications of HDACis in the treatment of retinal degenerative diseases in the future. PMID:26137316

  9. Rabeprazole: a second-generation proton pump inhibitor in the treatment of acid-related disease.

    PubMed

    Pallotta, Stefano; Pace, Fabio; Marelli, Silvia

    2008-08-01

    Rabeprazole is a proton pump inhibitor (PPI) presenting a very advantageous pharmacodynamic and pharmacokinetic profile over older PPIs. In particular, this drug has a very fast onset of action, due to a short activation time and a very high pKa, and may therefore be defined as a 'second generation' PPI. The aim of this article is to provide an update on the pharmacology and clinical profile of rabeprazole and its use in acid-related disorders, with a particular focus on its role in gastroesophageal reflux disease; in the treatment and prevention of duodenal and gastric ulcers and Zollinger-Ellison syndrome; in the therapy of the extraesophageal manifestations of gastroesophageal reflux disease (in particular the respiratory and ear, nose and throat ones); and in the eradication of Helicobacter pylori.

  10. A novel CDPK1 inhibitor--a potential treatment for cryptosporidiosis in calves?

    PubMed

    Lendner, Matthias; Böttcher, Denny; Delling, Cora; Ojo, Kayode K; Van Voorhis, Wesley C; Daugschies, Arwid

    2015-01-01

    Cryptosporidium parvum is a zoonotic agent that infects humans and animals occasionally causing severe, watery diarrhoea. In immunocompetent hosts, cryptosporidiosis is self-limiting but can have a fatal outcome in immunocompromised individuals. Cryptosporidium is one of the most common causes of waterborne diseases (recreational water and drinking water) in humans, a leading cause of moderate to severe childhood diarrhoea, and a major agent of diarrhoea in calves leading to high economic losses and up to 10% lethality. So far, available treatment options are insufficient for both veterinary and human clinical disease cases. Here, we report for the first time that the novel bumped kinase inhibitor (BKI) 1294 targeting the calcium-dependent protein kinase 1 (CDPK1) of Cryptosporidium is able to reduce the oocyst shedding of C. parvum by calves--its natural host--without obvious side effects. PMID:25398685

  11. Resistance to amprenavir before and after treatment with lopinavir/ritonavir in highly protease inhibitor-experienced HIV patients.

    PubMed

    Hasson, Hamid; Gianotti, Nicola; Danise, Anna; Seminari, Elena; Boeri, Enzo; Nozza, Silvia; Castagna, Antonella; Lazzarin, Adriano

    2004-01-01

    Genotypes in nine highly protease inhibitor (PI)-experienced patients were studied before and after lopinavir/ritonavir (LPV/r) treatment. Resistance to amprenavir was the rule both before and after LPV/r treatment. Treatment with LPV/r can select for the 50 V mutation. In this setting, significant differences in the inference of the amprenavir phenotype from genotype were observed when using different algorithms.

  12. Docking-based Design of Galantamine Derivatives with Dual-site Binding to Acetylcholinesterase.

    PubMed

    Stavrakov, Georgi; Philipova, Irena; Zheleva, Dimitrina; Atanasova, Mariyana; Konstantinov, Spiro; Doytchinova, Irini

    2016-07-01

    The enzyme acetylcholinesterase is a key target in the treatment of Alzheimer's disease because of its ability to hydrolyze acetylcholine via the catalytic binding site and to accelerate the aggregation of amyloid-β peptide via the peripheral anionic site (PAS). Using docking-based predictions, in the present study we design 20 novel galantamine derivatives with alkylamide spacers of different length ending with aromatic fragments. The galantamine moiety blocks the catalytic site, while the terminal aromatic fragments bind in PAS. The best predicted compounds are synthesized and tested for acetylcholinesterase inhibitory activity. The experimental results confirm the predictions and show that the heptylamide spacer is of optimal length to bridge the galantamine moiety bound in the catalytic site and the aromatic fragments interacting with PAS. Among the tested terminal aromatic fragments, the phenethyl substituent is the most suitable for binding in PAS. PMID:27492242

  13. Effects of treatment with an Hsp90 inhibitor in tumors based on 15 phase II clinical trials

    PubMed Central

    Wang, He; Lu, Mingjie; Yao, Mengqian; Zhu, Wei

    2016-01-01

    Heat shock protein (Hsp)90 serves as a chaperone protein that promotes the proper folding of proteins involved in a variety of signal transduction processes involved in cell growth. Hsp90 inhibitors, which inhibit the activity of critical client proteins, have emerged as the accessory therapeutic agents for multiple human cancer types. To better understand the effects of Hsp90 inhibitors in cancer treatment, the present study reviewed 15 published phase II clinical trials to investigate whether Hsp90 inhibitors will benefit patients with cancer. Information of complete response, partial response, stable disease, objective response and objective response rate was collected to evaluate clinical outcomes. Overall, Hsp90 inhibitors are effective against a variety of oncogene-addicted cancers, including those that have developed resistance to specific receptors.

  14. Microglial activation decreases retention of the protease inhibitor saquinavir: implications for HIV treatment

    PubMed Central

    2013-01-01

    Background Active HIV infection within the central nervous system (CNS) is confined primarily to microglia. The glial cell compartment acts as a viral reservoir behind the blood-brain barrier. It provides an additional roadblock to effective pharmacological treatment via expression of multiple drug efflux transporters, including P-glycoprotein. HIV/AIDS patients frequently suffer bacterial and viral co-infections, leading to deregulation of glial cell function and release of pro-inflammatory mediators including cytokines, chemokines, and nitric oxide. Methods To better define the role of inflammation in decreased HIV drug accumulation into CNS targets, accumulation of the antiretroviral saquinavir was examined in purified cultures of rodent microglia exposed to the prototypical inflammatory mediator lipopolysaccharide (LPS). Results [3H]-Saquinavir accumulation by microglia was rapid, and was increased up to two-fold in the presence of the specific P-glycoprotein inhibitor, PSC833. After six or 24 hours of exposure to 10 ng/ml LPS, saquinavir accumulation was decreased by up to 45%. LPS did not directly inhibit saquinavir transport, and did not affect P-glycoprotein protein expression. LPS exposure did not alter RNA and/or protein expression of other transporters including multidrug resistance-associated protein 1 and several solute carrier uptake transporters. Conclusions The decrease in saquinavir accumulation in microglia following treatment with LPS is likely multi-factorial, since drug accumulation was attenuated by inhibitors of NF-κβ and the MEK1/2 pathway in the microglia cell line HAPI, and in primary microglia cultures from toll-like receptor 4 deficient mice. These data provide new pharmacological insights into why microglia act as a difficult-to-treat viral sanctuary site. PMID:23642074

  15. Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment.

    PubMed

    Hellbom, Einar

    2006-01-01

    Some old antihistamines were selective serotonin-reuptake inhibitors (SSRIs) and the SSRI effect was discovered by Nobel Laureate Professor Arvid Carlsson as early as 1969. Chlorpheniramine was the most active of the tested drugs, and it compares favourably with amitriptyline and imipramine with respect to actions on both serotonergic and noradrenergic neurons. Chlorpheniramine can be called a SSRI, since the blocking of 5HT is stronger than the effect on noradrenaline neurons; however it might also be called a selective serotonin and noradrenaline reuptake inhibitor (SSNRI) and be compared with new drugs, such as venlafaxine. Carlsson suggested the potential value of clinical studies of the antidepressant properties of this and related antihistamine drugs. But, in the event, no such trials were ever performed at the time. However, later clinical observations of the benefits of dex-chlorpheniramine treatment in panic disorder have been published. Clinical experience suggests that patients using chlorpheniramine, and having also a concomitant depression or panic disorder, may experience a return of symptoms when their old drug is changed to a new antihistamine lacking SSRI effects. Yet this phenomenon is not known to many doctors, and even less known to the large number of patients buying chlorpheniramine under various trade names over-the-counter (OTC) at a low price for self-treatment of hay fewer or as a cold remedy. Chlorpheniramine was introduced in USA under the name Chlor-Trimeton as long ago as July 1950, and is still on the market. Therefore, this SSRI is now over 50 years old. If chlorpheniramine had been tested in depression in the nineteen seventies, it is probable that a safe, inexpensive SSRI drug could have been used some 15 years earlier than fluoxetine - which became available in 1987. Chlorpheniramine might have been the first safe, non-cardiotoxic and well-tolerated antidepressant. Billions of dollars in the development and marketing costs would

  16. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases.

    PubMed

    Roskoski, Robert

    2016-09-01

    The Janus kinase (JAK) family of non-receptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase-2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that regulates the adjacent protein kinase domain (JH1). JAK1/2 and TYK2 are ubiquitously expressed whereas JAK3 is found predominantly in hematopoietic cells. The Janus kinase family is regulated by numerous cytokines including interleukins, interferons, and hormones such as erythropoietin, thrombopoietin, and growth hormone. Ligand binding to cytokine and hormone receptors leads to the activation of associated Janus kinases, which then mediate the phosphorylation of the receptors. The SH2 domain of STATs (signal transducers and activators of transcription) binds to the receptor phosphotyrosines thereby promoting STAT phosphorylation by the Janus kinases and consequent activation. STAT dimers are translocated to the nucleus where they participate in the regulation of the expression of thousands of proteins. JAK-STAT dysregulation results in autoimmune disorders such as rheumatoid arthritis, ulcerative colitis, and Crohn disease. JAK-STAT dysregulation also plays a role in the pathogenesis of myelofibrosis, polycythemia vera, and other myeloproliferative illnesses. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and in a lower percentage of people with other neoplasms. JAK1/3 signaling participates in the pathogenesis of inflammatory afflictions while JAK1/2 signaling participates in the development of several malignancies including leukemias and lymphomas as well as myeloproliferative neoplasms. Tofacitinib is a pan-JAK inhibitor that is approved by the FDA for the treatment of rheumatoid arthritis and ruxolitinib is a JAK1/2 inhibitor that is approved for the treatment of polycythemia vera and myelofibrosis. PMID:27473820

  17. Adherence to Phosphodiesterase Type 5 Inhibitors in the Treatment of Erectile Dysfunction in Long-Term Users: How Do Men Use the Inhibitors?

    PubMed Central

    Carvalheira, Ana; Forjaz, Vera; Pereira, Nuno Monteiro

    2014-01-01

    Introduction The high effectiveness of phosphodiesterase type 5 inhibitors (PDE5-i) in the treatment of erectile dysfunction (ED) has been demonstrated. However, previous research shows that PDE5-i treatments have high discontinuation rates. Aim The main goals of this study were to (i) characterize the way men use PDE5-i and (ii) analyze the adherence to treatment, identifying the factors that influence PDE5-i use. Methods A total of 148 men with clinical diagnosis for ED who maintained the treatment with PDE5-i for over 3 years were interviewed. Interviews concerning their ongoing treatment were carried out using a standardized questionnaire with quantitative and qualitative items. Main Outcome Measures Physiological measures included the intracavernous alprostadil injection test, associated with penile rigidometry and penile Doppler ultrasound. The qualitative measure included two questions: “Do you use the drug in every sexual intercourse?” and “How do you use the inhibitor?” Results ED causes were classified as venogenic (31%), arteriogenic (23%), psychogenic (18%), iatrogenic (13%), neurogenic (8%), and diabetic (7%). Participation rate was 71.8%. Of the 148 patients studied, 75% claimed not to use PDE5-i in every intercourse. Most used tadalafil (66%), followed by sildenafil (20%), vardenafil (10%), and 4% alternated the type of medicine. Four main categories emerged concerning the factors that determine the intake of PDE5-i in some intercourse situations and not in others: (i) psychological factors; (ii) medication-related factors; (iii) circumstantial factors; and (iv) relational factors. Conclusion The analysis of men's narratives revealed a combination of factors that influence the adherence to PDE5-i. The psychological and medication-related factors were the most prevalent. This study highlighted the importance of taking these factors into account, both at the time of prescription and during the follow-up in order to improve adherence

  18. ATP-competitive inhibitors of mTOR: new perspectives in the treatment of renal cell carcinoma.

    PubMed

    Roulin, Didier; Demartines, Nicolas; Dormond, Olivier

    2011-04-01

    Targeting mTOR (mammalian target of rapamycin) is an effective approach in the treatment of advanced RCC (renal cell carcinoma). Rapamycin-like drugs (rapalogues) have shown clinical activities and have been approved for the treatment of RCC. Recently, with the development of ATP-competitive inhibitors of mTOR, therapies targeting mTOR have entered a new era. Here, we discuss the biological relevance of blocking mTOR in RCC and review the mechanisms of action of rapalogues in RCC. We also advance some perspectives on the use of ATP-competitive inhibitors of mTOR in RCC.

  19. [Successful treatment of venous thromboembolism with a Factor Xa inhibitor, edoxaban, in patients with lenalidomide-treated multiple myeloma].

    PubMed

    Kawaguchi, Masato; Uchimura, Norio; Okuda, Yuko; Konuma, Satomi; Nehashi, Yoshio

    2015-08-01

    Two multiple myeloma (MM) patients developed venous thromboembolism (VTE) while being treated with lenalidomide and low-dose dexamethasone. Aspirin is recommended for VTE prophylaxis when using lenalidomide/dexamethasone for MM patients with a standard risk of VTE. Despite aspirin administration, however, these two patients experienced VTE. Following VTE development, warfarin and then a Factor Xa inhibitor, edoxaban, were administered. The edoxaban treatment, especially, resulted in favorable and effective control of VTE. Considering these observations, Factor Xa inhibitors may in future become a preferred option for prevention and treatment of VTE when managing MM patients. PMID:26345573

  20. Converting maslinic acid into an effective inhibitor of acylcholinesterases.

    PubMed

    Schwarz, Stefan; Loesche, Anne; Lucas, Susana Dias; Sommerwerk, Sven; Serbian, Immo; Siewert, Bianka; Pianowski, Elke; Csuk, René

    2015-10-20

    During the last decade, maslinic acid has been evaluated for many biological properties, e.g. as an anti-tumor or an anti-viral agent but also as a nutraceutical. The potential of maslinic acid and related derivatives to act as inhibitors of acetyl- or butyryl-cholinesterase was examined in this communication in more detail. Cholinesterases do still represent an interesting group of target enzymes with respect to the investigation and treatment of the Alzheimer's disease and other dementia illnesses as well. Although other triterpenoic acids have successfully been tested for their ability to act as inhibitors of cholinesterases, up to now maslinic acid has not been part of such studies. For this reason, three series of maslinic acid derivatives possessing modifications at different centers were synthesized and subjected to Ellman's assay to determine their inhibitory strength and type of inhibitory action. While parent compound maslinic acid was no inhibitor in these assays, some of the compounds exhibited an inhibition of acetylcholinesterase in the single-digit micro-molar range. Two compounds were identified as inhibitors of butyrylcholinesterase showing inhibition constants comparable to those of galantamine, a drug often used in the treatment of Alzheimer's disease. Furthermore, additional selectivity as well as cytotoxicity studies were performed underlining the potential of several derivatives and qualifying them for further investigations. Docking studies revealed that the different kinetic behavior within the same compound series may be explained by the ability of the compounds to enter the active site gorge of AChE. PMID:26383128

  1. Efficacy of the triple therapy: proton pomp inhibitors, amoxicillin and tynidazole in Helicobacter pylori infection treatment.

    PubMed

    Kos, Marek; Zinkiewicz, Krzysztof; Stefanek, Janusz; Dabrowski, Andrzej

    2002-01-01

    The aim of the paper is to present the triple therapy results combined with the application of proton pump inhibitors with amoxicillin and tynidazole in treatment of the contagion caused by Helicobacter pylori. The therapy was carried out among 108 people after realization of endoscopic biopsy and with quick urease test. In the endoscopic investigation 72 people were found to have duodenum ulceration. Inflammation of mucous duodenum was found in 36 patients. Among 108 people under investigation 51.85% were men and 48.15% women. These people were aged between 15-81 (the average age was 44). After the use of eradication 99 out of 108 patients (91.66%) were cured. The lack of improvement was found in 9 people (8.34%). The age of these people varied from 18 to 75, which gives the average age 54.5 (this age is about 10 years and a half higher in relation to the average age of the examined group of patients). The results prove high efficiency of this schema of treatment in relation to comparatively low costs. They also indicate greater efficiency of the treatment of contagious caused by Helicobacter pylori in younger people. PMID:12898919

  2. Chlamydia Serine Protease Inhibitor, targeting HtrA, as a New Treatment for Koala Chlamydia infection.

    PubMed

    Lawrence, Amba; Fraser, Tamieka; Gillett, Amber; Tyndall, Joel D A; Timms, Peter; Polkinghorne, Adam; Huston, Wilhelmina M

    2016-01-01

    The koala, an iconic marsupial native to Australia, is a threatened species in many parts of the country. One major factor in the decline is disease caused by infection with Chlamydia. Current therapeutic strategies to treat chlamydiosis in the koala are limited. This study examines the effectiveness of an inhibitor, JO146, which targets the HtrA serine protease for treatment of C. pecorum and C. pneumoniae in vitro and ex vivo with the aim of developing a novel therapeutic for koala Chlamydia infections. Clinical isolates from koalas were examined for their susceptibility to JO146. In vitro studies demonstrated that treatment with JO146 during the mid-replicative phase of C. pecorum or C. pneumoniae infections resulted in a significant loss of infectious progeny. Ex vivo primary koala tissue cultures were used to demonstrate the efficacy of JO146 and the non-toxic nature of this compound on peripheral blood mononuclear cells and primary cell lines established from koala tissues collected at necropsy. Our results suggest that inhibition of the serine protease HtrA could be a novel treatment strategy for chlamydiosis in koalas. PMID:27530689

  3. Chlamydia Serine Protease Inhibitor, targeting HtrA, as a New Treatment for Koala Chlamydia infection

    PubMed Central

    Lawrence, Amba; Fraser, Tamieka; Gillett, Amber; Tyndall, Joel D. A.; Timms, Peter; Polkinghorne, Adam; Huston, Wilhelmina M.

    2016-01-01

    The koala, an iconic marsupial native to Australia, is a threatened species in many parts of the country. One major factor in the decline is disease caused by infection with Chlamydia. Current therapeutic strategies to treat chlamydiosis in the koala are limited. This study examines the effectiveness of an inhibitor, JO146, which targets the HtrA serine protease for treatment of C. pecorum and C. pneumoniae in vitro and ex vivo with the aim of developing a novel therapeutic for koala Chlamydia infections. Clinical isolates from koalas were examined for their susceptibility to JO146. In vitro studies demonstrated that treatment with JO146 during the mid-replicative phase of C. pecorum or C. pneumoniae infections resulted in a significant loss of infectious progeny. Ex vivo primary koala tissue cultures were used to demonstrate the efficacy of JO146 and the non-toxic nature of this compound on peripheral blood mononuclear cells and primary cell lines established from koala tissues collected at necropsy. Our results suggest that inhibition of the serine protease HtrA could be a novel treatment strategy for chlamydiosis in koalas. PMID:27530689

  4. Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors

    PubMed Central

    Haefner, Martin; Bluethner, Thilo; Niederhagen, Manuel; Moebius, Christian; Wittekind, Christian; Mossner, Joachim; Caca, Karel; Wiedmann, Marcus

    2008-01-01

    AIM: To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer. METHODS: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral activity of the drugs was assessed by immunoblotting for p21WAF-1, acH4, cell cycle analysis, TUNEL assay, and immunohistochemistry for MIB-1. RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and increased apoptosis. In vivo, NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation. CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer, although the precise mechanism of in vivo drug action is not yet completely understood. Therefore, further preclinical and clinical studies for the treatment of pancreatic cancer are recommended. PMID:18595135

  5. Chlamydia Serine Protease Inhibitor, targeting HtrA, as a New Treatment for Koala Chlamydia infection.

    PubMed

    Lawrence, Amba; Fraser, Tamieka; Gillett, Amber; Tyndall, Joel D A; Timms, Peter; Polkinghorne, Adam; Huston, Wilhelmina M

    2016-01-01

    The koala, an iconic marsupial native to Australia, is a threatened species in many parts of the country. One major factor in the decline is disease caused by infection with Chlamydia. Current therapeutic strategies to treat chlamydiosis in the koala are limited. This study examines the effectiveness of an inhibitor, JO146, which targets the HtrA serine protease for treatment of C. pecorum and C. pneumoniae in vitro and ex vivo with the aim of developing a novel therapeutic for koala Chlamydia infections. Clinical isolates from koalas were examined for their susceptibility to JO146. In vitro studies demonstrated that treatment with JO146 during the mid-replicative phase of C. pecorum or C. pneumoniae infections resulted in a significant loss of infectious progeny. Ex vivo primary koala tissue cultures were used to demonstrate the efficacy of JO146 and the non-toxic nature of this compound on peripheral blood mononuclear cells and primary cell lines established from koala tissues collected at necropsy. Our results suggest that inhibition of the serine protease HtrA could be a novel treatment strategy for chlamydiosis in koalas.

  6. Ondansetron augmentation of serotonin reuptake inhibitors as a treatment strategy in obsessive-compulsive disorder.

    PubMed

    Andrade, Chittaranjan

    2015-01-01

    Serotonin reuptake inhibitors (SRIs) are the mainstay in the treatment of obsessive-compulsive disorder (OCD). Patients who do not respond adequately to SRIs commonly receive augmentation therapy with another agent, usually an atypical antipsychotic drug. Atypical antipsychotics, however, may not be appropriate for or acceptable to all patients. Ondansetron is an experimental alternative for such patients. There have been at least 6 trials that have examined a short-term (8-12 weeks) role for ondansetron in patients with OCD. These include 1 placebo-controlled crossover trial (N = 11); 1 uncontrolled monotherapy trial (N = 8); 2 low-dose (0.5-1.0 mg/d), uncontrolled augmentation trials in patients who did not respond adequately to ongoing or earlier treatments (pooled N = 35); and 2 moderate- to high-dose (4-8 mg/d) randomized, placebo-controlled augmentation trials in patients with undocumented past treatment history (pooled N = 88). Ondansetron was modestly effective in the uncontrolled trials and strikingly effective in the controlled trials. Ondansetron was also very well tolerated in all of the studies. These enthusiastic observations must be tempered by the limitations of the reviewed data, such as small sample sizes, short study durations, lack of data on the effects of blinded ondansetron discontinuation, lack of long-term data, and study-specific limitations. At best, ondansetron (1-8 mg/d) may be considered an experimental SRI augmentation agent in OCD patients for whom augmentation with an atypical antipsychotic drug is problematic.

  7. Treatment of Arabidopsis thaliana seeds with an HSP90 inhibitor increases plant resistance

    NASA Astrophysics Data System (ADS)

    Kozeko, Liudmyla

    2016-07-01

    Resistance of plants to unfavourable conditions is an important feature to use them as an autotrophic link of Life Support Systems in space exploration missions. It significantly depends on basic and stress-induced levels of heat shock proteins (HSP) in cells. It is known that HSP90 can bind and maintain heat shock transcription factors (HSF) as a monomer that lacks DNA binding activity and thereby regulate HSP expression. Modulation of activity of the HSP synthesis and resistance by HSP90 in plants is not well investigated. The objective of this study was to determine how treatment of seeds with an HSP90 inhibitor affects environmental responsiveness in Arabidopsis thaliana. Seed treatment with geldanamycin (GDA) was used to reduce HSP90 function. The affect of space flight stressors was simulated by gamma-irradiation and thermal upshift. Two series of experiments were carried out: 1) exposure of dry seeds to gamma-irradiation (1 kGy, ^{60}Co); 2) heat shock of seedlings. It was shown that GDA treatment of seeds stimulated the seedling growth after seed irradiation. It also increased both the basic thermotolerance (45°C for 45 min) and induced thermotolerance (45°C for 1,5-2,5 h after pretreatment at 37°C for 2 h) in seedlings. In addition, seed treatment with GDA had a prolonged effect on the HSP70 production in seedlings under normal and stressful conditions. It shows that the stimulatory effects of GDA may be caused by induction of HSP70 synthesis. The obtained data demonstrate that pre-treatment of seeds with GDA before planting allows inducing the stress resistance at least at early growth stages of plants.

  8. Histone deacetylase inhibitors stimulate the susceptibility of A549 cells to a plasma-activated medium treatment.

    PubMed

    Adachi, Tetsuo; Kano, Ayame; Nonomura, Saho; Kamiya, Tetsuro; Hara, Hirokazu

    2016-09-15

    The number of potential applications of non-thermal atmospheric pressure plasma (NTAPP) discharges in medicine, particularly in cancer therapy, has increased in recent years. NTAPP has been shown to affect cells not only by direct irradiation, but also by an indirect treatment with previously prepared plasma-activated medium (PAM). Histone deacetylase (HDAC) inhibitors have the potential to enhance susceptibility to anticancer drugs and radiation. The aim of the present study was to demonstrate the advantage of the combined application of PAM and HDAC inhibitors on A549 cancer cell survival and elucidate the underlying mechanisms. Cell death with DNA breaks in the nucleus was greater using combined regimens of PAM and HDAC inhibitors such as trichostatin A (TSA) and valproic acid (VPA) than a single PAM treatment and was accompanied by the activation of poly (ADP-ribose) polymerase-1 (PARP-1), depletion of ATP, and elevations in intracellular calcium levels. Moreover, the expression of Rad 51, a DNA repair factor in homologous recombination pathways, was significantly suppressed by the treatment with HDAC inhibitors. These results demonstrate that HDAC inhibitors may synergistically induce the sensitivity of cancer cells to PAM components. PMID:27470189

  9. Temperature and pressure adaptation of the binding site of acetylcholinesterase.

    PubMed

    Hochachka, P W

    1974-12-01

    1. Studies with a carbon substrate analogue, 3,3-dimethylbutyl acetate, indicate that the hydrophobic contribution to binding at the anionic site of acetylcholinesterase is strongly disrupted at low temperatures and high pressures. 2. Animals living in different physical environments circumvent this problem by adjusting the enthalpic and entropic contributions to binding. 3. An extreme example of this adaptational strategy is supplied by brain acetylcholinesterase extracted from an abyssal fish living at 2 degrees C and up to several hundred atmospheres of pressure. This acetylcholinesterase appears to have a smaller hydrophobic binding region in the anionic site, playing a measurably decreased role in ligand binding. PMID:4462739

  10. Temperature and pressure adaptation of the binding site of acetylcholinesterase

    PubMed Central

    Hochachka, Peter W.

    1974-01-01

    1. Studies with a carbon substrate analogue, 3,3-dimethylbutyl acetate, indicate that the hydrophobic contribution to binding at the anionic site of acetylcholinesterase is strongly disrupted at low temperatures and high pressures. 2. Animals living in different physical environments circumvent this problem by adjusting the enthalpic and entropic contributions to binding. 3. An extreme example of this adaptational strategy is supplied by brain acetylcholinesterase extracted from an abyssal fish living at 2°C and up to several hundred atmospheres of pressure. This acetylcholinesterase appears to have a smaller hydrophobic binding region in the anionic site, playing a measurably decreased role in ligand binding. PMID:4462739

  11. Combined Treatment with a BACE Inhibitor and Anti-Aβ Antibody Gantenerumab Enhances Amyloid Reduction in APPLondon Mice

    PubMed Central

    Ozmen, Laurence; Caruso, Antonello; Narquizian, Robert; Hilpert, Hans; Jacobsen, Bjoern; Terwel, Dick; Tanghe, An

    2014-01-01

    Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer‘s disease. Among the agents explored in clinical trials are anti-Aβ peptide antibodies and secretase inhibitors. Most anti-Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aβ. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aβ antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aβ and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time- and dose-dependent decrease in CSF Aβ, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance. PMID:25164658

  12. Bioimpedance in monitoring of effects of selective serotonin reuptake inhibitor treatment

    PubMed Central

    Alexeev, Vasiliy Grigorievich; Kuznecova, Ludmila Vasilievna

    2011-01-01

    Background Bioimpedance has been shown to be a safe technique when used in a number of biomedical applications. In this study, we used the Electro Interstitial Scan (EIS) to perform bioimpedance measurements to follow up the efficacy of selective serotonin reuptake inhibitor (SSRI) treatment in subjects diagnosed to have major depressive disorder. Methods We recruited 59 subjects (38 women, 21 men) aged 17–76 (mean 47) years diagnosed with major depressive disorder by psychiatric assessment at the Botkin Hospital according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Baseline Clinical Global Impression scores and EIS (electrical conductivity and dispersion α parameter) measurements were done before starting SSRI therapy. Treatment follow-up was undertaken using EIS bioimpedance measurements and by treatment response based on the Hamilton Depression Scale and Clinical Global Impression, every 15 days for 60 days. At day 45, we classified the patients into two groups, ie, Group 1, including treatment responders, and Group 2, including nonresponders. At day 60, patients were classified into two further groups, ie, Group 3, comprising treatment responders, and Group 4, comprising nonresponders. Results Comparing Group 1 and Group 2, electrical conductivity measurement of the pathway between the two forehead electrodes had a specificity of 72% and a sensitivity of 85.3% (P < 0.0001), with a cutoff >4.32. Comparing Group 3 and Group 4, electrical conductivity measurements in the same pathway had a specificity of 47.6% and a sensitivity of 76.3% (P < 0.16), with a cutoff >5.92. Comparing Group 1 and Group 2, the electrical dispersion α parameter of the pathway between the two disposable forehead electrodes had a specificity of 80% and a sensitivity of 85.2% (P < 0.0001) with a cutoff >0.678. Comparing Group 3 and Group 4, the electrical dispersion α parameter of the same pathway had a specificity of 100%, a sensitivity of 89

  13. The value of inhibitors of factor Xa for the treatment of pulmonary embolism.

    PubMed

    Prandoni, Paolo; Temraz, Sally; Barbar, Sofia; Pesavento, Raffaele; Taher, Alì

    2014-09-01

    The introduction of factor Xa inhibitors advocated the initiation of clinical trials that addressed the value of anticoagulation in patients with hemodynamically stable primary pulmonary embolism (PE). In the Matisse trial in patients with PE, fondaparinux administered at therapeutic doses followed by vitamin K antagonists (VKA) has shown a comparable efficacy and safety profile to that seen with intravenous adjusted-dose unfractionated heparin/VKA. A long-acting derivative of fondaparinux, idraparinux, failed to achieve similar results. On the other hand, the Cassiopea study revealed that once weekly injections of idrabiotaparinux, a slightly modified form of idraparinux, have similar efficacy and better safety profile compared to VKAs in the long-term treatment of patients with PE. However, the inconvenient parenteral administration of both fondaparinux and idrabiotaparinux limits their routine clinical use. The availability of antithrombotic compounds that can be administered orally in fixed dose, owing to their predictable pharmacokinetics and pharmacodynamics, and have a lower potential for drug and food interactions has opened new horizons for the treatment of patients with PE. The Einstein PE, Amplify and Hokusai studies, conducted with rivaroxaban, apixaban and edoxaban, respectively, showed that for the treatment of PE they possess a more favorable benefit-to-risk profile than the conventional antithrombotic drugs. In addition, rivaroxaban and apixaban make it possible to treat uncomplicated PE patients from the beginning, without the need for the parenteral administration of heparins or fondaparinux, and edoxaban allows the treatment of fragile patients with lower doses. All of them cover a wide spectrum of clinical presentations, including PE patients at intermediate risk. PMID:24871638

  14. Histone Deacetylase Inhibitor Treatment Attenuates Coagulation Imbalance in a Lethal Sepsis Model

    PubMed Central

    Zhao, Ting; Li, Yongqing; Liu, Baoling; Wu, Erxi; Sillesen, Martin; Velmahos, George C.; Halaweish, Ihab; Alam, Hasan B.

    2014-01-01

    Background Sepsis has a profound impact on the inflammatory and hemostatic systems. In addition to systemic inflammation, it can produce disseminated intravascular coagulation, microvascular thrombosis, consumptive coagulopathy, and multiple organ failure. We have shown that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice. However, its effect on coagulation remains unknown. The goal of this study was to quantify the impact of SAHA treatment on coagulopathy in sepsis. Methods C57BL/6J mice were subjected to CLP, and 1 hour later given intraperitoneally either SAHA dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Sham-operated animals were handled in similar manner without CLP. Blood samples were collected by cardiac puncture and evaluated using the TEG® 5000 Thrombelastograph® Hemostasis Analyzer System. Results Compared to the sham group, all animals in DMSO vehicle group died within 72 hrs, and developed coagulopathy that manifested as prolonged initial fibrin formation and fibrin cross-linkage time, and decreased clot formation speed, platelet function and clot rigidity. SAHA treatment significantly improved survival and was also associated with improvement in fibrin cross-linkage, clot formation, as well as platelet function and clot rigidity, without a significant impact on the clot initiation parameters. Conclusions SAHA treatment enhances survival and attenuates sepsis-associated coagulopathy by improving fibrin cross-linkage, rate of clot formation, platelet function and clot strength. HDACI may represent a novel therapeutic strategy for correcting sepsis-associated coagulopathy. PMID:24957668

  15. Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies.

    PubMed

    Seidah, Nabil G

    2013-01-01

    The discovery of PCSK9 in 2003 and its identification as the third protagonist responsible for ADH opened many new avenues of research in the cardiovascular field. Liver PCSK9 binds the LDLR and promotes its degradation in the endosomal/lysosomal pathway. A higher activity of PCSK9 leads to lower liver LDLR levels, resulting in a reduction in LDL-uptake from circulation, and thus in hypercholesterolemia and associated atherosclerosis. Although PCSK9 mutations are rare, their associated phenotypes can be devastating. The most powerful PCSK9 gain-of-function mutation, D374Y, is responsible for LDL cholesterol (LDLc) levels of ~10 mmol/L versus ~3 mmol/L in normal subjects.The aim of this manuscript is to review the available literature on the identification and pharmacological applications of potent inhibitors of PCSK9 function and/or activity, and to present the latest data on the ongoing clinical trials, mostly related to the use of monoclonal antibodies (mAb) that interfere with PCSK9 function on the LDLR, resulting in a significant drop in circulating LDLc.The clinical data, so far, are very encouraging with Phase-2 trials from various pharmaceutical companies showing a drop of >60% in LDLc for at least 2 weeks after a single injection of a humanized PCSK9 mAb in the presence or absence of adjunct statin therapy. In view of the absence of overt toxicity associated with this treatment Phase-3 clinical trials have started with >20,000 individuals being tested and anticipated primary outcomes results should be forthcoming by 2016. Other approaches including the use of recombinant adnectins, antisense RNAi or small molecule inhibitors are also undergoing early pre-clinical testing or are already in Phase-1 clinical trials.Very recent data revealed that absence of PCSK9 can be protective against melanoma invasion in mouse liver, and that this is due to lower circulating LDLc. This opens the door to novel applications of PCSK9 inhibitors/silencers in cancer

  16. Antitumor effects of immunotoxins are enhanced by lowering HCK or treatment with SRC kinase inhibitors.

    PubMed

    Liu, Xiu-Fen; Xiang, Laiman; FitzGerald, David J; Pastan, Ira

    2014-01-01

    Recombinant immunotoxins (RIT) are agents being developed for cancer treatment. They are composed of an Fv that binds to a cancer cell, fused to a 38-kDa fragment of Pseudomonas exotoxin A. SS1P is a RIT that targets mesothelin, a protein expressed on mesothelioma as well as pancreatic, ovarian, lung, and other cancers. Because the protein tyrosine kinase family regulates a variety of cellular processes and pathways, we hypothesized that tyrosine kinases might regulate susceptibility to immunotoxin killing. To investigate their role, we used siRNAs to lower the level of expression of the 88 known tyrosine kinases. We identified five tyrosine kinases, INSR, HCK, SRC, PDGFRβ, and BMX that enhance the activity of SS1P when their level of expression is lowered by siRNAs. We further investigated the Src family member HCK in this study. Knocking down of SRC slightly increased SS1P killing in A431/H9 cells, but knocking down HCK substantially enhanced killing by SS1P. We investigated the mechanism of enhancement and found that HCK knockdown enhanced SS1P cleavage by furin and lowered levels of Mcl-1 and raised Bax. We then found that Src inhibitors mimic the stimulatory effect of HCK knockdown; both SU6656 and SKI-606 (bosutinib) enhanced immunotoxin killing of mesothelin-expressing cells by SS1P and CD22-expressing cells by HA22 (moxetumomab pasudotox). SU6656 also enhanced the antitumor effects of SS1P and HA22 in mouse xenograft tumor models. Our data suggest that the combination of immunotoxin with tyrosine kinase inhibitors may be an effective way to treat some cancers. PMID:24145282

  17. Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice.

    PubMed

    Hetherington, Alexandra M; Sawyez, Cynthia G; Sutherland, Brian G; Robson, Debra L; Arya, Rigya; Kelly, Karen; Jacobs, René L; Borradaile, Nica M

    2016-09-01

    Eukaryotic elongation factor EEF1A1 is induced by oxidative and ER stress, and contributes to subsequent cell death in many cell types, including hepatocytes. We recently showed that blocking the protein synthesis activity of EEF1A1 with the peptide inhibitor, didemnin B, decreases saturated fatty acid overload-induced cell death in HepG2 cells. In light of this and other recent work suggesting that limiting protein synthesis may be beneficial in treating ER stress-related disease, we hypothesized that acute intervention with didemnin B would decrease hepatic ER stress and lipotoxicity in obese mice with nonalcoholic fatty liver disease (NAFLD). Hyperphagic male ob/ob mice were fed semipurified diet for 4 weeks, and during week 5 received i.p. injections of didemnin B or vehicle on days 1, 4, and 7. Interestingly, we observed that administration of this compound modestly decreased food intake without evidence of illness or distress, and thus included an additional control group matched for food consumption with didemnin B-treated animals. Treatment with didemnin B improved several characteristics of hepatic lipotoxicity to a greater extent than the effects of caloric restriction alone, including hepatic steatosis, and some hepatic markers of ER stress and inflammation (GRP78, Xbp1s, and Mcp1). Plasma lipid and lipoprotein profiles and histopathological measures of NAFLD, including lobular inflammation, and total NAFLD activity score were also improved by didemnin B. These data indicate that acute intervention with the EEF1A inhibitor, didemnin B, improves hepatic lipotoxicity in obese mice with NAFLD through mechanisms not entirely dependent on decreased food intake, suggesting a potential therapeutic strategy for this ER stress-related disease. PMID:27613825

  18. Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice.

    PubMed

    Hetherington, Alexandra M; Sawyez, Cynthia G; Sutherland, Brian G; Robson, Debra L; Arya, Rigya; Kelly, Karen; Jacobs, René L; Borradaile, Nica M

    2016-09-01

    Eukaryotic elongation factor EEF1A1 is induced by oxidative and ER stress, and contributes to subsequent cell death in many cell types, including hepatocytes. We recently showed that blocking the protein synthesis activity of EEF1A1 with the peptide inhibitor, didemnin B, decreases saturated fatty acid overload-induced cell death in HepG2 cells. In light of this and other recent work suggesting that limiting protein synthesis may be beneficial in treating ER stress-related disease, we hypothesized that acute intervention with didemnin B would decrease hepatic ER stress and lipotoxicity in obese mice with nonalcoholic fatty liver disease (NAFLD). Hyperphagic male ob/ob mice were fed semipurified diet for 4 weeks, and during week 5 received i.p. injections of didemnin B or vehicle on days 1, 4, and 7. Interestingly, we observed that administration of this compound modestly decreased food intake without evidence of illness or distress, and thus included an additional control group matched for food consumption with didemnin B-treated animals. Treatment with didemnin B improved several characteristics of hepatic lipotoxicity to a greater extent than the effects of caloric restriction alone, including hepatic steatosis, and some hepatic markers of ER stress and inflammation (GRP78, Xbp1s, and Mcp1). Plasma lipid and lipoprotein profiles and histopathological measures of NAFLD, including lobular inflammation, and total NAFLD activity score were also improved by didemnin B. These data indicate that acute intervention with the EEF1A inhibitor, didemnin B, improves hepatic lipotoxicity in obese mice with NAFLD through mechanisms not entirely dependent on decreased food intake, suggesting a potential therapeutic strategy for this ER stress-related disease.

  19. Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment

    PubMed Central

    Patel, Hardik J; Modi, Shanu; Chiosis, Gabriela; Taldone, Tony

    2011-01-01

    Introduction Over the last 15 – 20 years, targeted anticancer strategies have focused on therapies aimed at abrogating a single malignant protein. Agents that are directed towards the inhibition of a single oncoprotein have resulted in a number of useful drugs in the treatment of cancers (i.e., Gleevec, BCR-ABL; Tarceva and Iressa, EGFR). However, such a strategy relies on the notion that a cancer cell is dependent on a single signaling pathway for its survival. The possibility that a cancer cell may mutate or switch its dependence to another signaling pathway can result in the ineffectiveness of such agents. Recent advances in the biology of heat-shock protein 90 (Hsp90) have revealed intimate details into the complexity of the chaperoning process that Hsp90 is engaged in and, at the same time, have offered those involved in drug discovery several unique ways to interfere in this process. Areas covered This review provides the current understanding of the chaperone cycle of Hsp90 and presents the multifaceted approaches used by researchers in the discovery of potential Hsp90 drugs. It discusses the phenotypic outcomes in cancer cells on Hsp90 inhibition by these several approaches and also addresses several distinctions observed among direct Hsp90 ATP-pocket competitors providing commentary on the potential biological outcomes as well as the clinical relevance of such features. Expert opinion The significantly different phenotypic outcomes observed from Hsp90 inhibition by the many inhibitors developed suggest that the clinical development of Hsp90 inhibitors would be better served by careful consideration of the pharmacokinetic/pharmacodynamic properties of individual candidates rather than a generic approach directed towards the target. PMID:22400044

  20. Treatment of Cognitive Impairment in Schizophrenia: Potential Value of Phosphodiesterase Inhibitors in Prefrontal Dysfunction.

    PubMed

    Duinen, Marlies Van; Reneerkens, Olga A H; Lambrecht, Lena; Sambeth, Anke; Rutten, Bart P F; Os, Jim Van; Blokland, Arjan; Prickaerts, Jos

    2015-01-01

    No pharmacological treatment is available to date that shows satisfactory effects on cognitive symptoms in patients diagnosed with schizophrenia. Phosphodiesterase inhibitors (PDE-Is) improve neurotransmitter signaling by interfering in intracellular second messenger cascades. By preventing the breakdown of cAMP and/or cGMP, central neurotransmitter activity is maintained. Different PDE families exist with distinct characteristics among which substrate specificity and regional distribution. Preclinical data is promising especially with regard to inhibition of PDE2, PDE4, PDE5 and PDE10. In addition, cognitive improvement has been reported in both elderly and/or non-impaired young human subjects after PDE1 or PDE4 inhibition. Moreover, some of these studies show effects on cognitive domains relevant to schizophrenia, in particular memory. The current review incorporates an overview of the distinct molecular characteristics of the different PDE families and their relationship to the neurobiological mechanisms related to cognitive dysfunction in schizophrenia. So far, procognitive effects of only three types of PDE-Is have been assessed in patients diagnosed with schizophrenia inhibiting PDE3, PDE5 and PDE10. However, the limited data available do not allow to draw firm conclusions on the value of PDE-Is as cognitive enhancers in schizophrenia yet. The field is still in its infancy, but nevertheless different PDE-Is seem promising as candidate to optimise neural communication in the prefrontal cortex favouring cognitive functioning in patients diagnosed with schizophrenia, in particular dual inhibitors including PDE1-Is, PDE3-Is and PDE10A-Is.

  1. Apatinib: A novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer.

    PubMed

    Roviello, Giandomenico; Ravelli, Andrea; Polom, Karol; Petrioli, Roberto; Marano, Luigi; Marrelli, Daniele; Roviello, Franco; Generali, Daniele

    2016-03-28

    Metastatic gastric cancer is a lethal disease characterized by a very short overall survival, underlining a critical need of new therapeutic options. Unfortunately, although several molecular targets have been investigated, only very few recently approved agents, such as trastuzumab in the HER2-positive setting and ramucirumab, led to a clinical improvement in the outcome of metastatic gastric cancer patients. VEGF (vascular endothelial growth factor) is one of the most potent angiogenic factors and is a signalling molecule secreted by many solid tumours. Since high VEGF expression is one of the characteristic features of gastric carcinomas, targeting VEGF is therefore considered as a promising therapeutic strategy for gastric cancer. In the scenario of possible new target therapies with particular regard to angiogenesis, apatinib is a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2. It is an orally-bioavailable agent currently being studied in several solid tumour types showing a promising activity in gastric cancer. Due to the recent positive results as a third line of treatment for metastatic gastric cancer patients, apatinib may be an interesting and novel type of targeted treatment for metastatic gastric cancer in several lines of therapy. In this review, we summarize the available data of apatinib, mainly focused on the clinical aspect, in advanced/metastatic gastric cancer. PMID:26797419

  2. Biosensor-based control of nitrification inhibitor in municipal wastewater treatment plants.

    PubMed

    Okayasu, Y; Tanaka, H; Inui, T; Tanaka, Y

    2006-01-01

    The effect of potassium cyanide (KCN) on nitrification processes in municipal wastewater treatment plants was studied by batch nitrification tests, which indicated that nitrification processes tend to be inhibited at a lower KCN concentration than the present discharge standard to sewerage. The experiment of the biosensor using nitrifying bacteria was also conducted for continuous monitoring of nitrification inhibitor in influent wastewater, and demonstrated that the biosensor can detect KCN at as low as EC10 of the abovementioned batch nitrification test. Moreover, to determine the effectiveness of application of the biosensor to avoid the impact of KCN due to an accidental spillage in a sewerage system, KCN was intentionally injected into the experimental models of activated sludge process equipped both with and without the biosensor. The model with the biosensor that could detect KCN could divert the wastewater including KCN to a refuge tank, which resulted in the avoidance of upset of the activated sludge process. On the other hand, the model without the biosensor was upset in the nitrification process due to KCN. Such differences demonstrate the effectiveness of the biosensor applied to countermeasures of an accidental spillage of toxic chemicals to avoid upset of nitrification in municipal wastewater treatment plants.

  3. Vismodegib: A smoothened inhibitor for the treatment of advanced basal cell carcinoma.

    PubMed

    Aditya, Suruchi; Rattan, Aditya

    2013-10-01

    Incidence of basal cell carcinoma (BCC), the most common skin cancer in humans, is rising. Surgery is the mainstay of treatment but there is no standard of care for locally advanced or metastatic disease. Hedgehog signaling proteins are critical for cell growth and differentiation during embryogenesis; Hh pathway is silenced in adults. Dysregulated or aberrant Hh signaling has been implicated in the pathogenesis of BCC. This hyperactive pathway can be inhibited by use of smoothened inhibitors such as vismodegib. Food and drug administration approved this oral, once-daily medication in 2012 to treat adults with metastatic BCC or locally advanced, recurrent BCC after surgery and also for patients with locally advanced BCC who are not candidates for surgery or radiation treatment. Clinical studies have shown it to be highly efficacious and the most common adverse effects include, muscle spasms, alopecia and dysgeusia. Use of targeted biologic modifiers, exemplified by Hh directed therapeutics offer a new hope to patients with high-surgical morbidity or inoperable tumors.

  4. Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder.

    PubMed

    Saraceni, Megan M; Venci, Jineane V; Gandhi, Mona A

    2014-08-01

    In July 2013, the US Food and Drug Administration approved levomilnacipran extended release (ER; Fetzima), a serotonin-norepinephrine reuptake inhibitor, for the treatment of adults with major depressive disorder. Levomilnacipran is an active enantiomer of the racemic drug milnacipran that is currently approved in the United States for the treatment of fibromyalgia. This article provides an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of levomilnacipran ER. Relevant information was identified through a search of databases using the key word levomilnacipran. Additional information was obtained from fda.gov, by a review of the reference lists of identified articles, and from posters and abstracts from scientific meetings. Levomilnacipran ER, dosed once daily, is generally well tolerated and has demonstrated favorable effects compared to placebo in clinical trials of patients with major depressive disorder. The increased potency for norepinephrine reuptake inhibition is a characteristic that may represent a novel contribution for levomilnacipran. Additional studies comparing levomilnacipran ER to other commonly prescribed antidepressants are needed to further evaluate its place in therapy. PMID:24381243

  5. Masculinization of female golden rabbitfish Siganus guttatus using an aromatase inhibitor treatment during sex differentiation.

    PubMed

    Komatsu, Toru; Nakamura, Shigeo; Nakamura, Masaru

    2006-08-01

    To elucidate the involvement of endogenous estrogen (estradiol-17beta; E2) and the decisive factor (somatic or germinal element) in the ovarian differentiation of tropical marine teleosts, the effect of the aromatase inhibitor (AI) fadrozole on gonadal sex differentiation in the golden rabbitfish Siganus guttatus (Bloch) was examined for different dosages and periods of treatment. Fadrozole interrupted ovarian cavity formation at a dose of 500 microg g(-1) diet, while there was little effect at 10 or 100 microg g(-1). The gonads from both the 30-day and 90-day administration (500 microg g(-1) diet) groups were significantly biased toward testes (P=0.002 and <0.0001, respectively), which suggests strongly that E2 is involved in early ovarian differentiation and that its suppression is an indispensable condition for testicular differentiation in S. guttatus. The results from the two different AI treatment periods imply that the initial feminization of somatic gonadal elements determines subsequent ovarian differentiation, including oogenesis: a conclusion supported by the considerable time lag between ovarian cavity formation and subsequent oogenesis during normal ovarian differentiation in S. guttatus.

  6. Are tyrosine kinase inhibitors promising for the treatment of systemic sclerosis and other fibrotic diseases?

    PubMed

    Beyer, Christian; Distler, Jörg H W; Distler, Oliver

    2010-01-01

    Tissue fibrosis causes organ failure and death in patients with systemic sclerosis (SSc), but clearly effective anti-fibrotic therapies are not available. The tyrosine kinase inhibitor (TKI) imatinib, which blocks the pro-fibrotic c-Abl kinase and PDGF receptor, is currently evaluated in clinical proof-of-concept trials for the treatment of patients with SSc. In experimental models, imatinib efficiently prevented and reduced tissue fibrosis. First clinical case studies demonstrated anti-fibrotic effects of imatinib in selected patients with SSc and other fibrotic diseases, and observational studies in sclerotic chronic graft-versus-host disease showed promising results. Besides imatinib, the two novel TKIs of c-Abl and PDGF receptor nilotinib and dasatinib have recently proven efficacy in experimental models of SSc. The potential of TKIs of the VEGF receptor (e.g., semaxinib, vatalanib, sutent, and sorafenib) and the EGF receptor (e.g., erlotinib, gefitinib, lapatinib, and canertinib) as anti-fibrotic treatments are also discussed in this review. Prior to clinical use, however, controlled trials need to address efficacy as well as tolerability of TKIs in patients with different fibrotic diseases. PMID:20419513

  7. Role of inhibitors of mammalian target of rapamycin in the treatment of luminal breast cancer.

    PubMed

    Ciruelos, Eva; Cortes-Funes, Hernán; Ghanem, Ismael; Manso, Luis; Arteaga, Carlos

    2013-09-01

    Approximately 75% of patients with breast cancer present hormone receptor-positive tumors. This subtype of breast cancer initially shows a high overall response rate to hormonal treatments. However, resistance eventually develops, resulting in tumor progression. The PI3K/Akt/mTOR pathway regulates several cellular functions in cancer such as cell growth, survival, and proliferation. In addition, a high activation level of the PI3K/Akt/mTOR pathway is related to resistance to conventional chemotherapy and hormone therapy. The mTOR inhibitor everolimus, in combination with hormonal treatments, has led to excellent results in progression-free survival in patients with metastatic breast cancer resistant to hormone therapies. Therefore, everolimus has entered the National Comprehensive Cancer Network (NCCN) guidelines 2012 and its combination with exemestane was approved recently by the US Food and Drug Administration and the European Medicines Agency. This is the first time that a drug will have been approved for the restoration of hormone sensitivity in breast cancer.

  8. Acquired resistance to combination treatment through loss of synergy with MEK and PI3K inhibitors in colorectal cancer

    PubMed Central

    Bhattacharya, Bhaskar; Low, Sarah Hong Hui; Chong, Mei Ling; Chia, Dilys; Koh, King Xin; Sapari, Nur Sabrina; Kaye, Stanley; Hung, Huynh; Benoukraf, Touati; Soong, Richie

    2016-01-01

    Historically, understanding of acquired resistance (AQR) to combination treatment has been based on knowledge of resistance to its component agents. To test whether an altered drug interaction could be an additional factor in AQR to combination treatment, models of AQR to combination and single agent MEK and PI3K inhibitor treatment were generated. Combination indices indicated combination treatment of PI3K and MEK inhibitors remained synergistic in cells with AQR to single agent but not combination AQR cells. Differences were also observed between the models in cellular phenotypes, pathway signaling and drug cross-resistance. Genomics implicated TGFB2-EDN1 overexpression as candidate determinants in models of AQR to combination treatment. Supplementation of endothelin in parental cells converted synergism to antagonism. Silencing of TGFB2 or EDN1 in cells with AQR conferred synergy between PI3K and MEK inhibitor. These results highlight that AQR to combination treatment may develop through alternative mechanisms to those of single agent treatment, including a change in drug interaction. PMID:27081080

  9. Combining Stimulants and Monoamine Oxidase Inhibitors: A Reexamination of the Literature and a Report of a New Treatment Combination

    PubMed Central

    Israel, Joshua A.

    2015-01-01

    This report reviews the medical literature on combining stimulants with monoamine oxidase inhibitors. A case is also presented documenting successful treatment of major depressive disorder and comorbid attention-deficit/hyperactivity disorder using the previously undocumented combination of transdermal selegiline and lisdexamfetamine. This combination should be used cautiously and with ongoing monitoring of heart rate and blood pressure. PMID:27057401

  10. Synthesis and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory potential of hydrazide based Schiff bases.

    PubMed

    Rahim, Fazal; Ullah, Hayat; Taha, Muhammad; Wadood, Abdul; Javed, Muhammad Tariq; Rehman, Wajid; Nawaz, Mohsan; Ashraf, Muhammad; Ali, Muhammad; Sajid, Muhammad; Ali, Farman; Khan, Muhammad Naseem; Khan, Khalid Mohammed

    2016-10-01

    To discover multifunctional agents for the treatment of Alzheimer's disease, a series of hydrazide based Schiff bases were designed and synthesized based on multitarget-directed strategy. We have synthesized twenty-eight analogs of hydrazide based Schiff bases, characterized by various spectroscopic techniques and evaluated in vitro for acetylcholinesterase and butyrylcholinesterase inhibition. All compounds showed varied degree of acetylcholinesterase and butyrylcholinesterase inhibition when compared with standard Eserine. Among the series, compounds 10, 3 and 24 having IC50 values 4.12±0.01, 8.12±0.01 and 8.41±0.06μM respectively showed potent acetylcholinesterase inhibition when compared with Eserine (IC50=0.85±0.0001μM). Three compounds 13, 24 and 3 having IC50 values 6.51±0.01, 9.22±0.07 and 37.82±0.14μM respectively showed potent butyrylcholinesterase inhibition by comparing with eserine (IC50=0.04±0.0001μM). The remaining compounds also exhibited moderate to weak inhibitory potential. Structure activity relationship has been established. Through molecular docking studies the binding interaction was confirmed.

  11. Inhibitory effects of sodium arsenite and acacia honey on acetylcholinesterase in rats.

    PubMed

    Muhammad, Aliyu; Odunola, Oyeronke A; Gbadegesin, Michael A; Sallau, Abdullahi B; Ndidi, Uche S; Ibrahim, Mohammed A

    2015-01-01

    This study was conducted to investigate the effect of sodium arsenite and Acacia honey on acetylcholinesterase (AChE) activity and electrolytes in the brain and serum of Wistar rats. Male Wistar albino rats in four groups of five rats each were treated with distilled water, sodium arsenite (5 mg/kg body weight), Acacia honey (20% v/v), and sodium arsenite and Acacia honey, daily for one week. The sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the brain with the combined treatment being more potent. Furthermore, sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the serum. Strong correlation was observed between the sodium and calcium ion levels with acetylcholinesterase activity in the brain and serum. The gas chromatography mass spectrometry analysis of Acacia honey revealed the presence of a number of bioactive compounds such as phenolics, sugar derivatives, and fatty acids. These findings suggest that sodium arsenite and/or Acacia honey modulates acetylcholinesterase activities which may be explored in the management of Alzheimer's diseases but this might be counteracted by the hepatotoxicity induced by arsenics. PMID:25821630

  12. Inhibitory Effects of Sodium Arsenite and Acacia Honey on Acetylcholinesterase in Rats

    PubMed Central

    Odunola, Oyeronke A.; Gbadegesin, Michael A.; Sallau, Abdullahi B.; Ndidi, Uche S.; Ibrahim, Mohammed A.

    2015-01-01

    This study was conducted to investigate the effect of sodium arsenite and Acacia honey on acetylcholinesterase (AChE) activity and electrolytes in the brain and serum of Wistar rats. Male Wistar albino rats in four groups of five rats each were treated with distilled water, sodium arsenite (5 mg/kg body weight), Acacia honey (20% v/v), and sodium arsenite and Acacia honey, daily for one week. The sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the brain with the combined treatment being more potent. Furthermore, sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the serum. Strong correlation was observed between the sodium and calcium ion levels with acetylcholinesterase activity in the brain and serum. The gas chromatography mass spectrometry analysis of Acacia honey revealed the presence of a number of bioactive compounds such as phenolics, sugar derivatives, and fatty acids. These findings suggest that sodium arsenite and/or Acacia honey modulates acetylcholinesterase activities which may be explored in the management of Alzheimer's diseases but this might be counteracted by the hepatotoxicity induced by arsenics. PMID:25821630

  13. Treatment progression in sulfonylurea and dipeptidyl peptidase-4 inhibitor cohorts of type 2 diabetes patients on metformin

    PubMed Central

    Peng, Xiaomei; Jiang, Dingfeng; Liu, Dongju; Varnado, Oralee J; Bae, Jay P

    2016-01-01

    Background Metformin is an oral antidiabetic drug (OAD) widely used as first-line therapy in type 2 diabetes (T2D) treatments. Numerous treatment pathways after metformin failure exist. It is important to understand how treatment choices influence subsequent therapy progressions. This retrospective study compares adherence to, persistence with, and treatment progression in sulfonylurea (SU) and dipeptidyl peptidase-4 (DPP-4) inhibitor patient cohorts with T2D on metformin. Methods Using health insurance claims data, matched patient cohorts were created and OAD use was compared in patients with T2D initiating SU or DPP-4 inhibitors (index drugs) since January 1, 2010, to December 31, 2010, with background metformin therapy. Propensity score matching adjusted for possible selection bias. Persistence was measured via Cox regression as days to a ≥60-day gap in index drug possession; adherence was defined as proportion of days covered (PDC) ≥80%. Evolving treatment patterns were traced at 6-month intervals for 24 months following index drug discontinuation. Results From among 19,621 and 7,484 patients in the SU and DPP-4 inhibitor cohorts, respectively, 6,758 patient pairs were matched. Persistence at 12 months in the SU cohort was 48.0% compared to 52.5% for the DPP-4 inhibitor cohort. PDC adherence (mean [SD]) during the 12-month follow-up period was 63.3 (29.7) for the SU cohort and 65.5 (28.7) for the DPP-4 inhibitor cohort. PDC ≥80% was 40.5% and 43.4% in the SU and DPP-4 inhibitor cohorts, respectively. A higher percentage of patients in the SU cohort remained untreated. Following index drug discontinuation, monotherapy was more common in the SU cohort, while use of two or three OADs was more common in the DPP-4 inhibitor cohort. Insulin therapy initiation was higher in the SU cohort. Conclusion Slightly better adherence and persistence were seen in the DPP-4 inhibitor cohort. Adherence and persistence remain a challenge to many patients; understanding

  14. BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects

    PubMed Central

    Abedin, Sameem M; Boddy, Craig S; Munshi, Hidayatullah G

    2016-01-01

    The bromodomain and extra-terminal (BET) family of proteins are important epigenetic regulators involved in promoting gene expression of critical oncogenes. BET inhibitors have been demonstrated to repress c-Myc expression, and were initially shown to have efficacy in a number of c-Myc-dependent hematologic malignancies. Recent studies have now revealed a broader role for BET inhibitors in hematologic malignancies. In this review, we summarize the efficacy of BET inhibitors in preclinical models of acute leukemia, lymphoma, and multiple myeloma. We also summarize recent results of clinical trials utilizing BET inhibitors in hematologic malignancies, characterize potential resistance mechanisms to BET inhibitors, and discuss potential combination therapies with BET inhibitors in patients with hematologic malignancies. PMID:27729803

  15. SGLT2 inhibitors – an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin

    PubMed Central

    Seufert, Jochen

    2015-01-01

    Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM) are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These “concomitant effects” are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM. The efficacy and tolerability of canagliflozin have been tested in an extensive clinical trial program

  16. Home treatment of attacks with conestat alfa in hereditary angioedema due to C1-inhibitor deficiency.

    PubMed

    Farkas, Henriette; Csuka, Dorottya; Veszeli, Nóra; Zotter, Zsuzsanna; Szabó, Erika; Varga, Lilian

    2014-01-01

    Conestat alfa, a recombinant human C1 inhibitor (rhC1-INH) is a novel therapeutic option for the acute treatment of hereditary angioedema due to C1-INH (HAE-C1-INH) deficiency. Our aim was to investigate the efficacy and safety profile of conestat alfa in patients with HAE-C1-INH, under real-life conditions. We analyzed 65 edematous episodes requiring acute treatment and occurring in two female HAE-C1-INH patients. The patients were treated at home with rhC1-INH per occasion. They recorded the time of rhC1-INH administration, the time to the onset of improvement, and time to the complete resolution of symptoms, as well as the side effects. Symptom severity and patient satisfaction were measured with a visual analog scale (VAS). Thirty-three HAE attacks occurred in submucosal tissue, 17 in subcutaneous tissue, and 15 had mixed locations. After the administration of rhC1-INH, clinical symptoms improved within 0.50 (0.17-4.50 hours) hours and resolved completely within 9.00 (1.67-58.75 hours) hours. The time between the onset of the attack and the administration of rhC1-INH was correlated with the time when the symptoms stopped worsening (R = 0.3212; p = 0.0096) and the time to complete resolution of the symptoms (R = 0.4774; p < 0.0001). The time to response to the drug differed with attack location. The efficacy and safety of rhC1-INH persisted after repeated use. None of the patients experienced a recurrence of the HAE attack or drug-related systemic adverse events. The mean VAS score of patient satisfaction was 93.14. Home treatment with rhC1-INH was an effective and well-tolerated therapy for all types of HAE attacks.

  17. The effect of calcineurin inhibitors in the treatment of IgA nephropathy

    PubMed Central

    Peng, Wei; Tang, Yi; Jiang, Zheng; Li, Zi; Mi, Xuhua; Qin, Wei

    2016-01-01

    Abstract Background: Immunoglobin A nephropathy (IgAN), the most prevalent form of primary glomerulonephritis, represents the leading cause of kidney failure among East Asian populations. Immunosuppressive treatment regimen, except for a 6-month trial of corticosteroids, has not been approved by the KDIGO guideline yet. Specific and effective treatment is still lacking. We decided to evaluate the efficacy and safety of the calcineurin inhibitors (CNIs) in the treatment of IgAN. Methods: Database from the Cochrane library, PubMed, Embase, CBM, CNKI, and CENTRAL databases were searched and reviewed up to March 2016. Literature was screened by 2 independent reviewers accordingly. Clinical trials were analyzed using Stata 12.0. Results: Five random control trials and 2 nonrandomized concurrent control trials were selected and included in this study according to our inclusion and exclusion criteria. The rates of complete remission in patients with IgAN were significantly increased in the group of CNIs (RR 1.56, P = 0.002). No statistical difference was observed in the rates of partial remission, or response between the CNIs and steroids alone. Additionally, CNIs resulted in a significant reduction in urinary protein (WMD 0.34, P = 0.002) and increase in serum albumin level (WMD 1.89, P = 0.013). No differences were found in the serum creatinine, estimated glomerular filtration rate, and rates of adverse effects including infection, hyperglycemia, and liver dysfunction. Conclusion: With present evidence, CNIs may be promising immunosuppressive agents for IgAN in future. However, large, long-term, multicenter trials are required to confirm our findings. PMID:27583915

  18. Preclinical evaluation of an inhibitor of cytosolic phospholipase A2α for the treatment of asthma.

    PubMed

    Hewson, Christopher A; Patel, Sheena; Calzetta, Luigino; Campwala, Hinnah; Havard, Suzanne; Luscombe, Emma; Clarke, Philip A; Peachell, Peter T; Matera, Maria G; Cazzola, Mario; Page, Clive; Abraham, William M; Williams, Cara M; Clark, James D; Liu, Wai L; Clarke, Nicholas P; Yeadon, Michael

    2012-03-01

    Asthma is a chronic inflammatory lung disease with considerable unmet medical needs for new and effective therapies. Cytosolic phospholipase A(2)α (cPLA(2)α) is the rate-limiting enzyme that is ultimately responsible for the production of eicosanoids implicated in the pathogenesis of asthma. We investigated a novel cPLA(2)α inhibitor, PF-5212372, to establish the potential of this drug as a treatment for asthma. PF-5212372 was a potent inhibitor of cPLA(2)α (7 nM) and was able to inhibit prostaglandin (PG)D(2) and cysteinyl leukotriene release from anti-IgE-stimulated human lung mast cells (0.29 and 0.45 nM, respectively). In a mixed human lung cell population, PF-5212372 was able to inhibit ionomycin-stimulated release of leukotriene B(4), thromboxane A(2), and PGD(2) (2.6, 2.6, and 4.0 nM, respectively) but was significantly less effective against PGE(2) release (>301 nM; p < 0.05). In an in vitro cell retention assay, PF-5212372 retained its potency up to 24 h after being washed off. In a sheep model of allergic inflammation, inhalation of PF-5212372 significantly inhibited late-phase bronchoconstriction (78% inhibition; p < 0.001) and airway hyper-responsiveness (94% inhibition; p < 0.001), and isolated sheep lung mast cell assays confirmed species translation via effective inhibition of PGD(2) release (0.78 nM). Finally, PF-5212372 was assessed for its ability to inhibit the contraction of human bronchi induced by AMP. PF5212372 significantly inhibited AMP-induced contraction of human bronchi (81% inhibition; p < 0.001); this finding, together with the ability of this drug to be effective in a wide range of preclinical asthma models, suggests that inhibition of cPLA(2)α with PF-5212372 may represent a new therapeutic option for the treatment of asthma.

  19. Increased resistance to proteasome inhibitors in multiple myeloma mediated by cIAP2 - implications for a combinatorial treatment

    PubMed Central

    Agarwal, Prasoon; Arngården, Linda; Hammarberg, Anna; Maes, Ken; Van Valckenborgh, Els; Vanderkerken, Karin; Wiklund, Helena Jernberg

    2015-01-01

    Despite the introduction of new treatment options for multiple myeloma (MM), a majority of patients relapse due to the development of resistance. Unraveling new mechanisms underlying resistance could lead to identification of possible targets for combinatorial treatment. Using TRAF3 deleted/mutated MM cell lines, we evaluated the role of the cellular inhibitor of apoptosis 2 (cIAP2) in drug resistance and uncovered the plausible mechanisms underlying this resistance and possible strategies to overcome this by combinatorial treatment. In MM, cIAP2 is part of the gene signature of aberrant NF-κB signaling and is heterogeneously expressed amongst MM patients. In cIAP2 overexpressing cells a decreased sensitivity to the proteasome inhibitors bortezomib, MG132 and carfilzomib was observed. Gene expression analysis revealed that 440 genes were differentially expressed due to cIAP2 overexpression. Importantly, the data imply that cIAPs are rational targets for combinatorial treatment in the population of MM with deleted/mutated TRAF3. Indeed, we found that treatment with the IAP inhibitor AT-406 enhanced the anti-MM effect of bortezomib in the investigated cell lines. Taken together, our results show that cIAP2 is an important factor mediating bortezomib resistance in MM cells harboring TRAF3 deletion/mutation and therefore should be considered as a target for combinatorial treatment. PMID:26036313

  20. Inhibitors in childhood hemophilia A: genetic and treatment-related risk factors for development and eradication.

    PubMed

    DiMichele, Donna M

    2013-01-01

    The development of neutralizing antibodies remains a serious complication of hemophilia replacement therapy. Factor VIII inhibiting antibodies (inhibitors) occur commonly following replacement therapy in hemophilia A, creating a significant burden of clinical disease. This article will review our current understanding of risk factors and their known impact on inhibitor development in previously untreated or minimally treated children with severe and mild hemophilia A. It will also explore how the most recently elucidated immunology of inhibitor development might hold important clues to more effective inhibitor eradication and prevention in this heavily impacted patient population. PMID:23109404

  1. Design, synthesis and biological evaluation of novel 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives as potential cholinesterase inhibitors.

    PubMed

    Gulcan, Hayrettin Ozan; Unlu, Serdar; Esiringu, Ilker; Ercetin, Tugba; Sahin, Yasemin; Oz, Demet; Sahin, Mustafa Fethi

    2014-10-01

    Hydroxylated 6H-benzo[c]chromen-6-one derivatives (i.e., urolithins) are the main bioavailable metabolites, and biomarkers of ellagitannins present in various nutrition. Although these dietaries, the sources of urolithins, are employed in folk medicine as cognitive enhancer in the treatment of Alzheimer's Disease, urolithins have negligible potential to inhibit acetylcholinesterase and butyrylcholinesterase enzymes, the validated targets of Alzheimer's Disease. Therefore, within this research, a series of 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives has been designed, synthesized, and their biological activities were evaluated as potential acetylcholinesterase and butyrylcholinesterase inhibitors. The compounds synthesized exerted comparable activity in comparison to rivastigmine, galantamine, and donepezil both in in vitro and in vivo studies.

  2. Design, synthesis and biological evaluation of novel 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives as potential cholinesterase inhibitors.

    PubMed

    Gulcan, Hayrettin Ozan; Unlu, Serdar; Esiringu, Ilker; Ercetin, Tugba; Sahin, Yasemin; Oz, Demet; Sahin, Mustafa Fethi

    2014-10-01

    Hydroxylated 6H-benzo[c]chromen-6-one derivatives (i.e., urolithins) are the main bioavailable metabolites, and biomarkers of ellagitannins present in various nutrition. Although these dietaries, the sources of urolithins, are employed in folk medicine as cognitive enhancer in the treatment of Alzheimer's Disease, urolithins have negligible potential to inhibit acetylcholinesterase and butyrylcholinesterase enzymes, the validated targets of Alzheimer's Disease. Therefore, within this research, a series of 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives has been designed, synthesized, and their biological activities were evaluated as potential acetylcholinesterase and butyrylcholinesterase inhibitors. The compounds synthesized exerted comparable activity in comparison to rivastigmine, galantamine, and donepezil both in in vitro and in vivo studies. PMID:25189690

  3. Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease.

    PubMed

    Wu, Wen-Lian; Domalski, Martin; Burnett, Duane A; Josien, Hubert; Bara, Thomas; Rajagopalan, Murali; Xu, Ruo; Clader, John; Greenlee, William J; Brunskill, Andrew; Hyde, Lynn A; Del Vecchio, Robert A; Cohen-Williams, Mary E; Song, Lixin; Lee, Julie; Terracina, Giuseppe; Zhang, Qi; Nomeir, Amin; Parker, Eric M; Zhang, Lili

    2012-11-01

    An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease. PMID:24900404

  4. Comparison of efavirenz and protease inhibitor based combination antiretroviral therapy regimens in treatment-naïve people living with HIV with baseline resistance.

    PubMed

    Lim, Charlotte; McFaul, Katie; Kabagambe, Samuel; Sonecha, Sonali; Jones, Rachael; Asboe, David; Pozniak, Anton; Nwokolo, Nneka; Boffito, Marta

    2016-07-17

    A retrospective cohort analysis comparing the efficacy of boosted protease inhibitor-based and efavirenz-based combination antiretroviral therapy in treatment-naïve people living with HIV with baseline resistance found that efavirenz-based treatment led to a shorter mean time to undetectable viral load. A higher proportion of patients with nonnucleoside reverse transcriptase inhibitor related baseline resistance mutations in the efavirenz-treatment group achieved an undetectable viral load at both 6 and 12 months post-treatment initiation, compared with the boosted protease-inhibitor-treatment group.Supplementary content: http://links.lww.com/QAD/A930. PMID:27139315

  5. Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine.

    PubMed

    Darreh-Shori, T; Kadir, A; Almkvist, O; Grut, M; Wall, A; Blomquist, G; Eriksson, B; Långström, B; Nordberg, A

    2008-02-01

    The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by (11)C-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.

  6. The economics of inpatient on-demand treatment for haemophilia with high-responding inhibitors: a US retrospective data analysis.

    PubMed

    Pokras, S M; Petrilla, A A; Weatherall, J; Lee, W C

    2012-03-01

    Inpatient costs comprise >50% of annual healthcare costs for haemophilia patients with inhibitors but no reports exist on inpatient resource use and costs at a US national level. To quantify inpatient resource use and costs for on-demand treatment of bleeds of US haemophilia patients with inhibitors and compare costs and treatment duration between Factor VIII bypassing agents (BAs). Stays with haemophilia A from 2003-2008 were identified from inpatient billing records. Presence of inhibitors was inferred through use of BA; recombinant activated Factor VII and plasma-derived activated prothrombin complex concentrate. Duration and number of infusions of BA, length of stay, use of opioid-containing analgesics and costs were assessed and compared. Among 1322 stays mean BA treatment duration was 4.6 days with 4.9 infusions, 6.1 nights spent in hospital, and 58% administered opioid-containing analgesics. In unadjusted analyses there were significant differences in the above mentioned outcomes by BA use, reflecting underlying differences between the two patient populations. Average inpatient costs were $82,911. In adjusted analyses, African-American race, greater disease severity, hospital region outside the southern US and older age (cost model only) were significant predictors of longer BA treatment duration and higher costs. The economic burden of inpatient on-demand treatment of haemophilia with inhibitors is substantial and is associated with lengthy stays, high costs and inadequate pain relief. Availability of more effective BAs could reduce the need for re-treatment, reducing treatment costs and other medical costs, while improving health related quality of life.

  7. Effect of local acetylcholinesterase inhibition on sweat rate in humans

    NASA Technical Reports Server (NTRS)

    Shibasaki, M.; Crandall, C. G.

    2001-01-01

    ACh is the neurotransmitter responsible for increasing sweat rate (SR) in humans. Because ACh is rapidly hydrolyzed by acetylcholinesterase (AChE), it is possible that AChE contributes to the modulation of SR. Thus the primary purpose of this project was to identify whether AChE around human sweat glands is capable of modulating SR during local application of various concentrations of ACh in vivo, as well as during a heat stress. In seven subjects, two microdialysis probes were placed in the intradermal space of the forearm. One probe was perfused with the AChE inhibitor neostigmine (10 microM); the adjacent membrane was perfused with the vehicle (Ringer solution). SR over both membranes was monitored via capacitance hygrometry during microdialysis administration of various concentrations of ACh (1 x 10(-7)-2 M) and during whole body heating. SR was significantly greater at the neostigmine-treated site than at the control site during administration of lower concentrations of ACh (1 x 10(-7)-1 x 10(-3) M, P < 0.05), but not during administration of higher concentrations of ACh (1 x 10(-2)-2 M, P > 0.05). Moreover, the core temperature threshold for the onset of sweating at the neostigmine-treated site was significantly reduced relative to that at the control site. However, no differences in SR were observed between sites after 35 min of whole body heating. These results suggest that AChE is capable of modulating SR when ACh concentrations are low to moderate (i.e., when sudomotor activity is low) but is less effective in governing SR after SR has increased substantially.

  8. Identification of 4-aminoquinoline core for the design of new cholinesterase inhibitors

    PubMed Central

    Chen, Yao; Bian, Yaoyao; Sun, Yuan; Kang, Chen; Yu, Sheng; Fu, Tingming; Li, Wei

    2016-01-01

    Inhibition of acetylcholinesterase (AChE) using small molecules is still one of the most successful therapeutic strategies in the treatment of Alzheimer’s disease (AD). Previously we reported compound T5369186 with a core of quinolone as a new cholinesterase inhibitor. In the present study, in order to identify new cores for the designing of AChE inhibitors, we screened different derivatives of this core with the aim to identify the best core as the starting point for further optimization. Based on the results, we confirmed that only 4-aminoquinoline (compound 04 and 07) had cholinesterase inhibitory effects. Considering the simple structure and high inhibitory potency against AChE, 4-aminoquinoline provides a good starting core for further designing novel multifunctional AChEIs. PMID:27441112