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  • Estudo do mecanismo de ação das moléculas agonistas e antagonistas para o tratamento do mal de Alzheimer e da depressão
    2015
    Co-Authors: Nascimento, Érica Cristina Moreno
    Abstract:

    A Doença de Alzheimer (DA) é um tipo de demência degenerativa e progressiva de grande preocupação social. Estima-se hoje que, 45 milhões de pessoas no mundo apresentem algum tipo de demência, dentre essas, 25 milhões apresentam sintomas característicos da doença de Alzheimer. O estilo de vida imposto pela situação social e econômica e alterações no estado emocional causadas por traumas e doenças vêm contribuindo para o aumento dos casos de pessoas onde são observadas modificações no seu estado comportamental (estados depressivos: ED). Dados da Organização Mundial de Saúde indicam que mais de 20% da população mundial sofra fisiologicamente com alterações no seu estado emocional originando estados depressivos de alguma natureza. Por não terem suas causas determinadas e nem serem conhecidos os mecanismos que desencadeiem estas alterações nos estados neurológicos dos pacientes, estratégias de tratamento são empregadas para tentar sanar o problema, ou trazer melhora no estado de vida dos pacientes. As estratégias mais utilizadas para tratar pacientes com DA e ED estão relacionadas ao uso de drogas que atuem nas sinapses de maneira a inibir a função de enzimas responsáveis pela ativação e desativação dos neurotransmissores envolvidos diretamente nos processos que ocasionam as demências e o ED. A estratégia mais usada para tratar pacientes com DA é a terapia colinérgica, que consiste no uso de fármacos com ação inibitória frente à acetilcolinesterase (AChE) para impedir o decréscimo da concentração da acetilcolina nas fendas sinápticas. As drogas tacrina, donepezil, galantamina e a rivastigmina são drogas aprovadas para o tratamento da DA, classificadas como inibidoras da acetilcolinesterase (AChEI). Outras drogas como o metrifonato, diclorvos, huperzina A, fenserina e o dímero da tacrina estão em fases de teste clínico. O tratamento clássico da depressão é feito com o uso de medicamentos que promovam o aumento da serotonina nas regiões sinápticas, seja inibindo a ação das enzimas monoamina oxidase A e monoamina oxidase B que degradam o neurotransmissor, seja pela inibição seletiva de recaptura deste neurotransmissor pelos receptores específicos a essa função. As drogas moclobemida, isocarboxazida, iproniazida, tranilcipromina, fenelzina foram amplamente utilizadas no tratamento de ED, porém seus efeitos colaterais severos as classificam como drogas restritas ao uso, caso outras drogas não sejam eficientes. As drogas inibidoras das isoformas da monoamina oxidase de segunda geração, Clorgilina, Nialamida selegilina e rasigilina foram desenvolvidas para amenizar o tratamento do ED. Na tentativa de produzir drogas multi-alvos foi proposta a droga hibrida ladostigil, como potente inibidor da acetilcolinesterase e da monoamina oxidade B. Neste trabalho, foram realizados diversos estudos teóricos quânticos no intuito de elucidar o perfil farmacofórico de conhecidas drogas empregadas no tratamento da DA e do ED. Para isso foram realizados cálculos no vácuo e em meio solvatado no nível semi-empírico e ab initio para determinação de parâmetros estruturais, eletrônicos e espaciais dos inibidores das enzimas. Outra série de estudos, simulando o ambiente intracelular in sílico, foram também realizados para compreender o mecanismo de inibição da AChE, quando a enzima interage com alguns de seus inibidores. O método de multivariáveis de análise das componentes principais (PCA) foi aplicado a 20 parâmetros, das drogas citadas, para determinação do perfil farmacofórico dos inibidores das proteínas aqui estudadas. Os parâmetros foram obtidos através dos cálculos no vácuo e no modelo de solvatação CPCM em nível B3LYP/6- 31+G(d,p). O estudo da PCA foi realizado para reduzir o espaço amostral de propriedades, a fim de obter as propriedades que são relevantes e comuns entre essas drogas, que têm estrutura molecular diferenciada e, no entanto, apresentam os mesmos alvos. Com o intuito de determinar qualitativa e quantitativamente as interações entre a acetilcolinesterase e alguns de seus inibidores foram realizadas uma série de simulações utilizando o método híbrido QM/MM MD e vários cálculos teóricos usando o método FEP nos níveis AM1/MM empregando a biblioteca fDynamo. Propriedades eletrônicas, como a energia do orbital HOMO-1, dipolo e propriedades estruturais como, o tamanho da droga e a distância entre os dois hidrogênios mais ácidos da molécula são algumas das componentes principais participantes do perfil farmacofórico que correlacionam as drogas estudadas. As energias livres de interação dos sistemas proteína-ligante foram calculadas e observou-se uma grande contribuição da componente de van der Waals para as interações entre a acetilcolinesterase e seus inibidores. ___________________________________________________________________________ ABSTRACTAlzheimer's disease (AD) is a degenerative and progressive type of dementia of great social concern. The latest worldwide estimate shows that 45 million people have some form of dementia, among these 25 million have symptoms of Alzheimer's disease. The lifestyle imposed by social and economic conditions and changes in emotional state caused by trauma and disease have contributed to the increase in cases of people where changes in behavioral state (depressive states: DS) are observed. The World Health Organization estimates that more than 20% of the world population suffers physiologically with changes in its emotional state resulting in depressive states. The AD and DS specific causes and the mechanisms that trigger these changes in the neurological status of patients are not known, thus treatment strategies are employed to try to minimize the effect, or bring improvement in the state of patient life. The most common strategies used to treat patients with AD and DS are related to use drugs that act at the synapses so as to inhibit the function of enzymes responsible for the activation and deactivation of the neurotransmitters directly involved in the processes that cause dementia and the depression. The most used strategy to treat patients with AD is the cholinergic therapy, which consists in use drugs with inhibitory effects against acetylcholinesterase (AChE), in order to prevent the decrease of the concentration of acetylcholine (the neuroreceptor) in the synaptic region. Tacrine, donepezil, galanthamine and rivastigmine are drugs approved for treatment of AD and are classified as inhibitors of acetylcholinesterase. Other drugs such as Metrifonate, dichlorvos, huperzine, phenserine and the tacrine dimmer are in stages of clinical testing. The classical treatment of depression is done with the use of drugs that promote the increase of serotonin in the synaptic cleft, either inhibiting the action of the enzymes monoamine oxidase A and monoamine oxidase B, that degrades the neurotransmitter, or by selective inhibition of the reuptake of this neurotransmitter by specific receptors to such function. The drug moclobemide, isocarboxazid, iproniazid, tranylcypromine, phenelzine, have been widely used in the treatment of DS. Nevertheless, its severe side effect classifies as restricted to use, only if other drugs are not effective. The second generation drugs that inhibit monoamine oxidase isoforms Clorgyline, Nialamide selegiline and rasagiline were developed to help the treatment of depression. In an attempt to produce a multitarget drug, ladostigil a hybrid drug was proposed as a potent inhibitor of acetylcholinesterase and monoamine oxidase B. In this work several quantum theoretical approach were undertaken in order to elucidate the pharmacophore profile of known drugs used in the treatment of AD and DS. For this purpose calculations in vacuum and solvated medium at the semi-empirical and ab initio level were performed for determination of structural, electronic and spatial parameters of enzyme inhibitors. Another series of studies simulating the intracellular environment in silico was used in order to understand the mechanism of acetylcholinesterase inhibition, when enzyme interacts with some of its inhibitors. The multivariate method of the principal components analysis (PCA) was applied to selected 20 parameters of drugs cited before to determining the pharmacoforic profile of those protein inhibitors. The multivariate method of the principal components analysis was applied to selected 20 parameters of drugs cited before in order to determine the pharmacophoric profile of these protein inhibitors. The parameters were obtained from the calculations in vacuum and CPCM solvation model at the DFT B3LYP/6-31+G(d,p) level. PCA study was applied to reduce the sample space of properties to obtain the most relevant properties common to these drugs, which have the same target but have different molecular structure. A huge number of simulations were performed using the hybrid method QM/MM MD in order to qualitatively and quantitatively determine the interactions between acetylcholinesterase and some of its inhibitors. Additionally several theoretical calculations applying FEP method using the fDynamo library in AM1/MM level to compute the free binding energy of the systems acetylcholinesterase-inhibitor were performed. Electronic properties such as the orbital energy of HOMO-1 and the dipole momentum; structural properties such as the size of the drug and the distance between the two most acidic hydrogens of the molecule are some main components of the pharmacophoric profile correlating the drugs studied here. Free energies of interaction of the protein-ligand systems were calculated and revealed a major contribution of the van der Waals component to the interactions between acetylcholinesterase and its inhibitors

  • Estudo do mecanismo de ação das moléculas agonistas e antagonistas para o tratamento do mal de Alzheimer e da depressão
    'Biblioteca Central da UNB', 2014
    Co-Authors: Nascimento, Érica Cristina Moreno
    Abstract:

    Tese (doutorado)—Universidade de Brasília, Instituto de Química, Programa de Pós-Graduação em Química, 2014.A Doença de Alzheimer (DA) é um tipo de demência degenerativa e progressiva de grande preocupação social. Estima-se hoje que, 45 milhões de pessoas no mundo apresentem algum tipo de demência, dentre essas, 25 milhões apresentam sintomas característicos da doença de Alzheimer. O estilo de vida imposto pela situação social e econômica e alterações no estado emocional causadas por traumas e doenças vêm contribuindo para o aumento dos casos de pessoas onde são observadas modificações no seu estado comportamental (estados depressivos: ED). Dados da Organização Mundial de Saúde indicam que mais de 20% da população mundial sofra fisiologicamente com alterações no seu estado emocional originando estados depressivos de alguma natureza. Por não terem suas causas determinadas e nem serem conhecidos os mecanismos que desencadeiem estas alterações nos estados neurológicos dos pacientes, estratégias de tratamento são empregadas para tentar sanar o problema, ou trazer melhora no estado de vida dos pacientes. As estratégias mais utilizadas para tratar pacientes com DA e ED estão relacionadas ao uso de drogas que atuem nas sinapses de maneira a inibir a função de enzimas responsáveis pela ativação e desativação dos neurotransmissores envolvidos diretamente nos processos que ocasionam as demências e o ED. A estratégia mais usada para tratar pacientes com DA é a terapia colinérgica, que consiste no uso de fármacos com ação inibitória frente à acetilcolinesterase (AChE) para impedir o decréscimo da concentração da acetilcolina nas fendas sinápticas. As drogas tacrina, donepezil, galantamina e a rivastigmina são drogas aprovadas para o tratamento da DA, classificadas como inibidoras da acetilcolinesterase (AChEI). Outras drogas como o metrifonato, diclorvos, huperzina A, fenserina e o dímero da tacrina estão em fases de teste clínico. O tratamento clássico da depressão é feito com o uso de medicamentos que promovam o aumento da serotonina nas regiões sinápticas, seja inibindo a ação das enzimas monoamina oxidase A e monoamina oxidase B que degradam o neurotransmissor, seja pela inibição seletiva de recaptura deste neurotransmissor pelos receptores específicos a essa função. As drogas moclobemida, isocarboxazida, iproniazida, tranilcipromina, fenelzina foram amplamente utilizadas no tratamento de ED, porém seus efeitos colaterais severos as classificam como drogas restritas ao uso, caso outras drogas não sejam eficientes. As drogas inibidoras das isoformas da monoamina oxidase de segunda geração, Clorgilina, Nialamida selegilina e rasigilina foram desenvolvidas para amenizar o tratamento do ED. Na tentativa de produzir drogas multi-alvos foi proposta a droga hibrida ladostigil, como potente inibidor da acetilcolinesterase e da monoamina oxidade B. Neste trabalho, foram realizados diversos estudos teóricos quânticos no intuito de elucidar o perfil farmacofórico de conhecidas drogas empregadas no tratamento da DA e do ED. Para isso foram realizados cálculos no vácuo e em meio solvatado no nível semi-empírico e ab initio para determinação de parâmetros estruturais, eletrônicos e espaciais dos inibidores das enzimas. Outra série de estudos, simulando o ambiente intracelular in sílico, foram também realizados para compreender o mecanismo de inibição da AChE, quando a enzima interage com alguns de seus inibidores. O método de multivariáveis de análise das componentes principais (PCA) foi aplicado a 20 parâmetros, das drogas citadas, para determinação do perfil farmacofórico dos inibidores das proteínas aqui estudadas. Os parâmetros foram obtidos através dos cálculos no vácuo e no modelo de solvatação CPCM em nível B3LYP/6- 31+G(d,p). O estudo da PCA foi realizado para reduzir o espaço amostral de propriedades, a fim de obter as propriedades que são relevantes e comuns entre essas drogas, que têm estrutura molecular diferenciada e, no entanto, apresentam os mesmos alvos. Com o intuito de determinar qualitativa e quantitativamente as interações entre a acetilcolinesterase e alguns de seus inibidores foram realizadas uma série de simulações utilizando o método híbrido QM/MM MD e vários cálculos teóricos usando o método FEP nos níveis AM1/MM empregando a biblioteca fDynamo. Propriedades eletrônicas, como a energia do orbital HOMO-1, dipolo e propriedades estruturais como, o tamanho da droga e a distância entre os dois hidrogênios mais ácidos da molécula são algumas das componentes principais participantes do perfil farmacofórico que correlacionam as drogas estudadas. As energias livres de interação dos sistemas proteína-ligante foram calculadas e observou-se uma grande contribuição da componente de van der Waals para as interações entre a acetilcolinesterase e seus inibidores.Alzheimer's disease (AD) is a degenerative and progressive type of dementia of great social concern. The latest worldwide estimate shows that 45 million people have some form of dementia, among these 25 million have symptoms of Alzheimer's disease. The lifestyle imposed by social and economic conditions and changes in emotional state caused by trauma and disease have contributed to the increase in cases of people where changes in behavioral state (depressive states: DS) are observed. The World Health Organization estimates that more than 20% of the world population suffers physiologically with changes in its emotional state resulting in depressive states. The AD and DS specific causes and the mechanisms that trigger these changes in the neurological status of patients are not known, thus treatment strategies are employed to try to minimize the effect, or bring improvement in the state of patient life. The most common strategies used to treat patients with AD and DS are related to use drugs that act at the synapses so as to inhibit the function of enzymes responsible for the activation and deactivation of the neurotransmitters directly involved in the processes that cause dementia and the depression. The most used strategy to treat patients with AD is the cholinergic therapy, which consists in use drugs with inhibitory effects against acetylcholinesterase (AChE), in order to prevent the decrease of the concentration of acetylcholine (the neuroreceptor) in the synaptic region. Tacrine, donepezil, galanthamine and rivastigmine are drugs approved for treatment of AD and are classified as inhibitors of acetylcholinesterase. Other drugs such as Metrifonate, dichlorvos, huperzine, phenserine and the tacrine dimmer are in stages of clinical testing. The classical treatment of depression is done with the use of drugs that promote the increase of serotonin in the synaptic cleft, either inhibiting the action of the enzymes monoamine oxidase A and monoamine oxidase B, that degrades the neurotransmitter, or by selective inhibition of the reuptake of this neurotransmitter by specific receptors to such function. The drug moclobemide, isocarboxazid, iproniazid, tranylcypromine, phenelzine, have been widely used in the treatment of DS. Nevertheless, its severe side effect classifies as restricted to use, only if other drugs are not effective. The second generation drugs that inhibit monoamine oxidase isoforms Clorgyline, Nialamide selegiline and rasagiline were developed to help the treatment of depression. In an attempt to produce a multitarget drug, ladostigil a hybrid drug was proposed as a potent inhibitor of acetylcholinesterase and monoamine oxidase B. In this work several quantum theoretical approach were undertaken in order to elucidate the pharmacophore profile of known drugs used in the treatment of AD and DS. For this purpose calculations in vacuum and solvated medium at the semi-empirical and ab initio level were performed for determination of structural, electronic and spatial parameters of enzyme inhibitors. Another series of studies simulating the intracellular environment in silico was used in order to understand the mechanism of acetylcholinesterase inhibition, when enzyme interacts with some of its inhibitors. The multivariate method of the principal components analysis (PCA) was applied to selected 20 parameters of drugs cited before to determining the pharmacoforic profile of those protein inhibitors. The multivariate method of the principal components analysis was applied to selected 20 parameters of drugs cited before in order to determine the pharmacophoric profile of these protein inhibitors. The parameters were obtained from the calculations in vacuum and CPCM solvation model at the DFT B3LYP/6-31+G(d,p) level. PCA study was applied to reduce the sample space of properties to obtain the most relevant properties common to these drugs, which have the same target but have different molecular structure. A huge number of simulations were performed using the hybrid method QM/MM MD in order to qualitatively and quantitatively determine the interactions between acetylcholinesterase and some of its inhibitors. Additionally several theoretical calculations applying FEP method using the fDynamo library in AM1/MM level to compute the free binding energy of the systems acetylcholinesterase-inhibitor were performed. Electronic properties such as the orbital energy of HOMO-1 and the dipole momentum; structural properties such as the size of the drug and the distance between the two most acidic hydrogens of the molecule are some main components of the pharmacophoric profile correlating the drugs studied here. Free energies of interaction of the protein-ligand systems were calculated and revealed a major contribution of the van der Waals component to the interactions between acetylcholinesterase and its inhibitors

  • Determinação teórica de propriedades relevantes para a atividade de inibidor da acetilcolinesterase
    2010
    Co-Authors: Nascimento, Érica Cristina Moreno
    Abstract:

    A Doença de Alzheimer (DA) é um tipo de demência degenerativa e progressiva de grande preocupação social. Estima-se hoje que, 40 milhões de pessoas no mundo apresentem algum tipo de demência, dentre essas, 25 milhões apresentam sintomas característicos da doença de Alzheimer. As causas da DA não são determinadas, assim, os sintomas da doença podem ser apenas amenizados. A estratégia mais usada para tratar pacientes com DA é a terapia colinérgica, que consiste no uso de fármacos com ação inibitória à acetilcolinesterase (AChE) para impedir o decréscimo da concentração do neurorreceptor acetilcolina nas fendas sinápticas, que é drasticamente diminuída nas regiões neuronais do córtex cerebral de pessoas com DA. As drogas tacrina (THA), donepezil (E2020), galantamina (GALA), rivastigmina (RIVA) e a fisostigmina (PHYSO) são drogas aprovadas para o tratamento da DA, classificadas como inibidoras da acetilcolinesterase (AChEI). Outras drogas como o metrifonato (METRI), diclorvos (DDVP), huperzina A (HUPE), fenserina (PHEN) e o dímero da tacrina (DIMTHA) estão em fases de teste clínicos. Neste trabalho foram determinados parâmetros estruturais, eletrônicos e espaciais das AChEIs, bem como para análise das interações entre estas, a tríade catalítica (Ser200-Glu327-His440) e o sítio ativo (GORGE) da AChE por meio de cálculos ab initio e semi-empírico no vácuo e em meio solvatado. O método de multivariáveis de análise das componentes principais (PCA) foi aplicado a 18 parâmetros para determinação do perfil farmacofórico de um bom candidato a AChEI. Os parâmetros foram obtidos por meio dos cálculos nos níveis AM1, PM3, RHF/6-31G*, RHF6-31+G(d,p), B3LYP8/6-31G, B3LYP/6-31+G(d,p) e o modelo de solvatação CPCM no nível RHF/6-31G. O estudo da PCA foi realizado para redução do espaço amostral de propriedades, a fim de obter aqueles que são componentes principais entre essas AChEIs com estruturas moleculares diferenciadas. Propriedades eletrônicas como a energia do orbital HOMO-1 e o coeficiente de partição logP, propriedades estruturais como o tamanho da droga e a distância entre os dois hidrogênios mais ácidos da molécula são algumas das componentes principais utilizadas para a descrição do perfil farmacofórico de candidatos à AChEI. _________________________________________________________________________________________ ABSTRACTAlzheimer's disease (AD) is a degenerative and progressive type of dementia of great social concern. The latest worldwide estimate shows that 40 million people have some form of dementia, among these, 25 million have symptoms of Alzheimer's disease. The causes of AD are still not determined, thus the symptoms of this disease may only be relieved. Most patients are treated with the cholinergic therapy, which consists in use drugs with inhibitory effects against acetylcholinesterase (AChE), in order to prevent the decrease of the concentration of acetylcholine (the neurorreceptor) in the synaptic region, which is drastically reduced in regions of neuronal cerebral cortex of people with AD. The drugs tacrine (THA), donepezil (E2020), galanthamine (GALA), rivastigmine (RIVA) and physostigmine (PHYSO) were approved for treatment of AD and are classified as inhibitors of acetylcholinesterase (AChEI). Other drugs such as Metrifonate (METRI), dichlorvos (DDVP), huperzine A (HUPE), phenserine (PHENE) and the tacrine dimer (DIMTHA) are in clinical testing. In this work calculations were performed in vacuum and in solvated medium at ab initio and semi-empirical levels for determination structural, electronic and spatial parameters for AChEIs, as well as analysis of interactions between the AChEIs, the catalytic triad (Ser200-GLu327-His440) and the active site GORGE of AChE. The multivariate method of the principal components analysis (PCA) was applied to selected18 parameters of AChE for determining the pharmacoforic profile of a good candidate for AChEI. The parameters were obtained from the calculations in AM1, PM3, RHF/6-31G *, RHF6-31 + G (d, p), B3LYP8/6-31G, B3LYP/6-31 + G (d, p) and CPCM solvation model at the RHF/6-31G levels. The PCA study was applied to reduce the sample space of properties to obtain the most relevant properties that are major components of these AChEI, which have different molecular structure. Electronic properties such as the orbital energy of HOMO-1 and the partition coefficient logP, structural properties such as the size of the drug and the distance between the two most acidic hydrogens of the molecule are some main components of the pharmacoforic profile of candidates to AChEI

  • Determinação teórica de propriedades relevantes para a atividade de inibidor da acetilcolinesterase
    2009
    Co-Authors: Nascimento, Érica Cristina Moreno
    Abstract:

    Dissertação (mestrado)—Universidade de Brasília, Instituto de Química, 2009.A Doença de Alzheimer (DA) é um tipo de demência degenerativa e progressiva de grande preocupação social. Estima-se hoje que, 40 milhões de pessoas no mundo apresentem algum tipo de demência, dentre essas, 25 milhões apresentam sintomas característicos da doença de Alzheimer. As causas da DA não são determinadas, assim, os sintomas da doença podem ser apenas amenizados. A estratégia mais usada para tratar pacientes com DA é a terapia colinérgica, que consiste no uso de fármacos com ação inibitória à acetilcolinesterase (AChE) para impedir o decréscimo da concentração do neurorreceptor acetilcolina nas fendas sinápticas, que é drasticamente diminuída nas regiões neuronais do córtex cerebral de pessoas com DA. As drogas tacrina (THA), donepezil (E2020), galantamina (GALA), rivastigmina (RIVA) e a fisostigmina (PHYSO) são drogas aprovadas para o tratamento da DA, classificadas como inibidoras da acetilcolinesterase (AChEI). Outras drogas como o metrifonato (METRI), diclorvos (DDVP), huperzina A (HUPE), fenserina (PHEN) e o dímero da tacrina (DIMTHA) estão em fases de teste clínicos. Neste trabalho foram determinados parâmetros estruturais, eletrônicos e espaciais das AChEIs, bem como para análise das interações entre estas, a tríade catalítica (Ser200-Glu327-His440) e o sítio ativo (GORGE) da AChE por meio de cálculos ab initio e semi-empírico no vácuo e em meio solvatado. O método de multivariáveis de análise das componentes principais (PCA) foi aplicado a 18 parâmetros para determinação do perfil farmacofórico de um bom candidato a AChEI. Os parâmetros foram obtidos por meio dos cálculos nos níveis AM1, PM3, RHF/6-31G*, RHF6-31+G(d,p), B3LYP8/6-31G, B3LYP/6-31+G(d,p) e o modelo de solvatação CPCM no nível RHF/6-31G. O estudo da PCA foi realizado para redução do espaço amostral de propriedades, a fim de obter aqueles que são componentes principais entre essas AChEIs com estruturas moleculares diferenciadas. Propriedades eletrônicas como a energia do orbital HOMO-1 e o coeficiente de partição logP, propriedades estruturais como o tamanho da droga e a distância entre os dois hidrogênios mais ácidos da molécula são algumas das componentes principais utilizadas para a descrição do perfil farmacofórico de candidatos à AChEI. _________________________________________________________________________________________ ABSTRACTAlzheimer's disease (AD) is a degenerative and progressive type of dementia of great social concern. The latest worldwide estimate shows that 40 million people have some form of dementia, among these, 25 million have symptoms of Alzheimer's disease. The causes of AD are still not determined, thus the symptoms of this disease may only be relieved. Most patients are treated with the cholinergic therapy, which consists in use drugs with inhibitory effects against acetylcholinesterase (AChE), in order to prevent the decrease of the concentration of acetylcholine (the neurorreceptor) in the synaptic region, which is drastically reduced in regions of neuronal cerebral cortex of people with AD. The drugs tacrine (THA), donepezil (E2020), galanthamine (GALA), rivastigmine (RIVA) and physostigmine (PHYSO) were approved for treatment of AD and are classified as inhibitors of acetylcholinesterase (AChEI). Other drugs such as Metrifonate (METRI), dichlorvos (DDVP), huperzine A (HUPE), phenserine (PHENE) and the tacrine dimer (DIMTHA) are in clinical testing. In this work calculations were performed in vacuum and in solvated medium at ab initio and semi-empirical levels for determination structural, electronic and spatial parameters for AChEIs, as well as analysis of interactions between the AChEIs, the catalytic triad (Ser200-GLu327-His440) and the active site GORGE of AChE. The multivariate method of the principal components analysis (PCA) was applied to selected18 parameters of AChE for determining the pharmacoforic profile of a good candidate for AChEI. The parameters were obtained from the calculations in AM1, PM3, RHF/6-31G *, RHF6-31 + G (d, p), B3LYP8/6-31G, B3LYP/6-31 + G (d, p) and CPCM solvation model at the RHF/6-31G levels. The PCA study was applied to reduce the sample space of properties to obtain the most relevant properties that are major components of these AChEI, which have different molecular structure. Electronic properties such as the orbital energy of HOMO-1 and the partition coefficient logP, structural properties such as the size of the drug and the distance between the two most acidic hydrogens of the molecule are some main components of the pharmacoforic profile of candidates to AChEI

Piero Olliaro - One of the best experts on this subject based on the ideXlab platform.

  • Additional file 4: Figure S1. of Efficacy and safety of praziquantel 40 mg/kg in preschool-aged and school-aged children: a meta-analysis
    2017
    Co-Authors: Julien Zwang, Piero Olliaro
    Abstract:

    Forest plot for PZQ 40 mg/kg and comparator treatments for S. haematobium, cure rate (CR) and risk ratio (RR). Abbreviations: pzq40, praziquantel 40 mg/kg; pzq20, praziquantel 20 mg/kg; pzq30, praziquantel 30 mg/kg; pzq60, praziquantel 60 mg/kg; RR, risk ratio; comp, comparator group; AS, artesunate; MQ, mefloquine; ASMQ, artesunate + mefloquine; ASSP, artesunate + sulfadoxine-pyrimethamine; met10, Metrifonate 10 mg/kg. (TIF 7292 kb

  • drugs for treating urinary schistosomiasis
    Cochrane Database of Systematic Reviews, 2014
    Co-Authors: Christine V Kramer, Fan Zhang, David A Sinclair, Piero Olliaro
    Abstract:

    Background Urinary schistosomiasis causes long-term ill-health. This review examines the various treatment options and newer drugs. Objectives To evaluate antischistosomal drugs, used alone or in combination, for treating urinary schistosomiasis. Search strategy In August 2007, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2007, Issue 3), MEDLINE, EMBASE, LILACS, mRCT, and reference lists of articles. We also contacted experts in schistosomiasis research. Selection criteria Randomized and quasi-randomized controlled trials of praziquantel, Metrifonate, artemisinin derivatives, or albendazole, alone or in combination, versus placebo, different doses, or other antischistosomal drugs for treating urinary schistosomiasis. Data collection and analysis One author extracted data, and assessed eligibility and methodological quality, which were cross-checked by a second person. Dichotomous outcomes were combined using risk ratio (RR), and continuous data were combined using weighted mean difference (WMD); both presented with 95% confidence intervals (CI). Main results Twenty-four trials (6315 participants) met the inclusion criteria. Compared with placebo, participants receiving Metrifonate had fewer parasitological failures at follow up at one to three months (1 trial) and three to 12 months (3 trials). Egg reduction rate was over 90%, and no adverse events were reported (1 trial). One Metrifonate dose was inferior to three doses given fortnightly (both used 10 mg/kg). Praziquantel (standard single 40 mg/kg oral dose) was more effective than placebo at reducing parasitological failure at one to three months' follow up and three to 12 months. Egg reduction rates were improved with praziquantel (over 95% versus 5.3% to 64% with placebo). Mild to moderate adverse events were recorded in two trials. A comparison of Metrifonate (10 mg/kg x 3, once every 4 months for one year) with praziquantel (standard dose) showed little difference in parasitological failure. For praziquantel, there was no significant difference in effect between 20 mg/kg x 2, 30 mg/kg x 1, and 20 mg/kg x 1, and the standard dose for all outcomes. One small trial of artesunate showed no obvious benefit compared with placebo, and the artesunate-praziquantel combination was similar to praziquantel alone. Authors' conclusions Praziquantel and Metrifonate are effective treatments for urinary schistosomiasis and have few adverse events. Metrifonate requires multiple administrations and is therefore operationally less convenient in community-based control programmes. Evidence on the artemisinin derivatives is currently inconclusive, and further research is warranted on combination therapies. We suggest Metrifonate be reconsidered for the WHO Model List of Essential Medicines.

Jennifer Keiser - One of the best experts on this subject based on the ideXlab platform.

  • development of an in vitro drug screening assay using schistosoma haematobium schistosomula
    Parasites & Vectors, 2012
    Co-Authors: Monika Marxer, Katrin Ingram, Jennifer Keiser
    Abstract:

    Background: The development of novel antischistosomal drugs is crucial, as currently no vaccine and only a single drug is available for the treatment of schistosomiasis. Fast and accurate in vitro assays are urgently needed to identify new drug candidates and research efforts should include Schistosoma haematobium. The aim of the present study was to develop a S. haematobium drug sensitivity assay based on newly transformed schistosomula (NTS). Methods: We first undertook comparative studies on the cercarial emergence rhythms of the intermediate host snails Biomphalaria glabrata (S. mansoni) and Bulinus truncatus (S. haematobium). Two transformation methods as well as three purification methods were studied on S. haematobium cercariae in order to produce a large number of viable and clean NTS. Known antischistosomal drugs were tested in the established NTS assay in vitro. Drug effects were evaluated either microscopically or fluorometrically, using a resazurin based viability marker. Microscopically obtained IC50 values were compared with results obtained for S. mansoni. Results: A circadian rhythm existed in both snail species. Infected B. truncatus snails shed less cercariae than B. glabrata during the testing period. The highest transformation rate (69%) of S. haematobium cercariae into NTS was obtained with the vortex transformation (mechanical input) and the highest purification factor was observed using Percoll W . The fluorimetric readout based on resazurin was very precise in detecting dead or/and severely damaged schistosomula. Conclusions: With the use of viability markers such as resazurin, drug screening assays using S. haematobium NTS can be efficiently performed. However, drugs acting on the morphology and motility of S. haematobium NTS, such as Metrifonate are missed. Drug sensitivity assays with NTS of both species, S. haematobium and S. mansoni, showed very similar results using known antischistosomal drugs. The S. mansoni NTS assay might be more suitable as primary screen in drug discovery efforts, which ultimately aim for a broad-spectrum antischistosomal drug as a larger number of S. mansoni NTS can be generated.

Arjan Blokland - One of the best experts on this subject based on the ideXlab platform.

  • The Selective 5-HT_6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat
    Neuropsychopharmacology, 2005
    Co-Authors: Cindy K J Lieben, Arjan Blokland, Eric Sung, Petra Van Nieuwenhuizen, Rudy Schreiber
    Abstract:

    Antagonists at serotonin type 6 (5-HT_6) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT_6 antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic- (tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor Metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that Metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and Metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT_6 receptor antagonists.

  • Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation
    Psychopharmacology, 2005
    Co-Authors: Jos Prickaerts, Ayhan şik, Jan De Vente, Franz Josef Staay, Arjan Blokland
    Abstract:

    Rationale Phosphodiesterase enzyme type 5 (PDE5) inhibitors and acetylcholinesterase (AChE) inhibitors have cognition-enhancing properties. However, it is not known whether these drug classes affect the same memory processes. Objective We investigated the memory-enhancing effects of the PDE5 inhibitor sildenafil and AChE inhibitors Metrifonate and donepezil in the object recognition task to find out whether acquisition or consolidation processes were affected by these drugs. Methods The object recognition task measures whether rats remembered an object they have explored in a previous learning trial. All drugs were given orally 30 min before or immediately after learning to study acquisition and consolidation, respectively. Results Sildenafil given immediately after the first trial improved the memory performance after 24 h and resulted in an inverted U-shaped dose–effect curve with the peak dose at 3 mg/kg. When given before the first trial, sildenafil also improved the memory performance. However, the dose needed for the best performance under this condition was 10 mg/kg, suggesting that the dose–effect curve shifted to the right. This can be explained by the metabolic clearance of the high dose of sildenafil. Donepezil had no memory improving effect when given after the first trial. However, when given before the first trial, a gradually increasing dose–effect curve was found which had its maximum effect at the highest dose tested (1 mg/kg). Likewise, only when Metrifonate (30 mg/kg) was given before the first trial did rats show an improved memory performance. Conclusion Our data strongly suggest that PDE5 inhibitors improve processes of consolidation of object information, whereas AChE inhibitors improve processes of acquisition of object information.

  • the selective 5 ht6 receptor antagonist ro4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat
    Neuropsychopharmacology, 2005
    Co-Authors: Cindy K J Lieben, Arjan Blokland, Eric Sung, A Sik, P Van Nieuwenhuizen, Rudy Schreiber
    Abstract:

    Antagonists at serotonin type 6 (5-HT6) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT6 antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic- (tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor Metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that Metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and Metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT6 receptor antagonists.

  • effects of Metrifonate and tacrine in the spatial morris task and modified irwin test evaluation of the efficacy safety profile in rats
    Drug Development Research, 1995
    Co-Authors: Arjan Blokland, Volker Hinz, Bernard Schmidt
    Abstract:

    In the present study we investigated the efficacy/safety profile of the cholinesterase inhibitors Metrifonate (MTF) and tacrine [tetrahydroaminoacridine (THA)]. We tested the efficacy of MTF (12, 39, and 120 μmol/kg po) and THA (1.3, 4.3, and 13 μmol/kg po) in the spatial Morris task in 19-month-old rats. The modified Irwin test was used to evaluate the safety of both drugs, using in 19-month-old rats. In this observation test, higher doses of MTF (39, 120, and 390 μmol/kg) and THA (4.3, 13, and 43 μmol/kg) were tested. MTF was found to improve the performance of rats in the spatial Morris task. Independent of dose, MTF-treated rats performed better than vehicle-treated rats in the Morris task during the 2nd week of testing. THA treatment (1.3 μmol/kg) had only a minor effect on the spatial discrimination performance, i.e., effect on the probe trial after 2 weeks of training. In the modified Irwin test, both MTF and THA dose dependently induced side effects which were classified as being typically cholinergic. The threshold dose for the occurrence of side effects for acutely administered MTF and THA was 39 and 4.3 μmol/kg, respectively. Remarkably, repeated administration of 390 μmol/kg MTF (5 day treatment) resulted in fewer side effects. This was not observed for THA treatment. The data of the present study indicate that the efficacy/safety profile of MTF is more favorable than that of THA. © 1995 Wiley-Liss, Inc.

John F Disterhoft - One of the best experts on this subject based on the ideXlab platform.

  • Metrifonate Increases Neuronal Excitability in CA1 Pyramidal Neurons from Both Young and Aging Rabbit Hippocampus
    2015
    Co-Authors: John M Power, Pamela L Moriearty, Lucien T Thompson, John F Disterhoft
    Abstract:

    The effects of Metrifonate, a second generation cholinesterase inhibitor, were examined on CA1 pyramidal neurons from hip-pocampal slices of young and aging rabbits using current-clamp, intracellular recording techniques. Bath perfusion of Metrifonate (10–200 mM) dose-dependently decreased both postburst afterhyperpolarization (AHP) and spike frequency ad-aptation (accommodation) in neurons from young and aging rabbits (AHP: p, 0.002, young; p, 0.050, aging; accommo-dation: p, 0.024, young; p, 0.001, aging). These reduction

  • modulation of cholinergic transmission enhances excitability of hippocampal pyramidal neurons and ameliorates learning impairments in aging animals
    Neurobiology of Learning and Memory, 2003
    Co-Authors: John F Disterhoft
    Abstract:

    Four cholinesterase inhibitors have been approved by the US Food and Drug Administration for treating behavioral symptoms of Alzheimer's disease. Here we review our experiences with two cholinesterase inhibitors (Metrifonate and galanthamine) and a muscarinic acetylcholine receptor agonist (CI-1017) in behavioral pharmacological and brain slice experiments in aging and young rabbits. Aging rabbits are impaired in their ability to acquire the hippocampus-dependent trace eyeblink conditioning task, as compared to young controls. A large proportion of aging animals cannot reach behavioral criterion in this task. Those that do learn, do so more slowly. In addition, the post-burst afterhyperpolarization and spike frequency accommodation is increased in hippocampal pyramidal neurons from aging animals, i.e., cellular excitability is reduced as compared to those from young animals. Metrifonate, galanthamine, and CI-1017 reduced the learning deficits observed in aging rabbits so that they learned almost as quickly as young controls. These cholinergic compounds also enhanced the postsynaptic excitability of hippocampal pyramidal neurons in vitro. Therefore, we propose that the amelioration of learning impairment with the cholinergic compounds may in part be due to the enhanced excitability of hippocampal pyramidal neurons. The potential relevance of our studies to further understanding the cellular and behavioral changes that occur with normal aging and Alzheimer's Disease is discussed.

  • Metrifonate increases neuronal excitability in CA1 pyramidal neurons from both young and aging rabbit hippocampus
    1999
    Co-Authors: John M Power, Pamela L Moriearty, Lucien T Thompson, John F Disterhoft
    Abstract:

    The effects of Metrifonate, a second generation cholinesterase inhibitor, were examined on CA1 pyramidal neurons from hippocampal slices of young and aging rabbits using currentclamp, intracellular recording techniques. Bath perfusion of Metrifonate (10-200 M) dose-dependently decreased both postburst afterhyperpolarization (AHP) and spike frequency adaptation (accommodation) in neurons from young and aging rabbits (AHP: p Ͻ 0.002, young; p Ͻ 0.050, aging; accommodation: p Ͻ 0.024, young; p Ͻ 0.001, aging). These reductions were mediated by muscarinic cholinergic transmission, because they were blocked by addition of atropine (1 M) to the perfusate. The effects of chronic Metrifonate treatment (12 mg/kg for 3 weeks) on CA1 neurons of aging rabbits were also examined ex vivo. Neurons from aging rabbits chronically treated with Metrifonate had significantly reduced spike frequency accommodation, compared with vehicle-treated rabbits. Chronic Metrifonate treatment did not result in a desensitization to Metrifonate ex vivo, because bath perfusion of Metrifonate (50 M) significantly decreased the AHP and accommodation in neurons from both chronically Metrifonateand vehicle-treated aging rabbits. We propose that the facilitating effect of chronic Metrifonate treatment on acquisition of hippocampus-dependent tasks such as trace eyeblink conditioning by aging subjects may be caused by this increased excitability of CA1 pyramidal neurons