Bio-relevant media to assess drug permeability: sodium taurocholate and lecithin combination or crude bile?

The assessment of in vivo drug absorption with in vitro permeability models demands the use of transport media with surface acting compounds. With the aim to establish their influence on in vitro permeability of 30 drugs through Caco-2 monolayers, cell vitality/integrity and micellar drug entrapment, taurocholate/lecithin (NaTC/Leci) and pig crude bile were applied. Drug permeabilities were correlated to fraction of drugs absorbed and appropriate NaTC/Leci and bile concentrations were proposed to simulate fasted/fed conditions in vitro (bile in the concentration range 1-5 v/v% or 0.2/0.05mM NaTC/Leci for fasted; 10 v/v% bile or 3/0.75mM NaTC/Leci for fed conditions) without detrimental effects on monolayer integrity/vitality (NaTC/Leci was more toxic than bile). Surfactants exerted different affinities for drugs; free drug concentration (c(free)) of some was significantly lowered only by bile, while for the others NaTC/Leci and bile significantly diminished c(free). For some substances NaTC/Leci and bile significantly increased their permeabilities (i.e. more than 3-times) in spite of profound c(free) decrease indicating the existence of an alternative absorption mechanism. Based on these data, the impact of bile on in vitro drug permeability and micellar drug entrapment cannot be adequately simulated by NaTC/Leci, because their effects on drug absorption differ.     

Blood pressure before and after electroconvulsive therapy in hypertensive and nonhypertensive patients

The effect of a course of electroconvulsive therapy (ECT) on blood pressure control in hypertensive patients has not been studied. We retrospectively examined pre- and post-ECT blood pressures in hypertensive and nonhypertensive patients. In neither group was there a statistically significant change in blood pressure with a course of ECT. We conclude that a course of ECT does not worsen blood pressure in hypertensive patients beyond the peritreatment period.     

Cardiac biomarkers in patients with permanent pacemakers and implantable cardioverter-defibrillators undergoing an MRI scan

Background: Recent series suggest that magnetic resonance imaging (MRI) scanning can be performed safely in select patients with pacemakers or implantable cardioverter‐defibrillators (ICDs). Limited data have been reported on cardiac biomarker release following MRI scans in patients with pacemakers. The current study evaluated cardiac biomarkers pre‐ and postscan in patients with permanent pacemakers or ICDs undergoing MRI scanning of any body region without peak specific absorption rate (SAR) limit. Methods: Thirty‐seven patients with a total of 75 leads underwent a total of 40 MRI scans of both truncal and nontruncal regions using usual protocols with standard peak SAR settings for the scan. No patient was pacemaker dependent. Pacemaker magnet mode and ICD therapy were disabled during the scan. Baseline cardiac troponin‐I and myoglobin levels were obtained immediate pre‐ and 6–12 hours postscan. Pacemaker capture thresholds were measured immediately pre‐ and postscan. Results: The median peak SAR was 2.4 (1.3, 3.2) W/kg for all scans. Cardiac troponin‐I was unchanged following an MRI scan (0.01 (0.01, 0.02) versus 0.01 (0.01, 0.02) ng/mL, P = 0.90). Capture thresholds were no different pre‐ and postscan (0.67 (0.50, 0.80) versus 0.70 (0.50, 0.79) V at 0.5 ms, P = 0.50). Conclusions: The current series suggests that an MRI scan may be performed safely in carefully selected patients with close monitoring during the scan without limitation on peak SAR level or body landmark. Furthermore, it is unlikely that an MRI scan will produce sufficient tissue heating to cause enough myocardial cell necrosis to result in cardiac biomarker release.     

Obesity following kidney transplantation and steroid avoidance immunosuppression

Abstract:  Obesity is an important co-morbidity within end-stage renal disease (ESRD) and renal transplant populations. Previous studies have suggested that chronic corticosteroids result in increased body weight post-transplant. With the recent adoption of steroid-sparing immunosuppressive strategies, we evaluated the effect of these strategies on body mass index (BMI) after renal transplantation. We examined 95 renal transplant recipients enrolled in National Institutes of Health clinical transplant trials over the past three yr who received either lymphocyte depletion-based steroid sparing or traditional immunosuppressive therapy that included steroids for maintenance immunosuppression. Recipients were overweight prior to transplant and no significant differences existed in pre-transplant BMI among treatment groups. Regardless of therapy, BMI increased post-transplant in all recipients. The BMI increase consisted of an average weight gain of 5.01 ± 7.12 kg (mean, SD) post-transplant. Additionally, in a number of recipients placed on maintenance steroids, subsequent withdrawal at a mean of 100 d post-transplant had no impact on weight gain. Thus, body weight and BMI increase following kidney transplantation, even in the absence of steroids. Thus, patients gain weight after renal transplantation regardless of the treatment strategy. Steroid avoidance alone does not reduce risk factors associated with obesity in our patient population.     

Long-term comparative outcomes between 2 common ureteroneocystostomy techniques for renal transplantation

PURPOSE: We compared the incidence of ureteral complications between the classic (Lich-Gregoir) technique and the recently popularized single stitch (Shanfield) technique in renal transplantation. MATERIALS AND METHODS: The charts of 721 consecutive transplant recipients from May 1999 to July 2002 were retrospectively reviewed. Ureteral and nonureteral complications were reviewed at 3 to 5-year followup. RESULTS: Of the 721 recipients evaluated 713 were included in the study. There were 360 recipients in the Lich-Gregoir group and 353 in the Shanfield group. A significantly higher rate of ureteral complications occurred in the Shanfield group compared to the Lich-Gregoir group (15.6% vs 3.9%, p <0.0001). The Shanfield group consisted of 20 patients with ureteral leakage, 21 with hematuria, 11 with strictures and 3 who had ureteral stones. The Lich-Gregoir group had 8 patients with ureteral leakage, 5 with hematuria and 1 with a stricture. In comparison, urinary tract infections, delayed graft function and rejection rates were not significantly different between the 2 groups (p = 0.76, 0.12 and 0.19, respectively). CONCLUSIONS: In contrast to other reports, the Shanfield group had significantly more ureteral complications. In particular the Shanfield technique may predispose patients to higher rates of hematuria and stone formation. Based on this large series and published meta-analyses we believe that the stented Lich-Gregoir anastomosis is the superior ureteroneocystostomy technique in renal transplantation.     

Chronic acidosis rewires cancer cell metabolism through PPARα signaling

The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pH_e) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pH_e, but not at acidic pH_e. Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.     

Muscarinic Receptor Loss and Preservation of Presynaptic Cholinergic Terminals in Hippocampal Sclerosis

Summary: Purpose: Prior single-photon emission tomography studies showed losses of muscarinic acetylcholine receptor (MAChR) binding in patients with refractory mesial temporal lobe epilepsy. Experimental animal studies demonstrated transient losses of MAChR due to electrically induced seizures originating in the amygdala. However, the relations between cholinergic synaptic markers, seizures, and underlying neuro-pathology in human temporal lobe epilepsy are unknow. We tested the hypotheses that human brain MAChR changes are attributable to hippocampal sclerosis (HS), and that HS resembles axon-sparing lesions in experimental animal models.
Methods: We measured MAChR binding-site density, an intrinsic neuronal marker, within the hippocampal formation (HF) in anterior temporal lobectomy specimens from 10 patients with HS and in 10 autopsy controls. Binding-site density of the presynaptic vesicular acetylcholine transporter (VAChT) was measured as a marker of extrinsic cholinergic afferent integrity. MAChR and VAChT results were compared with neuronal cell counts to assess their relations to local neuronal losses.
Results: Reduced MAChR binding-site density was demonstrated throughout the HF in the epilepsy specimens compared with autopsy controls and correlated in severity with reductions in cell counts in several HF regions. In contrast to MAChR, VAChT binding-site density was unchanged in the epilepsy specimens compared with autopsy controls.
Conclusions: Reduction in MAChR binding in HS is attributable to intrinsic neuronal losses. Sparing of afferent septal cholinergic terminals is consistent with the hypothesis that an excitotoxic mechanism may contribute to the development of HS and refractory partial epilepsy in humans.