Comparative pharmacokinetics of vinblastine after a 96-hour continuous infusion in wild-type mice and mice lacking mdr1a P-glycoprotein

To determine the tissue-specific impact of P-glycoprotein on the accumulation of a substrate drug, we have studied the tissue distribution of vinblastine in mdr1a(-/-) and wild-type mice at approximately similar, relatively low plasma levels. Vinblastine was administered as a 96-h continuous infusion at dose rates of 1 to 10 microgram/h, which were delivered by a s.c.-implanted osmotic pump. Drug concentrations were determined in plasma and tissues by HPLC. In comparison to wild-type mice, 4.4- to 9.6-fold higher drug concentrations were observed in the brains of mdr1a(-/-) mice (p 相似文献   

Role of blood-brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally acting analgaesic drug.

Studies with knockout mice lacking mdr1a P-glycoprotein (P-gp) have previously shown that blood-brain barrier P-gp is important in preventing the accumulation of several drugs in the brain. Asimadoline (EMD 61753) is a peripherally selective kappa-opioid receptor agonist which is under development as a therapeutic analgaesic. From the structural characteristics of this drug and its peripheral selectivity, we hypothesized that it is transported by P-gp. Using a pig-kidney polarized epithelial cell line transfected with mdr cDNAs, we demonstrate that asimadoline is transported by the mouse mdr1a P-gp and the human MDR1 P-gp. Furthermore, we show that in mdr1a/1b double knockout mice, the absence of P-gp leads to a 9 fold increased accumulation of asimadoline in the brain. In line with this accumulation difference, mdr1a/1b (-/-) mice are at least 8 fold more sensitive to the sedative effect of asimadoline than wild-type mice. Interestingly, the oral uptake of asimadoline was not substantially altered in mdr1a/1b (-/-) mice. Our results demonstrate that for some drugs, P-gp in the blood-brain barrier can have a therapeutically beneficial effect by limiting brain penetration, whereas at the same time intestinal P-gp is not a significant impediment to oral uptake of the drug.     

P-Glycoprotein, a gatekeeper in the blood-brain barrier

The blood-brain barrier is a major impediment to the entry of many therapeutic drugs into the brain. P-Glycoprotein is an ATP-dependent drug transport protein that is predominantly found in the apical membranes of a number of epithelial cell types in the body, including the blood luminal membrane of the brain capillary endothelial cells that make up the blood-brain barrier. Since P-glycoprotein can actively transport a huge variety of hydrophobic amphipathic drugs out of the cell, it was hypothesized that it might be responsible for the very poor penetration of many relatively large (>400 Da) hydrophobic drugs in the brain, by performing active back-transport of these drugs to the blood. Extensive experiments with in vitro models and with knockout mice lacking blood-brain barrier P-glycoprotein or other animal models treated with blockers of P-glycoprotein have fully confirmed this hypothesis. Absence of functional P-glycoprotein in the blood-brain barrier leads to highly increased brain penetration of a number of important drugs. Depending on the pharmacological target of these drugs in the central nervous system (CNS), this can result in dramatically increased neurotoxicity, or fundamentally altered pharmacological effects of the drug. Given the variety of drugs affected by P-glycoprotein transport, it may be of tremendous therapeutic value to apply these insights to the development of drugs that should have either very poor or very good brain penetration, whichever is preferred for pharmacotherapeutic purposes. The clinical application of P-glycoprotein blockers should also be considered in order to improve the blood-brain barrier permeability of certain drugs that currently display insufficient brain penetration for effective therapy.     

Are GP patients’ needs being met? Unfulfilled information needs among native-Dutch and Turkish-Dutch patients

Objective

This study aims to assess unfulfilled information needs of native-Dutch and Turkish-Dutch general practitioner (GP) patients in the Netherlands. In addition, the relation between perceived and recorded information provision by GPs is studied.

Methods

Unfulfilled information needs of native-Dutch (N = 117) and Turkish-Dutch patients (N = 74) were assessed through pre- and post-consultation questionnaires. Audiotapes of GP consultations were made to code GPs’ information provision.

Results

Turkish-Dutch patients experience more unfulfilled information needs than native-Dutch patients, in particular those who identify equally with Dutch and Turkish culture. Overall, perceived information provision is hardly related to recorded information provision.

Conclusion

GPs insufficiently provide Turkish-Dutch patients and, to a lesser extent, native-Dutch patients as well, the information they need.

Practice implications

GPs should be trained in giving adequate, tailored information to patients with various ethnic and cultural backgrounds.     

Seven-year follow-up after dobutamine stress echocardiography: impact of gender on prognosis

OBJECTIVES: The aim of this study was to investigate the effects of gender on long-term prognosis of patients undergoing dobutamine stress echocardiography (DSE). BACKGROUND: Gender differences in the predictors of outcome among patients with known or suspected coronary artery disease undergoing DSE have not been adequately studied. METHODS: We studied 2,276 men and 1,105 women with known or suspected coronary artery disease who underwent DSE. Follow-up events were cardiac death and nonfatal myocardial infarction (MI). RESULTS: Dobutamine stress echocardiography was normal in 687 men (30%) and 483 women (44%) (p <0.0001). Ischemia on DSE was present in 1,194 men (52%) and 416 women (38%) (p <0.001). During a mean follow-up of 7 +/- 3.4 years, there were 894 (26%) deaths (442 attributed to cardiac causes) and 145 (4%) nonfatal MIs. The annual cardiac event rate was 2.5% in men and 1.2% in women with normal DSE. Independent predictors of cardiac events in patients with normal DSE using a Cox proportional hazards regression analysis were male gender (hazard ratio [HR]: 1.7 [range 1.1 to 2.8]), age (HR: 1.02 [range 1.01 to 1.04]), history of heart failure (HR: 3.4 [range 1.5 to 7.9]), previous MI (HR: 1.7 [range 1.1 to 2.8]), and diabetes (HR: 2.4 [range 1.3 to 4.5]). Independent predictors of cardiac events in patients with an abnormal DSE were age (HR: 1.03 [range 1.02 to 1.04]), history of heart failure (HR: 1.7 [range 1.3 to 2.1]), diabetes (HR: 1.4 [range 1.1 to 1.8]), heart rate at rest (HR: 2.8 [range 1.4 to 5.8]), wall motion abnormalities at rest (HR: 1.06 [range 1.04 to 1.09]), and ischemia on DSE (HR: 1.04 [range 1.02 to 1.07]). Myocardial ischemia was an independent predictor of cardiac events in both men and women. CONCLUSIONS: Dobutamine stress echocardiography provides independent prognostic information in both men and women. In patients with normal DSE, gender is independently associated with cardiac events. The outcome of patients with abnormal DSE is not related to gender, after adjusting for stress echocardiographic abnormalities.     

Does resting two-dimensional echocardiography identify patients with ischemic cardiomyopathy and low likelihood of functional recovery after coronary revascularization?

OBJECTIVE: To evaluate the potential of a simple and widely available technique as two-dimensional (2D) echocardiography to identify patients with ischemic cardiomyopathy and low likelihood of functional recovery after coronary revascularization. METHODS: Two-dimensional echocardiography and radionuclide ventriculography (RNV) were performed before coronary revascularization in 94 patients with ischemic cardiomyopathy. Left ventricular ejection fraction (LVEF) was measured by RNV. Regional wall motion abnormalities, wall motion score index, end-diastolic wall thickness (EDWT), left ventricular (LV) volumes and LV sphericity index were assessed in the echocardiographic images. RNV was repeated 9-12 months after revascularization to assess LVEF change; an improvement >or=5% was considered clinically significant. RESULTS: Nine hundred and ninety-nine segments were severely dysfunctional; 149 out of 999 (15%) had an EDWT or=100 ml/ml) and of the end-systolic volume index (>or=80 ml) was present in 32 (34%) and 21 (22%) patients, respectively. A spherical shape of the LV was observed in 35 (37%) patients. LVEF after revascularization increased in 30 out of 94 patients (32%) from 30+/-8% to 39+/-9% (P<0.0001). On multivariate analysis, the EDVI was the only predictor of no recovery in LVEF [odds ratio, 1.06, confidence interval (CI), 1.04-1.1, P<0.0001]. The cut-off value of EDVI >or=90 ml/ml accurately identified patients that virtually never recover. Post-operatively, LVEF increased in three out of 42 (7%, 95% CI 0-15%) patients with EDVI >or=90 ml/ml as compared to 27 out of 52 (52%) patients with EDVI<90 ml/ml (P<0.0001). CONCLUSIONS: In patients with ischemic cardiomyopathy and severe LV enlargement, improvement of LVEF after revascularization is unlikely to occur. Conversely, in patients with relatively preserved LV size, a higher likelihood of functional recovery may be anticipated.     

Safety of dobutamine stress echocardiography in patients with aortic stenosis

BACKGROUND AND AIM OF THE STUDY: Aortic valve disease is becoming one of the most important cardiac diseases in western society. Low-dose dobutamine stress echocardiography (DSE) is recommended in patients with low-gradient aortic stenosis (AS) and severe left ventricular (LV) dysfunction. DSE is also used in patients with AS and moderately reduced or normal LV function for diagnostic purposes. The study aim was to assess the safety of DSE in the setting of AS and various degrees of LV dysfunction. METHODS: A total of 75 patients with AS who underwent DSE at the authors' center between 1997 and 2001 was reviewed. Group A patients (n = 20) had severely reduced mean LV ejection fraction (LVEF) of 25 +/- 6% and underwent low-dose DSE; group B patients (n = 55) had moderate to normal LV function (LVEF 51 +/- 8%) and underwent high-dose DSE. The mean pressure gradient, valve area and side effects after DSE were evaluated. RESULTS: Serious cardiac arrhythmias occurred in 10 patients. In group A, four patients (20%) developed non-sustained ventricular tachycardia. In group B, two patients (4%) had non-sustained ventricular tachycardia (VT), four (7%) had paroxysmal supraventricular tachycardias, and two (4%) severe symptomatic hypotension. Among the 20 patients with evidence of ischemia on DSE, three developed adverse side effects (no difference compared with patients without ischemia; p = 0.922). Fourteen patients received atropine during DSE, and 1 of these developed non-sustained VT after atropine administration. CONCLUSION: Serious cardiac arrhythmias occur frequently during both low-dose and high-dose DSE in patients with AS. Adverse side effects do not relate to stress-induced ischemia or atropine addition.     

S151A δ-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice

So far, the role of mutations in the δ-sarcogylcan (Sgcd) gene in causing autosomal dominant dilated cardiomyopathy (DCM) remains inconclusive. A p.S151A missense mutation in exon 6 of the Sgcd gene was reported to cause severe isolated autosomal dominant DCM without affecting skeletal muscle. This is controversial to our previous findings in a large consanguineous family where this p.S151A mutation showed no relevance for cardiac disease. In this study, the potential of the p.S151A mutation to cause DCM was investigated by using two different approaches: (1) engineering and characterization of heterozygous knock-in (S151A-) mice carrying the p.S151A mutation and (2) evaluation of the potential of adeno-associated virus (AAV) 9-based cardiac-specific transfer of p.S151A-mutated Sgcd cDNA to rescue the cardiac phenotype in Sgcd-deficient (Sgcd-null) mice as it has been demonstrated for intact, wild-type Sgcd cDNA. Heterozygous S151A knock-in mice developed a rather mild phenotype of cardiomyopathy. Increased heart to body weight suggests cardiac enlargement in 1-year-old S151A knock-in mice. However, at this age cardiac function, assessed by echocardiography, is maintained and histopathology completely absent. Myocardial expression of p.S151A cDNA, similar to intact Sgcd cDNA, restores cardiac function, although not being able to prevent myocardial histopathology in Sgcd-null mice completely. Our results suggest that the p.S151A mutation causes a mild, subclinical phenotype of cardiomyopathy, which is prone to be overseen in patients carrying such sequence variants. Furthermore, this study shows the suitability of an AAV-mediated cardiac gene transfer approach to analyze whether a sequence variant is a disease-causing mutation.