共查询到20条相似文献,搜索用时 718 毫秒
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Camilla Niva Joanna Parkinson Fredrik Olsson Erno van Schaick Johan Lundkvist Sandra A. G. Visser 《European journal of clinical pharmacology》2013,69(6):1247-1260
Purpose
To date, γ-secretase inhibition is the most frequently studied mechanism of reducing Aβ in clinical trials with as yet no therapeutic success for AD patients, as measured by the slowing down of cognitive decline or an improvement in cognitive function. The aims of this investigation were to evaluate whether the amyloid hypothesis has been tested clinically, and to explore whether preclinical data are predictive of clinical Aβ effects.Methods
A model-based-meta analysis on Aβ levels and drug exposure over time was performed on published and in-house (pre-)clinical data with γ-secretase inhibitors (GSIs; semagacestat, avagacestat, begacestat, PF-3074014, and MK0752).Results
The clinical data available did not show any significant or robust reduction of CNS Aβ over time at dose levels intended for AD patients. In contrast, these doses resulted in an average increase in plasma Aβ levels over a 24-h interval. A general agreement between preclinical and clinical data was found and allowed for interspecies extrapolations.Conclusions
More substantially, CNS Aβ-lowering drugs are needed to test whether inhibition of Aβ production is efficacious in mild AD. Predictions based on preclinical data could assist in the selection of drug candidates and trial design. 相似文献4.
Yue Qiu Liang Li Tian-yan Zhou Wei Lu Alzheimer's Disease Neuroimaging Initiative 《Acta pharmacologica Sinica》2014,35(9):1111-1120
Aim:
Biomarkers and image markers of Alzheimer''s disease (AD), such as cerebrospinal fluid Aβ42 and p-tau, are effective predictors of cognitive decline or dementia. The aim of this study was to integrate these markers with a disease progression model and to identify their abnormal ranges.Methods:
The data of 395 participants, including 86 normal subjects, 108 early mild cognitive impairment (EMCI) subjects, 120 late mild cognitive impairment (LMCI) subjects, and 81 AD subjects were obtained from the Alzheimer''s Disease Neuroimaging Initiative (ADNI) database. For the participants, baseline and long-term data on cerebrospinal fluid Aβ42 and p-tau, hippocampal volume, and ADAS-cog were available. Various linear and nonlinear models were tested to determine the associations among the ratio of Aβ42 to p-tau (the Ratio), hippocampal volume and ADAS-cog.Results:
The most likely models for the Ratio, hippocampal volume, and ADAS-cog (logistic, Emax, and linear models, respectively) were used to construct the final model. Baseline disease state had an impact on all the 3 endpoints (the Ratio, hippocampal volume, and ADAS-cog), while APOEε4 genotype and age only influence the Ratio and hippocampal volume.Conclusion:
The Ratio can be used to identify the disease stage for an individual, and clinical measures integrated with the Ratio improve the accuracy of mild cognitive impairment (MCI) to AD conversion forecasting. 相似文献5.
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Gianluca Trifirò Silvia Tillati Edoardo Spina Carmen Ferrajolo Marianna Alacqua Eugenio Aguglia Laura Rizzi Achille P. Caputi Claudio Cricelli Fabio Samani 《European journal of clinical pharmacology》2013,69(2):227-236
Purpose
Our purpose was to explore antidepressant drug (AD) prescribing patterns in Italian primary care.Methods
Overall, 276 Italian general practitioners (GPs) participated in this prospective study, recruiting patients >18 years who started AD therapy during the enrolment period (January 2007 to June 2008). During visits at baseline and 3, 6, and 12 months, data about patients’ characteristics and AD treatments were collected by the GPs. Discontinuation rate among new users of AD classes [i.e., selective serotonin reuptake inhibitors (SSRI); tricyclics (TCAs); other ADs) were compared. Logistic regression analyses were performed to identify predictors of AD discontinuation.Results
SSRIs were the most frequently prescribed ADs (N?=?1,037; 75.3 %), especially paroxetine and escitalopram. SSRIs were more likely to be prescribed because of depressive disorders (80 %), and by GPs (51.1 %) rather than psychiatrists (31.8 %). Overall, 27.5 % (N?=?378) of AD users discontinued therapy during the first year, mostly in the first 3 months (N?=?242; 17.6 %), whereas 185 (13.4 %) were lost to follow-up. SSRI users showed the highest discontinuation rate (29 %). In patients with depressive disorders, younger age, psychiatrist-based diagnosis, and treatment started by GPs were independent predictors of SSRI discontinuation.Conclusions
In Italy, ADs—especially SSRIs—are widely prescribed by GPs because of depressive/anxiety disorders. Active monitoring of AD users in general practice might reduce the AD discontinuation rate. 相似文献7.
Gabriel J. Mazur Gabriel Wood-Isenberg Elizabeth Watterson Federico Sanabria 《Psychopharmacology》2014,231(12):2471-2482
Rationale
Attention-deficit hyperactivity disorder (ADHD) is associated with a higher prevalence of smoking, which may be related to potential therapeutic effects of nicotine on ADHD symptoms. Whereas nicotine offers robust improvements in sustained attention, the effects of nicotine on impulsivity are unclear.Objectives
The present study examined the effects of nicotine on the response inhibition capacity of spontaneously hypertensive rats (SHR), an animal model of ADHD, compared to that of a normotensive control Wistar Kyoto (WKY), using the fixed minimum interval (FMI) schedule of reinforcement.Methods
Tests were conducted following acute injections of subcutaneous nicotine (0.1–0.6 mg/kg). On each FMI trial, the first lever press initiated an inter-response time (IRT); a head entry into a food receptacle terminated the IRT. IRTs longer than 6 s were intermittently reinforced with sucrose.Results
A model that assumes that only a proportion of IRTs are sensitive to the timing contingencies of the FMI provided a close fit to the data, regardless of strain or treatment. No baseline difference in FMI performance was observed between SHR and WKY. Nicotine reduced the duration of timed IRTs and the duration of latencies to the IRT-initiating lever press similarly for both strains. Nicotine dose-dependently increased the proportion of timed IRTs; the dose-response curve was shifted leftwards in SHR relative to WKY.Conclusions
These results suggest that nicotine (a) reduces response-inhibition capacity, (b) enhances the reinforcing efficacy of sucrose, and (c) dose-dependently enhances attention-like sensitivity to contingencies of reinforcement, through mechanisms that are yet unknown. 相似文献8.
Purpose
To develop a mechanism based translational pharmacokinetic-pharmacodynamic (PKPD) model in preclinical species and to predict the intraocular pressure (IOP) following drug treatment in patients with glaucoma or ocular hypertension (OHT).Methods
Baseline diurnal IOP of normotensive albino rabbits, beagle dogs and patients with glaucoma or OHT was collected from literature. In addition, diurnal IOP of patients treated with brimonidine or Xalatan® were also obtained from literature. Healthy normotensive New Zealand rabbits were topically treated with a single drop of 0.15% brimonidine tartrate and normotensive beagle dogs were treated with a single drop of Xalatan®. At pre-determined time intervals, IOP was measured and aqueous humor samples were obtained from a satellite group of animals. Population based PKPD modeling was performed to describe the IOP data and the chosen model was extended to predict the IOP in patients.Results
Baseline IOP clearly depicts a distinctive circadian rhythm in rabbits versus human. An aqueous humor dynamics based physiological model was developed to describe the baseline diurnal IOP across species. Model was extended to incorporate the effect of drug administration on baseline IOP in rabbits and dogs. The translational model with substituted human aqueous humor dynamic parameters predicted IOP in patients following drug treatment.Conclusions
A physiology based mechanistic PKPD model was developed to describe the baseline and post-treatment IOP in animals. The preclinical PKPD model was successfully translated to predict IOP in patients with glaucoma or OHT and can be applied in assisting dose and treatment selection and predicting outcome of glaucoma clinical trials. 相似文献9.
Rationale
It has previously been shown that impairment of postural stability is a side effect of typical antipsychotic drugs, which are largely administered to control psychosis and behavioral symptoms in elderly patients. Surprisingly, no study has yet addressed this problem with second-generation antipsychotics.Objective
The objective of this study was to determine the extent to which risperidone at low doses altered balance control in healthy participants.Methods
Twelve healthy young adults received, following a randomized double-blind crossover design, a single oral dose of placebo, 1 and 3?mg of risperidone on separate days at least 14?days apart. Evaluation of extrapyramidal symptoms using the Extrapyramidal Symptom Rating Scale-abbreviated scoring form (ESRS-A) and measures of postural sway using a force platform were assessed over 9?h following drug ingestion.Results
There is a significant increase in the postural stability item of the ESRS-A parkinsonism subscale at 3 and 6?h following 3?mg of risperidone only when compared to placebo. With regard to balance control, body sway measures were increased at 1?mg of risperidone but more pronounced at 3?mg. The peak effects were observed at 3?h after administration of the drug and had not completely returned to baseline after 9?h.Conclusions
Risperidone administered at low doses did not elicit clinically detectable EPS but had significant effects on balance control. A dose?Cresponse effect on impairment of balance was observed that followed the expected time course of the drug pharmacokinetics. These results are likely to apply to older or demented individuals who have pre-existing balance control deficit. 相似文献10.
Wang X Shang D Ribbing J Ren Y Deng C Zhou T Guo F Lu W 《European journal of clinical pharmacology》2012,68(8):1157-1166
Objective
Our objective was to describe the time course of the placebo effect in asthma and quantitatively investigate the affective factors of the placebo effect for the placebo response simulation during the asthma clinical study design.Methods
We conducted a systemic search of public data sources for the study-level forced expiratory volume in 1 second (FEV1) to build the placebo effect model for studies by oral or inhaled administrations simultaneously. The administration routes, types of inhalation device, mean patient age, mean male proportion, baseline FEV1, disease severity, year of publication, inhaled corticosteroid status during the treatment, and dropout rate were tested as covariates.Results
There are 34 literature sources containing 178 mean values for FEV1 presenting the individual observations from about 3,703 patients. The exponential models adequately described the time course of placebo effect with the typical value of the maximum placebo effect (Pmax) of 0.060?L. Dropout rate incorporated in the residual error model and the disease severity (mild to moderate and moderate to severe) at baseline were covariates that remained in the final model.Conclusions
The placebo effect is adequately described by an exponential model over time. By incorporating the dropout rate in the residual error model, the estimation precision was improved. The model could predict the placebo response profile in mild to severe asthmatic patients for the asthma clinical study design and could also be a structure model of the placebo effect for the pure drug effect evaluation in the asthma clinical trials. 相似文献11.
Mitchell K. P. Lai Shirley W. Tsang Margaret M. Esiri Paul T. Francis Peter T.-H. Wong Christopher P. Chen 《Psychopharmacology》2011,213(2-3):431-439
Rationale
Previous studies have shown extensive serotonergic deficits in the hippocampus of Alzheimer??s disease (AD) patients. However, it is unclear whether such deficits play a role in non-cognitive, neuropsychiatric behaviors that occur frequently in AD and cause significant caregiver distress.Objectives
In this study, we aimed to correlate serotonergic markers in the AD hippocampus with neuropsychiatric behaviors.Methods
Using postmortem hippocampal homogenates from aged controls as well as a cohort of longitudinally assessed AD patients, measurements of 5-HT1A receptors, 5-HT2A receptors, and serotonin re-uptake (5-HTT) sites were performed by binding with 3H-labeled 8-OH-DPAT, ketanserin, and citalopram, respectively.Results
Alterations of 5-HT1A receptors and 5-HTT were found to be differentially involved in neuropsychiatric behaviors, with loss of 5-HT1A receptors specifically correlated with depressive symptoms, while 5-HTT sites were preserved or up-regulated in patients with aggressive behaviors.Conclusions
Our data suggest that neuropsychiatric behaviors in AD share certain neurochemical features with psychiatric disorders like major depression and that serotonergic drugs used in psychiatric disorders may also be efficacious against behavioral symptoms in AD. 相似文献12.
Shahin Akhondzadeh Mehdi Shafiee Sabet Mohammad Hossein Harirchian Mansoreh Togha Hamed Cheraghmakani Soodeh Razeghi Seyyed Shamssedin Hejazi Mohammad Hossein Yousefi Roozbeh Alimardani Amirhossein Jamshidi Shams-Ali Rezazadeh Aboulghasem Yousefi Farhad Zare Atbin Moradi Ardalan Vossoughi 《Psychopharmacology》2010,207(4):637-643
Rationale
There is increasing evidence to suggest the possible efficacy of Crocus sativus (saffron) in the management of Alzheimer’s disease (AD).Objective
The purpose of the present investigation was to assess the efficacy of C. sativus in the treatment of patients with mild-to-moderate AD.Methods
Fifty-four Persian-speaking adults 55 years of age or older who were living in the community were eligible to participate in a 22-week, double-blind study of parallel groups of patients with AD. The main efficacy measures were the change in the Alzheimer’s Disease Assessment Scale—cognitive subscale and Clinical Dementia Rating Scale—Sums of Boxes scores compared with baseline. Adverse events (AEs) were systematically recorded. Participants were randomly assigned to receive a capsule saffron 30 mg/day (15 mg twice per day) or donepezil 10 mg/day (5 mg twice per day).Results
Saffron at this dose was found to be effective similar to donepezil in the treatment of mild-to-moderate AD after 22 weeks. The frequency of AEs was similar between saffron extract and donepezil groups with the exception of vomiting, which occurred significantly more frequently in the donepezil group.Conclusion
This phase II study provides preliminary evidence of a possible therapeutic effect of saffron extract in the treatment of patients with mild-to-moderate Alzheimer’s disease. This trial is registered with the Iranian Clinical Trials Registry (IRCT138711051556N1). 相似文献13.
Kun Ma Ying Zhang Hongliang Kan Linfeng Cheng Ling Luo Qing Su Jing Gao Yuan Gao Jianjun Zhang 《Pharmaceutical research》2014,31(7):1766-1778
Purpose
The aim of this study was to perform a thermodynamic and kinetic investigation on the crucial factors affecting the cocrystallization between adefovir dipivoxil (AD) and saccharin (SAC).Methods
Phase solubility diagrams and ternary phase diagrams were constructed based on the solubility data of AD, SAC and their cocrystals in ethanol, isopropanol and ethyl acetate at different temperatures. The conductimetric method was used to determine the induction time. A quantitative and intuitive technique modified from dissolution testing was employed to investigate the cocrystallization kinetics.Results
AD-SAC cocrystals exhibited different crystal habits but only one cocrystal polymorph was confirmed. The effects of several crucial factors, including the input amounts of two components, AD/SAC ratio, solvent and temperature, on the crystallization of single-component alone, cocrystal formation, cocrystal stability, supersaturation, nucleation, crystal growth and cocrystal yield were determined. Thermodynamic and kinetic parameters provided the rationale for this spontaneous cocrystallization system without the need of solvent evaporation and temperature change.Conclusions
This systemic investigation enriched the present understanding of thermodynamics and kinetics of cocrystals and built the groundwork for AD-SAC cocrystal scale-up. 相似文献14.
M. Köster R. Grohmann R. R. Engel M. A. Nitsche E. Rüther D. Degner 《Psychopharmacology》2013,230(2):191-201
Rationale
There is little clinical data available about seizure rates in psychiatric inpatients, and there are no studies with reference data to the frequencies of antidepressant (AD) use for this important clinical population.Objective
This study investigates seizure rates during AD treatment in psychiatric inpatient settings, drawn from the transnational pharmacovigilance programme Arzneimittelsicherheit in der Psychiatrie (AMSP) in relation to the known frequencies of ADs used in the participating clinics. Comparisons are made to former publications and their limitations.Results
Seventy-seven cases were identified with grand mal seizures (GMS) during AD treatment between 1993 and 2008, with a total number of 142,090 inpatients under surveillance treated with ADs in the participating hospitals. The calculated overall rate of reported seizures of patients during AD treatment in this collective is 0.05 % for ADs imputed alone or in combination with other psychotropic drug groups and 0.02 % when only ADs were given and held responsible for GMS. The patients receiving tri- or tetracyclic ADs (TCAs) had a 2-fold risk to develop a seizure as compared to the overall average rate in this sample. In 11 cases, there was only one AD imputed—the majority of these cases (9/11) were TCA. Monotherapy with selective serotonin reuptake inhibitors (SSRI) or dual serotonin and noradrenaline reuptake inhibitors (SNRI) were never imputed alone in this sample.Conclusions
The results of the study favour the assumption that SSRIs, noradrenergic and specific serotonergic antidepressants (NaSSA) and dual SNRI might be more appropriate than TCAs for the treatment of psychiatric patients with an enhanced seizure risk. 相似文献15.
Smith WB Marbury TC Komjathy SF Sumeray MS Williams GC Hu MY Mould DR 《European journal of clinical pharmacology》2012,68(10):1385-1394
Purpose
Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion.Method
Doses of 2, 4, 8, or 16.0?mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0?mg/h and force-titrated in doubling increments every 3?min to target dose, then maintained for 72?h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8?h after termination of infusion, although oral therapy could be restarted at 4?h. Clevidipine blood levels were obtained during infusion and for 1?hour after termination.Results
Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6?h after termination of the clevidipine infusion. At 8?h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8?h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline.Conclusion
This study supports the use of up to 72?h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated. 相似文献16.
Purpose
To develop a model-based approach for interspecies scaling of the preclinical pharmacokinetics of exenatide and to predict concentration-time profiles in humans.Methods
A target-mediated drug disposition (TMDD) model was simultaneously fit to concentration-time profiles of exenatide over a wide range of intravenous (IV) and subcutaneous (SC) doses obtained from mice, rats, and monkeys. Allometric relationships were incorporated into the model to scale parameters based on species body weight. Human pharmacokinetic profiles following IV and SC administration were simulated using the final model structure and parameter estimates and compared to clinical data.Results
The final model provided a good simultaneous fit to all animal data and reasonable parameter estimates. Exenatide receptor binding affinity and baseline receptor concentrations were species-dependent. Absorption parameters from rat provided the best prediction of exenatide SC absorption in humans, but good predictions could also be obtained using allometric scaling of preclinical absorption parameters.Conclusions
A TMDD model combined with allometric scaling was successfully used to simultaneously describe preclinical data for exenatide from three animal species following both IV and SC administration. The majority of model parameters could be shared among the animal species and further used for projecting exenatide behavior in humans. 相似文献17.
Martine R. van Schouwenburg Marcel P. Zwiers Marieke E. van der Schaaf Dirk E. M. Geurts Arnt F. A. Schellekens Jan K. Buitelaar Robbert J. Verkes Roshan Cools 《Psychopharmacology》2013,227(3):521-531
Rationale
The neurotransmitter dopamine plays a key role in cognitive functions that are associated with fronto-striatal circuitry and has been implicated in many neuropsychiatric disorders. However, there is a large variability in the direction and extent of dopaminergic drug effects across individuals.Objectives
We investigated whether individual differences in dopaminergic drug effects on human fronto-striatal functioning are associated with individual differences in white matter tracts.Methods
The effects of the dopamine receptor agonist bromocriptine were assessed using functional magnetic resonance imaging in 22 healthy volunteers in a placebo-controlled, double-blind, within-subject design. Human psychopharmacology and functional neuroimaging were combined with functional connectivity analyses and structural connectivity analyses to establish a link between dopaminergic drug effects on fronto-striatal function and fronto-striatal anatomy.Results
We demonstrate that bromocriptine alters functional signals associated with attention switching in the basal ganglia. Crucially, individual differences in the drug’s effect on these signals could be predicted from individual differences in fronto-striato-thalamic white matter tracts, as indexed by diffusion tensor imaging. Anatomical fronto-striatal connectivity also predicted drug effects on switch-related functional connectivity between the basal ganglia and the prefrontal cortex.Conclusions
These data reinforce the link between dopamine, cognition and the basal ganglia and have implications for the individual tailoring of dopaminergic drug therapy based on anatomical fronto-striatal connection strength. 相似文献18.
Rationale
To date, there is no medication specifically approved for cocaine addiction. Agonist medications are used clinically in the treatment of other addictions, which suggests that this method of drug therapy could potentially be successful in treating cocaine addiction as well.Objective
The objective of this study was to determine the effect of extended d-amphetamine treatment on responding on a progressive ratio (PR) schedule reinforced by cocaine.Materials and methods
Rats were trained to self-administer cocaine (0.19, 0.38, 0.75, or 1.5 mg/kg/injection) or food on a PR schedule. After stable baseline breakpoints (the number of reinforcers earned in one session) were established over 3 days, animals were implanted with osmotic mini-pumps that continuously delivered d-amphetamine (5 mg/kg/day) for a duration of either 7 or 14 days. Breakpoints were then determined during and/or after this treatment period.Results
Rats demonstrated dose-dependent decreases in cocaine-reinforced responding over the d-amphetamine treatment period. Breakpoints for doses of 0.75 mg/kg/injection and below decreased significantly when compared to baseline and remained decreased for up to 14 days after mini-pump removal, whereas those for the highest dose of cocaine remained unchanged. Additionally, d-amphetamine treatment during a 14-day abstinence period from cocaine self-administration had no effect on breakpoints when tested the day after mini-pump removal.Conclusions
These data suggest that the reduction in cocaine-reinforced responding after continuous d-amphetamine treatment cannot be accounted for by tolerance alone. Instead, the roles of learning and the interaction between cocaine and d-amphetamine must be considered and examined in future studies. 相似文献19.
Follmann, Brittain, and Powers in 2013 proposed a method for demonstrating efficacy in the context of noninferiority trials of anti-infective drugs by identifying a subset of the population where the new drug is superior to the active control drug. Minimum inhibitory concentration, a pharmacometric value based on a drug’s test tube performance on a patient’s baseline sample (e.g., blood, sputum, etc.), predicts clinical efficacy in that patient for that drug. Using these predictions, the superiority test focused on patients with both high predicted efficacy to the new drug and low predicted efficacy to the control drug. Simulations indicated this can be a powerful approach to demonstrate efficacy. We now apply this strategy to analyze three datasets submitted to the FDA. We incorporated enhancements: (i) another pharmacometric measure, area under the curve of drug concentration, to improve outcome prediction, (ii) different tests, and (iii) analogous analyses based on the pharmacometric parameter in the active control drug alone. Superiority for some patient subset was shown in two of the three datasets. This superiority testing approach can eliminate the need for historical data about the magnitude of the active control drug's benefit, guide drug selection for individual patients, develop drug resistance thresholds, and validate assay sensitivity. 相似文献
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Chase H. Bourke Catherine F. Capello Swati M. Rogers Megan L. Yu Katherine A. Boss-Williams Jay M. Weiss Zachary N. Stowe Michael J. Owens 《Psychopharmacology》2013,227(2):231-241