RESUMO
Opioid use disorder (OUD) is defined as a compulsion to seek and take opioids, loss of control over intake and the development of a negative emotional state when access to opioids is denied. Using functional magnetic resonance imaging (fMRI) data in a rat model of OUD, we demonstrate that the escalation of heroin self-administration (SA) and the increased heroin SA following an injection of an opioid receptor antagonist (naloxone) are associated with changes in distinct brain circuits, centered on the cingulate cortex (Cg). Here, SA escalation score was negatively associated with changes in resting state functional connectivity (rsFC) between the Cg and the dorsal striatum. Conversely, increased heroin SA following naloxone injection, was associated with increased connectivity between the Cg and the extended amygdala and hypothalamus. Naloxone-induced increased SA was also positively associated with changes in the amplitude of low frequency fluctuations within the Cg, a measure of spontaneous neuronal activity. Characterizing the distinct brain circuit and behavior changes associated with different facets of addiction increases our understanding of OUD and may provide insight into addiction prevention and treatment.
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Contemporary neuroscience aims to understand how neuronal activity produces internal processes and observable behavioral states. This aim crucially depends on systems-level, circuit-based analyses of the working brain, as behavioral states arise from information flow and connectivity within and between discrete and overlapping brain regions, forming circuits and networks. Functional magnetic resonance imaging (fMRI), offers a key to advance circuit neuroscience; fMRI measures inter and intra- regional circuits at behaviorally relevant spatial-temporal resolution. Herein, we argue that cross-sectional observations in human populations can be best understood via mechanistic and causal insights derived from brain circuitry obtained from preclinical fMRI models. Using nicotine addiction as an exemplar of a circuit-based substance use disorder, we review fMRI-based observations of a circuit that was first shown to be disrupted among human smokers and was recently replicated in rodent models of nicotine dependence. Next, we discuss circuits that predispose to nicotine dependence severity and their interaction with circuits that change as a result of chronic nicotine administration using a rodent model of dependence. Data from both clinical and preclinical fMRI experiments argue for the utility of fMRI studies in translation and reverse translation of a circuit-based understanding of brain disease states. We conclude by discussing the future of circuit neuroscience and functional neuroimaging as an essential bridge between animal models and human populations to the understanding of brain function in health and disease.
Assuntos
Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Tabagismo/diagnóstico por imagem , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos Transversais , Humanos , Neurônios/patologia , Neurociências/métodos , Nicotina/efeitos adversos , Ratos , Tabagismo/patologiaRESUMO
Cognitive deficits during nicotine withdrawal may contribute to smoking relapse. However, interacting effects of chronic nicotine dependence and acute nicotine withdrawal on cognitive control are poorly understood. Here we examine the effects of nicotine dependence (trait; smokers (n = 24) vs. non-smoking controls; n = 20) and acute nicotinic stimulation (state; administration of nicotine and varenicline, two FDA-approved smoking cessation aids, during abstinence), on two well-established tests of inhibitory control, the Go-Nogo task and the Flanker task, during fMRI scanning. We compared performance and neural responses between these four pharmacological manipulations in a double-blind, placebo-controlled crossover design. As expected, performance in both tasks was modulated by nicotine dependence, abstinence, and pharmacological manipulation. However, effects were driven entirely by conditions that required less inhibitory control. When demand for inhibitory control was high, abstinent smokers showed no deficits. By contrast, acutely abstinent smokers showed performance deficits in easier conditions and missed more trials. Go-Nogo fMRI results showed decreased inhibition-related neural activity in right anterior insula and right putamen in smokers and decreased dorsal anterior cingulate cortex activity on nicotine across groups. No effects were found on inhibition-related activity during the Flanker task or on error-related activity in either task. Given robust nicotinic effects on physiology and behavioral deficits in attention, we are confident that pharmacological manipulations were effective. Thus findings fit a recent proposal that abstinent smokers show decreased ability to divert cognitive resources at low or intermediate cognitive demand, while performance at high cognitive demand remains relatively unaffected, suggesting a primary attentional deficit during acute abstinence.
Assuntos
Atenção/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Função Executiva/efeitos dos fármacos , Inibição Psicológica , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Tabagismo/fisiopatologia , Tabagismo/psicologia , Adolescente , Adulto , Atenção/fisiologia , Encéfalo/fisiopatologia , Mapeamento Encefálico , Estudos Cross-Over , Método Duplo-Cego , Função Executiva/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Abandono do Hábito de Fumar/psicologia , Vareniclina/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Methamphetamine abuse is linked with brain abnormalities, but its peripheral effects constitute an integral aspect of long-term methamphetamine use. METHODS: Eight male rhesus monkeys with long histories of intravenous methamphetamine self-administration were evaluated 1 day, and 1, 4, 12, 26, and 52 weeks after their last methamphetamine self-administration session. On test days, isoflurane-anesthetized animals received a 0.35 mg/kg IV methamphetamine challenge. A control group consisted of 10 age and gender matched drug naïve monkeys. Cardiovascular responses to methamphetamine were followed for 2.5h. Echocardiograms were acquired at 3 and 12 months of abstinence and in the control animals. RESULTS: No pre-methamphetamine baseline differences existed among 7 physiological measures across all conditions and controls. As expected, methamphetamine increased heart rate and blood pressure in controls. However, immediately following the self-administration period, the blood pressure response to methamphetamine challenge was reduced when compared to control monkeys. The peak and 150-min average heart rate increases, as well as peak blood pressure increases following methamphetamine were significantly elevated between weeks 12 to 26 of abstinence. These data indicate the development of tolerance followed by sensitization to methamphetamine cardiovascular effects. Echocardiography demonstrated decreased left ventricular ejection fraction and cardiac output at 3 months of abstinence. Importantly, both cardiovascular sensitization and cardiotoxicity appeared to be reversible as they returned toward control group levels after 1 year of abstinence. CONCLUSIONS: Enhanced cardiovascular effects may occur after prolonged abstinence in addicts relapsing to methamphetamine and may underlie clinically reported acute cardiotoxic events.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Metanfetamina/administração & dosagem , Metanfetamina/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Estudos de Casos e Controles , Tolerância a Medicamentos , Ecocardiografia , Macaca mulatta , Masculino , Metanfetamina/sangue , Autoadministração , Fatores de TempoRESUMO
One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.
Assuntos
Biomarcadores , Descoberta de Drogas/métodos , Abandono do Hábito de Fumar , Humanos , Neuroimagem/métodos , Farmacogenética/métodos , Pesquisa Translacional Biomédica/métodosRESUMO
Nicotine and tonic dopamine (DA) levels [as inferred by catechol-O-methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine × COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine × COMT genotype interaction for BOLD signal during performance feedback in cortico-striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy.
Assuntos
Corpo Estriado/fisiologia , Dopamina/metabolismo , Retroalimentação Psicológica , Nicotina/farmacologia , Córtex Pré-Frontal/fisiologia , Fumar/fisiopatologia , Adulto , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Feminino , Heterozigoto , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Recompensa , Fumar/genética , Fumar/metabolismo , Dispositivos para o Abandono do Uso de TabacoRESUMO
Psychostimulant addicts often take high doses of drugs, and high doses of psychostimulants such as methamphetamine (METH) are neurotoxic to striatal dopamine (DA) terminals. Yet, the effects of high doses of METH on drug-seeking and drug-taking behavior have not been examined. In the present study, we found that single high doses of METH in rats (10-20 mg/kg) dose-dependently increased cocaine self-administration under fixed-ratio 2 (FR2) reinforcement conditions, while higher doses (40 mg/kgx1 or 10 mg/kg/2 hx4) caused high mortality among rats maintained on daily cocaine self-administration. The increased cocaine self-administration appeared to be a compensatory response to reduced cocaine reward after METH, because the same doses of METH caused a dose-dependent reduction both in "break-point" levels for cocaine self-administration under progressive-ratio reinforcement and in nucleus accumbens DA response to acute cocaine. Further, METH (10-20 mg/kg) produced large DA release (4000%-6000% over baseline), followed by a significant reduction in striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) contents, but without significant changes in striatal DA transporter levels. These findings suggest that the present high doses of METH caused striatal DA depletion or hypofunction without severe damage in DA terminals, which may contribute to the increased cocaine-taking behavior observed in the present study. Provided that the present doses of METH may mimic METH overdose incidents in humans, the present findings suggest that METH-induced DA depletion or neurotoxicity may lead to an increase in subsequent drug-taking and drug-seeking behavior.
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Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/administração & dosagem , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Metanfetamina/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Espaço Extracelular/metabolismo , Febre/induzido quimicamente , Masculino , Metanfetamina/administração & dosagem , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , AutoadministraçãoRESUMO
OBJECTIVE: Functional and morphological changes of the arterial wall already present in young children with heterozygous familial hypercholesterolemia (HeFH) suggest that treatment should be initiated early in life to prevent premature atherosclerotic cardiovascular disease. The purpose of this study was to assess the efficacy and particularly safety of statin therapy in children with HeFH. METHODS AND RESULTS: We performed a meta-analysis of randomized, double-blind, placebo-controlled trials evaluating statin therapy in children aged 8 to 18 years with HeFH. Six studies (n=798 children) with 12 to 104 weeks of treatment were included. Total cholesterol, LDL cholesterol, and apolipoprotein B were significantly reduced, whereas HDL cholesterol and apolipoprotein A1 were significantly increased by statin therapy. No statistically significant differences were found between statin- and placebo-treated children with respect to the occurrence of adverse events (RR 0.99; 95% CI: 0.79 to 1.25), sexual development (RR of advancing > or = 1 stage in Tanner classification 0.96; 95% CI: 0.79 to 1.17), muscle toxicity (RR of CK > or = 10 times the upper limit of normal [ULN] 1.38; 95% CI: 0.18 to 10.82), or liver toxicity (RR of > or = 3 times the ULN for ASAT 0.98; 95% CI: 0.23 to 4.26 and for ALAT 2.03; 95% CI: 0.24 to 16.95). We found a minimal difference in growth in favor of the statin group (0.33 cm; 95% CI: 0.03 cm to 0.63 cm). CONCLUSION: In addition to the fact that statin treatment is efficacious, our results support the notion that statin treatment in children with HeFH is safe. Thus, even though further studies are required to assess lifelong safety, statin treatment should be considered for all children aged 8 to 18 with HeFH.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Fatores Etários , Criança , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Intervalos de Confiança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Probabilidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Resultado do TratamentoRESUMO
Concerns regarding a potential link between statin treatment and increased risk of cancer were raised following the increased cancer incidence observed in patients treated with pravastatin in the Cholesterol and Recurrent Events and Pravastatin in Elderly Individuals at Risk of Vascular Disease studies. The aim of the present study was to investigate the risk of cancer associated with fluvastatin treatment in clinical trials. A pooled analysis of all available, randomised, placebo-controlled trials with fluvastatin with a minimum treatment period of 24 weeks was performed. The cancer incidences were compared in 3512 patients receiving fluvastatin, 20-80 mg/day, and 3289 patients receiving placebo. Overall, fewer patients were diagnosed with cancer in the fluvastatin group compared with the placebo group [220/3512 (6.3%) vs. 263/3289 (8.0%) respectively; p = 0.0309]. Cox regression analysis, adjusted for baseline covariates and stratified by study, revealed a hazard ratio for first cancer diagnosis of 0.812 [95% confidence interval (CI) 0.667-0.989; p = 0.037] for fluvastatin compared with placebo. No significant differences were observed in the incidence of cancers by site, with the exception of non-melanoma skin cancer (103 vs. 125 cases in the fluvastatin and placebo groups respectively; p = 0.047). Cox regression analysis showed that there was no association between baseline low-density lipoprotein cholesterol levels and the risk of developing cancer (hazard ratio 0.998, 95% CI 0.995-1.000; p = 0.107). In conclusion, fluvastatin treatment is not associated with an increased risk of cancer compared with placebo in clinical trials, independent of patient age, treatment duration and baseline cholesterol levels.
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Ácidos Graxos Monoinsaturados/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Indóis/efeitos adversos , Neoplasias/induzido quimicamente , Adulto , Idoso , Feminino , Fluvastatina , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoRESUMO
Midline brain activation subsequent to errors has been proposed to reflect error detection and, alternatively, conflict-monitoring processes. Adjudicating between these alternatives is challenging as both predict high activation on error trials. In an effort to resolve these interpretations, subjects completed a GO/NOGO task in which errors of commission were frequent and response conflict was independently varied by manipulating response speeds. A mixed-block and event-related fMRI design identified task-related, tonic activation and event-related activations for correct and incorrect trials. The anterior cingulate was the only area with error-related activation that was not modulated by the conflict manipulation and hence is implicated in specific error-related processes. Conversely, activation in the pre-SMA was not specific to errors but was sensitive to the conflict manipulation. A significant region by conflict interaction for tonic activation supported a functional dissociation between these two midline areas. Finally, an intermediate, caudal cingulate area was implicated in both error processing and conflict monitoring. The results suggest that these two action-monitoring processes are distinct and dissociable and are localised along the midline.
Assuntos
Encéfalo/fisiologia , Conflito Psicológico , Lateralidade Funcional/fisiologia , Desempenho Psicomotor/fisiologia , Adolescente , Adulto , Potenciais Evocados , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Inibição Psicológica , Masculino , Pessoa de Meia-IdadeRESUMO
Attention switching between items being stored and manipulated in working memory (WM) is proposed to be an elementary executive function. Experiment 1 reveals a similar attentional limitation within and between verbal and visuospatial WM and identifies a supramodal switching process required for switching between WM items. By using functional magnetic resonance imaging, Experiment 2 investigated brain activation correlates of parametrically varied attention switching within and between these two WM modalities. Attention switching activation was broadly distributed, was quite similar across the three conditions, and, in almost all areas, increased with increasing switching demand, indicating that attention switching recruits and modulates the entire WM network. Dorsolateral prefrontal cortex was implicated in both within- and between-modality attention switching, but no significant activation was found in ventrolateral areas, supporting dorsal-ventral process models of prefrontal organization. A functional dissociation between anterior frontal and dorsolateral prefrontal cortex was found with the former being more activated when switching attention between modalities was required. The data challenge the notion of an anatomically separate attention switching executive function, but suggest that anterior frontal areas are recruited for the additional demand of coordinating the verbal and visuospatial WM slave systems.
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Lobo Frontal/fisiologia , Memória de Curto Prazo/fisiologia , Rede Nervosa/fisiologia , Recrutamento Neurofisiológico/fisiologia , Percepção Espacial/fisiologia , Aprendizagem Verbal/fisiologia , Adolescente , Adulto , Atenção/fisiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologiaRESUMO
The present study employed event-related fMRI and EEG to investigate the biological basis of the cognitive control of behavior. Using a GO/NOGO task optimized to produce response inhibitions, frequent commission errors, and the opportunity for subsequent behavioral correction, we identified distinct cortical areas associated with each of these specific executive processes. Two cortical systems, one involving right prefrontal and parietal areas and the second regions of the cingulate, underlay inhibitory control. The involvement of these two systems was predicated upon the difficulty or urgency of the inhibition and each was employed to different extents by high- and low-absent-minded subjects. Errors were associated with medial activation incorporating the anterior cingulate and pre-SMA while behavioral alteration subsequent to errors was associated with both the anterior cingulate and the left prefrontal cortex. Furthermore, the EEG data demonstrated that successful response inhibition depended upon the timely activation of cortical areas as predicted by race models of response selection. The results highlight how higher cognitive functions responsible for behavioral control can result from the dynamic interplay of distinct cortical systems.
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Atenção/fisiologia , Córtex Cerebral/fisiologia , Imagem Ecoplanar , Eletroencefalografia , Giro do Cíngulo/fisiologia , Imageamento Tridimensional , Inibição Neural/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Desempenho Psicomotor/fisiologia , Adulto , Mapeamento Encefálico , Córtex Cerebral/anatomia & histologia , Dominância Cerebral/fisiologia , Feminino , Lobo Frontal/anatomia & histologia , Lobo Frontal/fisiologia , Giro do Cíngulo/anatomia & histologia , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Rede Nervosa/anatomia & histologia , Rede Nervosa/fisiologia , Putamen/anatomia & histologia , Putamen/fisiologia , Tempo de Reação/fisiologia , Aprendizagem Seriada/fisiologia , Tálamo/anatomia & histologia , Tálamo/fisiologiaRESUMO
Functional magnetic resonance imaging (fMRI), a still-emerging, non-invasive neuroimaging tool, has been applied to a wide range of questions in sensory, motor control, and cognitive psychology. Only more recently has it been applied to understand the sites and mechanisms of action of pharmacological agents within the human CNS. However, in so doing, a new set of problems and concerns surrounding the technique must be addressed because of the unique transduction mechanisms (both physiological and biophysical) that exist to produce the fMRI signal from the underlying neuronal activity. Experimental design and control issues become paramount in performing fMRI pharmacological protocols and in signal interpretation. With these caveats, the use of pharmacological agents with fMRI is likely to greatly increase in the near term as new questions about both brain physiology and neuropharmacological mechanisms become addressable for the first time. Examples are given using nicotine and cocaine as a prototypical agents.
Assuntos
Mapeamento Encefálico/métodos , Encéfalo/metabolismo , Cocaína/farmacocinética , Imageamento por Ressonância Magnética , Nicotina/farmacocinética , Encéfalo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Distribuição TecidualRESUMO
Human lesion and functional imaging data suggest a central role for the amygdala in the processing of negative stimuli. To determine whether the amygdala's role in affective processing extends beyond negative stimuli, subjects viewed pictures that varied in emotional content (positive vs negative valence) and arousal level (high vs low) while undergoing functional magnetic resonance imaging. Amygdala activation, relative to a low arousal and neutral valence picture baseline, was significantly increased for both positively and negatively valenced stimuli and did not differ for the two valences. There were no laterality effects. Whereas arousal level appeared to modulate the amygdala response for negative stimuli, all positively valenced pictures (both high and low in arousal) produced significant amygdala responses. These results clearly demonstrate a role for the amygdala in processing emotional stimuli that extends beyond negative and fearful stimuli.
Assuntos
Afeto/fisiologia , Tonsila do Cerebelo/fisiologia , Nível de Alerta/fisiologia , Emoções/fisiologia , Estimulação Luminosa/métodos , Adolescente , Adulto , Análise de Variância , Feminino , Humanos , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND AND AIM: Recently, several studies have indicated there may be differences among statins regarding a possible association between therapy and a reduction in risk of fractures. No data from prospective randomised clinical trials designed to assess either biochemical or clinical effects on bone metabolism are yet available. We assayed levels of biochemical markers of bone formation in stored serum samples from a recently completed randomised clinical trial conducted to compare the effects of simvastatin and atorvastatin on the lipid profile of patients with hypercholesterolaemia. METHODS AND RESULTS: This 12-week, randomised, multicenter, open-label study was designed to compare the safety and lipid-lowering efficacy of simvastatin 40 mg or 80 mg with that of atorvastatin 20 mg or 40 mg in 846 hypercholesterolaemic patients. Stored serum samples from this study were analysed to compare the effects of simvastatin and atorvastatin on 2 biomarkers of bone turnover, bone-specific alkaline phosphatase (BSAP), a marker of bone formation, and C-teleopeptide of type 1 collagen (CTx), a marker of bone resorption. Treatment with simvastatin 40 and 80 mg/day, but not atorvastatin 20 and 40 mg/day, led to significant (p < 0.05) reductions in BSAP in both men (4.1-5.4% reduction) and women (4.2-7.4% reduction). In addition, there appeared to be a dose-dependent effect with greater reductions in BSAP seen with the 80 mg dose of simvastatin. Treatment with either 20 mg or 40 mg of atorvastatin had no significant effect on BSAP levels on the groups as a whole or in the gender-specific subgroups. CTx showed a small, but not statistically significant, decrease with simvastatin, again with an apparent dose-related trend. Atorvastatin treatment generally resulted in small, non significant increases in CTx. CONCLUSIONS: The present serum bone biomarker results show that treatment with simvastatin, but not atorvastatin, decreases BSAP and suggest that simvastatin may have a beneficial effect on bone turnover.
Assuntos
Anticolesterolemiantes/farmacologia , Osso e Ossos/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Hipercolesterolemia/tratamento farmacológico , Pirróis/farmacologia , Sinvastatina/farmacologia , Adulto , Idoso , Fosfatase Alcalina/sangue , Anticolesterolemiantes/uso terapêutico , Atorvastatina , Biomarcadores/sangue , Desenvolvimento Ósseo/efeitos dos fármacos , Reabsorção Óssea , Osso e Ossos/enzimologia , Osso e Ossos/metabolismo , Colágeno/sangue , Colágeno Tipo I , Relação Dose-Resposta a Droga , Feminino , Ácidos Heptanoicos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/sangue , Pirróis/uso terapêutico , Sinvastatina/uso terapêuticoRESUMO
Many properties of nitric oxide, NO, (localization, diffusiveness, half-life, vasodilatory affects) have supported its potential role in mediating the link between local cerebral activity and blood flow. However, evidence that both supports and refutes a role for NO in functional hyperemia have been presented. The present study employed multiple nitric oxide synthase inhibitors, two anesthetic regimes and laser-Doppler flowmetry to test the hypothesis that NO is critically involved in mediating the functional hyperemic response within rodent whisker-barrel cortex (WBC). In urethane anesthetized animals, functional hyperemic responses were obtained both before and after 1 mg/kg atropine infusion, 30 mg/kg i.v. L-NAME (N-Nitro-L-arginine methylester) infusion, 30 mg/kg L-NA (N-Nitro-L-arginine) infusion or 25 mg/kg 7-NI (7-nitroindazole). L-NAME was also tested in a group of animals pretreated with halothane before urethane anesthesia. Neither the magnitude of the blood flow response nor its time course was altered by NO blockade or atropine administration when compared to pre-infusion controls in urethane anesthetized rats. In contrast, animals that were pretreated with halothane exhibited a 33% inhibition of functional hyperemia after L-NAME administration. Taken together, these data do not support a primary role for NO in rat WBC functional hyperemia and suggest that previous reports of inhibition may have been secondary to the anesthesia employed.
Assuntos
Anestesia Geral , Anestésicos Inalatórios/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Halotano/farmacologia , Hiperemia/fisiopatologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Óxido Nítrico/fisiologia , Córtex Somatossensorial/irrigação sanguínea , Tato/fisiologia , Vibrissas/inervação , Anestésicos Intravenosos/farmacologia , Animais , Atropina/farmacologia , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Masculino , Antagonistas Muscarínicos/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroarginina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/efeitos dos fármacos , Uretana/farmacologia , VasodilataçãoRESUMO
Clinical trial data are now sufficient to support aggressive treatment of dyslipidemia. Cholesterol-lowering therapy is known to reduce the risk of clinical events across a wide range of lipid levels, even in patients with "normal" levels. Current data support lowering low-density lipoprotein cholesterol (LDL-C) levels at least to those recommended by the National Cholesterol Education Program, but perhaps even more aggressively in some patients. Of the available cholesterol-lowering agents, statins produce the greatest reductions in LDL-C levels and coronary events and are currently the best treatment option for most patients.
Assuntos
Doença das Coronárias/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , LDL-Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/fisiopatologia , Endotélio Vascular/fisiopatologia , Humanos , Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fatores de RiscoRESUMO
SCH 48461, an inhibitor of gastrointestinal absorption of cholesterol, was evaluated for its effects on lipid parameters in patients with primary hypercholesterolemia in a multicenter, double-blind, randomized, parallel-group study. Following the baseline phase, which consisted of a 2- to 10-week drug washout and dietary stabilization phase and a 4-week placebo lead-in (placebo baseline phase), 190 patients were randomized to an 8-week double-blind active drug (SCH 48461 1, 6.25, 25, 100, 200, or 400 mg) or 40 mg lovastatin once daily each morning or placebo treatment phase. By week 2, patients who received SCH 48461 6.25 to 400 mg or lovastatin demonstrated greater reduction from baseline in directly measured low-density lipoprotein cholesterol (LDL-C) levels than patients in the placebo group (p < or = 0.03). Overall, the percent reductions in LDL-C from baseline increased as the dose of SCH 48461 increased, with 0.6% to 15.5% reductions from the minimum dose of 1 mg to the maximum dose of 400 mg. Lovastatin 40 mg/day reduced LDL-C by 30.7% (p < 0.01). Statistically significant decreases were also seen for total cholesterol and apolipoprotein B (apo B) with doses of 25 mg to 400 mg of SCH 48461 and lovastatin. SCH 48461 was well tolerated. There was a similar incidence of adverse events in each SCH 48461- or lovastatin-treated group compared to placebo. This study demonstrated a clinically and statistically significant cholesterol-lowering effect of SCH 48461 in patients with primary hypercholesterolemia.
Assuntos
Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , LDL-Colesterol/sangue , Hipercolesterolemia/tratamento farmacológico , Anticolesterolemiantes/efeitos adversos , Apolipoproteína A-I/sangue , Azetidinas/efeitos adversos , HDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Hipercolesterolemia/sangue , Lovastatina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Placebos , Triglicerídeos/sangueRESUMO
The need for greater reductions in LDL cholesterol, although remaining to be proven as clinically beneficial, continues to drive the development of either higher doses of currently approved and marketed statins or the development of new, more effective agents.
Assuntos
Hipolipemiantes/administração & dosagem , Pirimidinas , Sulfonamidas , Atorvastatina , LDL-Colesterol/metabolismo , Relação Dose-Resposta a Droga , Ácidos Graxos Monoinsaturados/administração & dosagem , Fluorbenzenos/administração & dosagem , Fluvastatina , Ácidos Heptanoicos/administração & dosagem , Humanos , Indóis/administração & dosagem , Lovastatina/administração & dosagem , Pravastatina/administração & dosagem , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Rosuvastatina Cálcica , Sinvastatina/administração & dosagemRESUMO
There is now ample evidence to demonstrate that atherosclerosis begins in childhood and is significantly accelerated in certain genetic disorders, most notably familial hypercholesterolemia (FH). Untreated FH, both the homozygous and heterozygous forms, carry a substantial burden of morbidity and mortality if left untreated or inadequately treated. Males with FH are at earlier and greater risk than females and thus should begin therapy earlier, preferably at about 10. While bile acid sequestrants have long been considered the drug of choice in children, they have never been approved for pediatric use by FDA, are poorly tolerated, marginally effective at lowering low-density lipoprotein cholesterol and have minimal well controlled studies in children upon which to adequately assess safety. Over the last decade statins have been studied extensively in children and adolescents, although many of these studies have also been poorly controlled, of short duration, too small and lack detailed assessment. However there has been at least one large, randomized, placebo-controlled and comprehensive study with lovastatin in adolescent males that indicated efficacy similar to that anticipated in adults and no apparent safety concerns. While additional well-controlled studies are needed, especially those focusing on surrogates of atherosclerosis to determine clinical benefit, it is opportune for re-evaluation of current treatment guidelines.