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1.
Psychiatr Danub ; 31(Suppl 3): 276-281, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488740

RESUMO

Anxiety and depression contribute to a substantial burden of Chronic Obstructive Pulmonary Disease-related morbidity by impairing quality of life and by reducing adherence to treatment. The identification of COPD patients with comorbid depression or anxiety symptoms is vital, as it is estimated that only a third of patients with these co-morbidities are receiving appropriate treatment. The aim of this audit was therefore to identify whether current methods of anxiety and depression screening in elderly patients (over the age of 65) with severe COPD (FEV1 <50% at most recent spirometry reading) are adequate by assessing how frequently anxiety and depression is reported as "discussed with patient" in COPD review appointments across two practices. SystmOne was used to identify a total of 83 patients, and the recording of depression and anxiety discussions in this cohort's review appointments was analysed and compared with the incidence of QOF-coded depression and anxiety in the patient notes. The results show that both the rate and the quality of depression and anxiety reporting in these review appointments is highly heterogeneous, and has led to 'missed' patients suffering from comorbid mental health issues. Additionally, this audit identified a number of patients with depression or anxiety directly related to their COPD, and it highlighted a trend among this cohort towards more frequent appointments with their General Practitioner, and towards related presentations at the Emergency Department. The results of this audit suggest there is room for amelioration of the current practice, such as the implementation of a structured screening tool into System One's COPD review appointment template.


Assuntos
Ansiedade/complicações , Ansiedade/diagnóstico , Auditoria Clínica , Depressão/complicações , Depressão/diagnóstico , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/psicologia , Idoso , Humanos , Qualidade de Vida
2.
Psychiatr Danub ; 31(Suppl 3): 608-612, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488799

RESUMO

Schizophrenic patients have traditionally suffered from high rates of cardiovascular disease and early mortality. NICE guidelines suggest that several physical health measures be monitored regularly in these patients, and particularly those on antipsychotic medication, which has a wide side-effect profile that may potentiate the risk of cardiovascular disease and other comorbidities. This general practice audit aimed to determine the rates of physical health monitoring in primary care in patients on antipsychotic medication for over a year for psychotic symptoms or schizophrenia. The search was conducted in three different general practices in March 2019, yielding 19, 8 and 30 patients respectively, with a total of 57 patients. This audit aims to record and analyse rates of monitoring of a range of physical health measures recommended by NICE guidelines over the past year. The results demonstrated that physical health monitoring was poor amongst all the practices audited, especially that of prolactin and waist circumference. We recommend that these rates of monitoring be improved, through implementing templates or the delivery of targeted education to general practitioners and nurses.


Assuntos
Antipsicóticos/efeitos adversos , Medicina Geral , Atenção Primária à Saúde , Transtornos Psicóticos/complicações , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Auditoria Clínica , Humanos , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia
3.
BMJ Case Rep ; 12(6)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31175114

RESUMO

Tarsal-carpal coalition syndrome is a progressive condition involving synostosis of the wrist, ankle and digits. We describe a mother and her newborn that have this rare inherited condition where the diagnosis was made only after the baby's birth. The baby's condition was suspected on antenatal scanning, and he was born with reduced range of motion of his digits, elbows and ankles. The mother's condition has progressed to involve a fixed flexion deformity of her bilateral elbows, synostoses of her second to fifth digits and extensive coalition of her tarsal and carpal bones. She has required regular osteotomies to improve limb functioning and quality of life.


Assuntos
Ossos do Carpo/anormalidades , Proteínas de Transporte/genética , Deformidades Congênitas do Pé/diagnóstico por imagem , Deformidades Congênitas do Pé/cirurgia , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/cirurgia , Estribo/anormalidades , Sinostose/diagnóstico por imagem , Sinostose/cirurgia , Ossos do Tarso/anormalidades , Ossos do Carpo/diagnóstico por imagem , Ossos do Carpo/cirurgia , Diagnóstico Precoce , Feminino , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Humanos , Recém-Nascido , Masculino , Idade Materna , Osteotomia , Polimorfismo de Nucleotídeo Único , Estribo/diagnóstico por imagem , Sinostose/genética , Ossos do Tarso/diagnóstico por imagem , Ossos do Tarso/cirurgia , Adulto Jovem
4.
BMC Hematol ; 16: 20, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27462400

RESUMO

BACKGROUND: Iron deficiency anemia is highly prevalent in patients with chronic kidney disease and is often treated with intravenous iron. There are few trials directly comparing the safety and efficacy of different intravenous iron products. METHODS: This post-hoc analysis pooled data from 767 patients enrolled in two randomized, controlled, open-label trials of similar design comparing the treatment of iron deficiency anemia with ferumoxytol and iron sucrose across patients with all stages of renal function. One trial was conducted in adults with CKD either on or not on dialysis and the second in adults with IDA of any underlying cause and a history of unsatisfactory oral iron therapy or in whom oral iron could not be used who had normal to no worse than moderately impaired renal function. Patients were categorized by chronic kidney disease stage (i.e., estimated glomerular filtration rate), and the primary efficacy endpoint was the mean change in hemoglobin from Baseline to Week 5. RESULTS: The overall incidence of adverse events was numerically lower in ferumoxytol-treated patients compared to those treated with iron sucrose (42.4 vs. 50.2 %, respectively); the incidence of treatment-related adverse events was generally similar between the two treatment groups (13.6 vs. 16.0 %, respectively). Adverse events of Special Interest (i.e., hypotension, hypersensitivity) occurred at lower rates in those treated with ferumoxytol compared to those treated with iron sucrose (2.5 vs. 5.3 %, respectively). Overall, mean hemoglobin increased in both treatment groups, regardless of degree of renal insufficiency, although greater increases were seen among those with less severe kidney damage. Mean increases in hemoglobin from Baseline to Week 5 were significantly greater with ferumoxytol than with iron sucrose treatment in the subgroup with an estimated glomerular filtration rate ≥90 mL/min (Least Squares mean difference = 0.53 g/dL; p < 0.001). There were no other consistent, significant differences in hemoglobin levels between treatment groups for the other chronic kidney disease categories except for isolated instances favoring ferumoxytol. CONCLUSIONS: The efficacy and safety of ferumoxytol is at least comparable to iron sucrose in patients with varying degrees of renal function. TRIAL REGISTRATION: (CKD-201; ClinicalTrials.gov identifier: NCT01052779; registered 15 January, 2010), (IDA-302; ClinicalTrials.gov identifier: NCT01114204; registered 29 April, 2010).

5.
J Biol Chem ; 290(17): 11041-51, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25767113

RESUMO

The chemokine receptors CCR5 and CCR2b share 89% amino acid homology. CCR5 is a co-receptor for HIV and CCR5 antagonists have been investigated as inhibitors of HIV infection. We describe the use of two CCR5 antagonists, Schering-C (SCH-C), which is specific for CCR5, and TAK-779, a dual inhibitor of CCR5 and CCR2b, to probe the CCR5 inhibitor binding site using CCR5/CCR2b chimeric receptors. Compound inhibition in the different chimeras was assessed by inhibition of chemokine-induced calcium flux. SCH-C inhibited RANTES (regulated on activation, normal T cell expressed and secreted) (CCL5)-mediated calcium flux on CCR5 with an IC50 of 22.8 nM but was inactive against monocyte chemoattractant protein-1 (CCL2)-mediated calcium flux on CCR2b. However, SCH-C inhibited CCL2-induced calcium flux against a CCR5/CCR2b chimera consisting of transmembrane domains IV-VI of CCR5 with an IC50 of 55 nM. A sequence comparison of CCR5 and CCR2b identified a divergent amino acid sequence located at the junction of transmembrane domain V and second extracellular loop. Transfer of the CCR5 sequence KNFQTLKIV into CCR2b conferred SCH-C inhibition (IC50 of 122 nM) into the predominantly CCR2b chimera. Furthermore, a single substitution, R206I, conferred partial but significant inhibition (IC50 of 1023 nM) by SCH-C. These results show that a limited amino acid sequence is responsible for SCH-C specificity to CCR5, and we propose a model showing the interaction with CCR5 Ile(198).


Assuntos
Amidas/química , Antagonistas dos Receptores CCR5/química , Modelos Moleculares , Compostos de Amônio Quaternário/química , Receptores CCR5/química , Sequência de Aminoácidos , Animais , Sinalização do Cálcio , Células HEK293 , Humanos , Isoleucina/química , Isoleucina/genética , Isoleucina/metabolismo , Macaca , Estrutura Terciária de Proteína , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores CCR5/genética , Receptores CCR5/metabolismo , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo
6.
J Behav Ther Exp Psychiatry ; 44(2): 207-12, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23207969

RESUMO

BACKGROUND AND OBJECTIVES: Thought-action fusion (TAF), or maladaptive cognitions regarding the relationship between mental events and behaviours, has been implicated in the development and maintenance of obsessive-compulsive disorder (OCD). As some religions promote TAF-like appraisals, it has been proposed that religiosity may play a role in the transformation of normally occurring intrusive thoughts into clinically distressing obsessions. No research, however, has experimentally investigated the mediating role of TAF on the relationship between religiosity and OC symptoms. METHODS: 85 Christian, Jewish, and Atheist/Agnostic participants were exposed to an experimental thought-induction protocol and reported on their associated levels of distress, guilt, feelings of responsibility, and urge to suppress target intrusions experienced during a 5-min monitoring period. Participants also completed measures of obsessive-compulsive symptomatology, TAF beliefs, and general psychopathology. RESULTS: Using PROCESS and bootstrapping analyses, a test of the conditional indirect effects of religiosity on obsessive-compulsive symptoms revealed that Christianity moderated the effects of religiosity on moral TAF beliefs, which in turn mediated the relationship between religiosity and obsessive-compulsive symptoms. Furthermore, in the Christian group, moral TAF beliefs mediated the relationship between religiosity and ratings of guilt and responsibility following the experimental protocol. LIMITATIONS: The use of university students with moderate levels of religiosity. CONCLUSIONS: Collectively the results suggest that obsessional thinking is not attributable to religion per se, but that teachings underlying certain religious doctrines may fuel TAF beliefs that are implicated in the maintenance of OCD.


Assuntos
Cognição , Transtorno Obsessivo-Compulsivo/psicologia , Espiritualidade , Pensamento , Adulto , Feminino , Culpa , Humanos , Masculino , Modelos Psicológicos , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/etiologia , Escalas de Graduação Psiquiátrica , Responsabilidade Social , Estresse Psicológico/psicologia
7.
Biochem Pharmacol ; 83(4): 472-9, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22146583

RESUMO

In order to enter and infect human cells HIV must bind to CD4 in addition to either the CXCR4 or the CCR5 chemokine receptor. AMD11070 was the first orally available small molecule antagonist of CXCR4 to enter the clinic. Herein we report the molecular pharmacology of AMD11070 which is a potent inhibitor of X4 HIV-1 replication and the gp120/CXCR4 interaction. Using the CCRF-CEM T cell line that endogenously expresses CXCR4 we have demonstrated that AMD11070 is an antagonist of SDF-1α ligand binding (IC50 = 12.5 ± 1.3 nM), inhibits SDF-1 mediated calcium flux (IC50 = 9.0 ± 2.0 nM) and SDF-1α mediated activation of the CXCR4 receptor as measured by a Eu-GTP binding assay (IC50 =39.8 ± 2.5 nM) or a [(35)S]-GTPγS binding assay (IC50 =19.0 ± 4.1 nM), and inhibits SDF-1α stimulated chemotaxis (IC50 =19.0 ± 4.0 nM). AMD11070 does not inhibit calcium flux of cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7, or ligand binding to CXCR7 and BLT1, demonstrating selectivity for CXCR4. In addition AMD11070 is able to inhibit the SDF-1ß isoform interactions with CXCR4; and N-terminal truncated variants of CXCR4 with equal potency to wild type receptor. Further mechanistic studies indicate that AMD11070 is an allosteric inhibitor of CXCR4.


Assuntos
Aminoquinolinas/farmacologia , Aminoquinolinas/farmacocinética , Benzimidazóis/farmacologia , Benzimidazóis/farmacocinética , HIV-1/efeitos dos fármacos , Receptores CXCR4/metabolismo , Internalização do Vírus/efeitos dos fármacos , Administração Oral , Aminoquinolinas/administração & dosagem , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Benzimidazóis/administração & dosagem , Disponibilidade Biológica , Linhagem Celular , Quimiocina CXCL12/antagonistas & inibidores , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Cães , Regulação da Expressão Gênica/efeitos dos fármacos , HIV-1/fisiologia , Compostos Heterocíclicos com 1 Anel , Humanos , Estrutura Molecular , Ligação Proteica , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
8.
J Am Chem Soc ; 133(41): 16477-85, 2011 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-21942640

RESUMO

The viral resistance of marketed antiviral drugs including the emergence of new viral resistance of the only marketed CCR5 entry inhibitor, maraviroc, makes it necessary to develop new CCR5 allosteric inhibitors. A mutagenesis/modeling approach was used (a) to remove the potential hERG liability in an otherwise very promising series of compounds and (b) to design a new class of compounds with an unique mutant fingerprint profile depending on residues in the N-terminus and the extracellular loop 2. On the basis of residues, which were identified by mutagenesis as key interaction sites, binding modes of compounds were derived and utilized for compound design in a prospective manner. The compounds were then synthesized, and in vitro evaluation not only showed that they had good antiviral potency but also fulfilled the requirement of low hERG inhibition, a criterion necessary because a potential approved drug would be administered chronically. This work utilized an interdisciplinary approach including medicinal chemistry, molecular biology, and computational chemistry merging the structural requirements for potency with the requirements of an acceptable in vitro profile for allosteric CCR5 inhibitors. The obtained mutant fingerprint profiles of CCR5 inhibitors were used to translate the CCR5 allosteric binding site into a general pharmacophore, which can be used for discovering new inhibitors.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Ureia/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Mutagênese , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
10.
Virology ; 413(2): 231-43, 2011 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-21388649

RESUMO

Based on the attrition rate of CCR5 small molecule antagonists in the clinic the discovery and development of next generation antagonists with an improved pharmacology and safety profile is necessary. Herein, we describe a combined molecular modeling, CCR5-mediated cell fusion, and receptor site-directed mutagenesis approach to study the molecular interactions of six structurally diverse compounds (aplaviroc, maraviroc, vicriviroc, TAK-779, SCH-C and a benzyloxycarbonyl-aminopiperidin-1-yl-butane derivative) with CCR5, a coreceptor for CCR5-tropic HIV-1 strains. This is the first study using an antifusogenic assay, a model of the interaction of the gp120 envelope protein with CCR5. This assay avoids the use of radioactivity and HIV infection assays, and can be used in a high throughput mode. The assay was validated by comparison with other established CCR5 assays. Given the hydrophobic nature of the binding pocket several binding models are suggested which could prove useful in the rational drug design of new lead compounds.


Assuntos
Antagonistas dos Receptores CCR5 , Inibidores da Fusão de HIV/farmacologia , HIV-1/fisiologia , HIV-1/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Modelos Moleculares , Mutagênese Sítio-Dirigida , Mutação , Conformação Proteica , Receptores CCR5/genética , Reprodutibilidade dos Testes , Estereoisomerismo , Internalização do Vírus
11.
Res Dev Disabil ; 32(1): 207-16, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21035302

RESUMO

The purpose of the present study was to investigate the handwriting characteristics of secondary school students with and without physical disabilities (PD). With the use of a computerized Chinese Handwriting Assessment Tool (CHAT), it was made possible to objectively assess and analyze in detail the handwriting characteristics of individual students. Fifty participants (age range: 15-19-years-old) were recruited from one mainstream secondary school and 20 participants (age range: 17-24-years-old) were recruited from two secondary schools for students with PD. They were asked to perform three consecutive handwriting tasks: copying 90 characters using the computerized CHAT, an English passage copying task, and a Chinese passage copying task. The data indicated that students with PD were significantly slower in copying both Chinese and English characters in passages when compared to the typical students. Significant differences in the measures of writing speed, air/ground time ratio, standard deviation of speed, standard deviation of size per character, and number of stroke errors measured by the CHAT were found between the two groups of students. Further analysis on the data of typical students indicated no significant difference in handwriting speed among students of different classes (i.e. arts or science) on copying Chinese and English passages, and on individual Chinese words (from CHAT). The academic results of students also showed no significant correlation with their handwriting speed measured by the three writing tasks. To conclude, the CHAT system was able to identify a number of characteristics of handwriting on students with and without PD. It was suggested that the CHAT should further be developed into an objective evaluation tool to explore the handwriting characteristics of the students with a wider range of disabilities in the future, and to make recommendations to arrange special examination arrangements (SEA) for students with physical disabilities or other special needs.


Assuntos
Agrafia/diagnóstico , Agrafia/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Escrita Manual , Processamento de Imagem Assistida por Computador , Adolescente , Grupo com Ancestrais do Continente Asiático , Estudos Transversais , Humanos , Destreza Motora , Multilinguismo , Desempenho Psicomotor , Saponinas , Software , Esteroides , Adulto Jovem
12.
Emotion ; 9(3): 430-4, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19485620

RESUMO

Substantial evidence demonstrates that ostracism has powerful negative effects on psychological well-being. However, little is known about how to ameliorate the negative effects of this ubiquitous social experience. A key preliminary strategy for developing effective methods to reduce the negative impact of ostracism is to examine factors that influence the persistence of these effects. Therefore, the authors examined whether the persistence of these negative effects is dependent on the vantage perspective from which an experience of exclusion is recalled. Using a virtual ball-toss game, being ostracized elicited an immediate aversive effect; furthermore, these effects persisted when individuals recalled the experience from an observer perspective compared with a field perspective. This study shows, for the first time, that the persistence of the debilitating effects of ostracism is influenced by how individuals recall that experience. These results have implications for the development of ameliorative strategies to manage the impact of social exclusion.


Assuntos
Relações Interpessoais , Rememoração Mental , Isolamento Social/psicologia , Adaptação Psicológica , Jogos Experimentais , Humanos , Individualidade , Desejabilidade Social , Estresse Psicológico/psicologia
13.
Biochem Pharmacol ; 78(8): 993-1000, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19540208

RESUMO

CXCR4 is widely expressed in multiple cell types, and is involved in neonatal development, hematopoiesis, and lymphocyte trafficking and homing. Disruption of the CXCL12/CXCR4 interaction has been implicated in stem cell mobilization. Additionally CXCR4 is a co-receptor for HIV. Selective small molecule antagonists of CXCR4 therefore have therapeutic potential. AMD3465 is an N-pyridinylmethylene monocyclam CXCR4 antagonist which can block infection of T-tropic, CXCR4-using HIV. Using the CCRF-CEM T-cell line which expresses CXCR4 we have demonstrated that AMD3465 is an antagonist of SDF-1 ligand binding (K(i) of 41.7+/-1.2nM), and inhibits SDF-1 mediated signaling as shown by inhibition of GTP binding, calcium flux, and inhibition of chemotaxis. AMD3465 is selective for CXCR4 and does not inhibit chemokine-stimulated calcium flux in cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7, nor does it inhibit binding of LTB(4) to its receptor, BLT1. The pharmacokinetics of AMD3465 was investigated in mice and dogs. Absorption was rapid following subcutaneous administration. AMD3465 was cleared from dog plasma in a biphasic manner with a terminal half-life of 1.56-4.63h. Comparison of exposure to the intravenous and subcutaneous doses indicated 100% bioavailability following subcutaneous administration. AMD3465 caused leukocytosis when administered subcutaneously in mice and dogs, with peak mobilization occurring between 0.5 and 1.5h following subcutaneous dosing in mice and with maximum peak plasma concentration of compound preceding peak mobilization in dogs, indicating that AMD3465 has the potential to mobilize hematopoietic stem cells. These data demonstrate the therapeutic potential for the CXCR4 antagonist AMD3465.


Assuntos
Compostos Heterocíclicos/farmacologia , Piridinas/farmacologia , Piridinas/farmacocinética , Receptores CXCR4/antagonistas & inibidores , Absorção , Animais , Área Sob a Curva , Células CHO , Cálcio/análise , Cálcio/metabolismo , Linhagem Celular , Quimiocina CXCL12/antagonistas & inibidores , Quimiotaxia/efeitos dos fármacos , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Fluoresceínas/metabolismo , Corantes Fluorescentes/metabolismo , Meia-Vida , Humanos , Concentração Inibidora 50 , Rim/citologia , Leucocitose/etiologia , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Estrutura Molecular , Ligação Proteica , Piridinas/efeitos adversos , Piridinas/sangue , Piridinas/química , Transfecção
14.
J Inorg Biochem ; 102(10): 1839-45, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18684510

RESUMO

The cysteine proteases of the trypanosomatid parasitic protozoa have been validated as targets for chemotherapy of Chagas' disease and leishmaniasis. Metal complexes of gold, platinum, iridium, palladium, rhodium and osmium have been reported to have activity against a variety of trypanosomatids, but the molecular target of these compounds has not been defined. The activity of gold(III) and palladium(II) cyclometallated complexes, and oxorhenium(V) complexes against mammalian and parasitic cysteine proteases was investigated. All gold(III) complexes (1-6) inhibited cathepsin B with IC(50) values in the range of 0.2-1.4 microM. Of the six palladium compounds, aceto[2,6-bis[(butylthio-kappa S)methyl]phenyl-kappa C]-, (SP-4-3)-palladium(II) (11) was the most potent inhibitor of cathepsin B with an IC(50) of 0.4 microM. A clear structure-activity relationship was observed with the oxorhenium(V) complexes with chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16) being the most potent inhibitor of cathepsin B with an IC(50) of 0.009 microM. Six complexes were further tested against the parasite cysteine proteases, cruzain from T. cruzi, and cpB from L. major; the most potent inhibitors were the two rhenium complexes (2(1H)-pyridinethionato-kappa S(2))[2,6-bis[(mercapto-kappa S)methyl]pyridine-kappa N(1)] oxorhenium(V) (15) and chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16). The compounds were also evaluated in assays for parasite growth. Two oxorhenium(V) compounds ((p-methoxyphenylthiolato-S)[2,6-bis[(mercapto-kappa S)methyl]pyridine-kappa N(1)] oxorhenium(V) (14) and (methanethiolato)[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium (V) (18)) and the palladium compound 11 inhibited T. cruzi intracellular growth, and compound 11 inhibited promastigote growth in three Leishmania species. In conclusion this preliminary data indicates that metal complexes targeted at parasite cysteine proteases show promise for the treatment of both Chagas' disease and leishmaniasis.


Assuntos
Catepsina B/metabolismo , Doença de Chagas/tratamento farmacológico , Inibidores de Cisteína Proteinase/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Metais/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma/efeitos dos fármacos , Animais , Catepsina B/antagonistas & inibidores , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/uso terapêutico , Humanos , Compostos Inorgânicos/química , Compostos Inorgânicos/farmacologia , Metais/uso terapêutico , Tripanossomicidas/uso terapêutico
15.
Biochem Pharmacol ; 72(5): 588-96, 2006 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-16815309

RESUMO

The chemokine receptor CXCR4 is widely expressed on different cell types, is involved in leukocyte chemotaxis, and is a co-receptor for HIV. AMD3100 has been shown to be a CXCR4 receptor antagonist, and to block HIV infection of T-tropic, X4-using, virus in vitro and in vivo. AMD3100 is an effective mobilizer of hematopoietic stem cells and is being investigated in clinical trials in multiple myeloma and non-Hodgkins lymphoma patients. Using the CCRF-CEM T-cell line that constitutively expresses CXCR4 we confirmed that AMD3100 was an antagonist of SDF-1/CXCL12 ligand binding (IC50=651+/-37 nM). We have also shown that AMD3100 inhibits SDF-1 mediated GTP-binding (IC50=27+/-2.2 nM), SDF-1 mediated calcium flux (IC50=572+/-190 nM), and SDF-1 stimulated chemotaxis (IC50=51+/-17 nM). AMD3100 did not inhibit calcium flux against cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7 when stimulated with their cognate ligands, nor did it inhibit receptor binding of LTB4. AMD3100 did not, on its own, induce a calcium flux in the CCRF-CEM cells, which express multiple GPCRs including CXCR4, CCR4 and CCR7. Furthermore, AMD3100 neither stimulated GTP-binding, an assay for GPCR activation, in CEM cell membranes; nor chemotaxis of CCRF-CEM cells. These data therefore demonstrate that AMD3100 is a specific antagonist of CXCR4, is not cross-reactive with other chemokine receptors, and is not an agonist of CXCR4.


Assuntos
Compostos Heterocíclicos/farmacologia , Receptores CXCR4/antagonistas & inibidores , Cálcio/metabolismo , Linhagem Celular , Quimiocina CXCL12 , Quimiocinas CXC/metabolismo , Quimiotaxia/efeitos dos fármacos , Humanos , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos
16.
Assay Drug Dev Technol ; 3(6): 637-48, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16438659

RESUMO

Chemokine receptors have been implicated in several disease processes such as acute and chronic inflammation, cancer, and allograft rejection and are therefore targets for drug development. The chemokine receptors CCR5 and CXCR4 are of particular interest as they serve as entry cofactors for human immunodeficiency virus. These receptors are members of the G protein-coupled receptor (GPCR) family. In this respect, assessing GPCR activation by GTP binding is an important tool to study the early stage of signal transduction. The assay normally utilizes the non-hydrolysable GTP analogue guanosine 5'-gamma-[35S]thiotriphosphate. In order to avoid the problems involved in working with radioactivity, a new non-radioactive version of the assay was developed using a europium-labeled GTP analogue in which europium-GTP binding can be assayed using time-resolved fluorescence. The assay was optimized for CXCR4 and CCR5 and validated for screening of chemokine antagonists using the small molecule CXCR4 antagonist AMD3100 and CCR5 antagonists.


Assuntos
Antagonistas dos Receptores CCR5 , Európio , Guanosina Trifosfato/metabolismo , Receptores CXCR4/antagonistas & inibidores , Fármacos Anti-HIV/farmacologia , Cálcio/metabolismo , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Quimiocinas/antagonistas & inibidores , Quimiocinas/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Fluorescência , Guanosina Difosfato , Guanosina Trifosfato/análogos & derivados , Compostos Heterocíclicos/farmacologia , Humanos , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Reprodutibilidade dos Testes , Saponinas , Transdução de Sinais , Cloreto de Sódio , Temperatura Ambiente , Fatores de Tempo
17.
Biochemistry ; 43(28): 9195-203, 2004 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-15248777

RESUMO

Ferric binding protein in Neisseria gonorrhoeae (nFbpA) transports iron from outer membrane receptors for host proteins across the periplasm to a permease in an alternative pathway to the use of siderophores in some pathogenic bacteria. Phosphate and nitrilotriacetate, both at pH 8, and vanadate at pH 9 are shown to be synergistic in promoting ferric binding to nFbpA, in contrast to carbonate and sulfate. Interestingly, only phosphate produces the fully closed conformation of nFbpA as defined by native electrophoresis. The role of phosphate was probed by constructing three mutants: Q58E, Q58R, and G140H. The anion and iron binding properties of the Q58E mutant are similar to the wild-type protein, implying that one phosphate oxygen is a hydrogen bond donor and may in part define the specificity of nFbpA for phosphate over sulfate. Phosphate is a weakly synergistic anion in the Q58R and G140H mutants, and these mutants do not form completely closed structures. Ferric binding was investigated by both isothermal titration and differential scanning calorimetry. The apparent affinity of nFbpA for iron in a solution of 30 mM citrate is 1 order of magnitude larger in the presence (K(app)= 1.7 x 10(5) M(-1)) of phosphate than in its absence (K(app) = 1.6 x 10(4) M(-1)) at pH 7. Similar results were obtained at pH 8. This increase in affinity with phosphate as well as the formation of closed structure allows nFbpA to compete for free ferric ions in solution and suggests that ferric binding to nFbpA is regulated by the synergistic phosphate anion at sites of iron uptake.


Assuntos
Ânions/farmacologia , Proteínas de Ligação ao Ferro/metabolismo , Ferro/metabolismo , Neisseria gonorrhoeae/química , Substituição de Aminoácidos , Sinergismo Farmacológico , Ferro/química , Proteínas de Ligação ao Ferro/química , Proteínas de Ligação ao Ferro/genética , Mutagênese Sítio-Dirigida , Ácido Nitrilotriacético/farmacologia , Fosfatos/farmacologia , Ligação Proteica , Conformação Proteica/efeitos dos fármacos , Titulometria
18.
J Bacteriol ; 186(10): 3266-9, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15126492

RESUMO

The fbpABC operon in Neisseria gonorrhoeae encodes an ATP-binding cassette transporter required for iron uptake from the host ferric binding proteins. The gene for the nucleotide-binding domain (fbpC) expressed in Escherichia coli has intrinsic ATPase activity (0.5 mmol/min/mg) uncoupled from the iron transport process. The FbpC E164D mutant is found to have a 10-fold reduction in specific activity. FbpC is covalently modified by 8-azido-[gamma32P]ATP, indicating that FbpC is a functional ATPase that likely combines with FbpB to form a ferric iron transporter.


Assuntos
Trifosfato de Adenosina/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Neisseria gonorrhoeae/metabolismo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/análogos & derivados , Azidas/metabolismo , Proteínas de Bactérias/química , Sequência de Bases , Sítios de Ligação , Proteínas de Transporte de Cátions/química , Transporte de Íons , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
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