Intracellular distribution and effect of the antimalarial drug mefloquine on lysosomes of rat liver

Abstract: Mefloquine was administered in a single dose (1–30 mg/100 g) to rats in order to study its subcellular distribution and effects on rat liver lysosomal structure and function. Subcellular fractionation showed a significant enrichment of mefloquine in lysosomes. Even repeated administration of mefloquine did not affect the levels of cytochrome-P-450 or its reductase, indicating, although not proving, that it is not metabolized by this mono-oxygenase system. Mefloquine caused an expansion of the lysosomal apparatus, earliest seen by 24 h and lasting for some 7 days. Initially, cytoplasmic constituents were seen inside the lysosomes. Later, the lysosomes harboured myelin-like figures (multilamellar bodies) disappearing after 7–10 days. The proteolytic and lipolytic capacity was assessed in isolated lysosomes. Mefloquine caused increased protein degradation but decreased breakdown of lipids. Concomitantly, all five major phospholipids (phosphatidyl-choline, -ethanolamine, -inositol, -serine and sphingomyelin) increased in the lysosomes. It is concluded that: (1) mefloquine is a lysosomotropic drug that accumulates in lysosomes; (2) mefloquine impairs lipid degradation with ensuing accumulation of lipids in lysosomes; and (3) lysosomal trapping explains the high volume distribution of mefloquine.     

Characterization of dihydropyridine binding sites in the rat brain: hypertension and age-dependent modulation of [H](+)-PN 200-110 binding

The properties of [³H]dihydropyridine (DHP), nitrendipine and (+)-PN 200-110, binding to rat cerebral membranes were investigated. In normotensive Wistar-Kyoto (WKY) adult rats, the highest densities of [³H]DHP binding sites were found in the hippocampus. Frontal cerebral cortex and hypothalamus had intermediate levels and no specific binding of [³H]DHP and [¹²⁵I]iodipine could be detected in the brainstem membranes and more precisely in the nucleus tractus solitarius and in the locus coeruleus. Changes in the maximal number of DHP binding sites (B_max) were observed in spontaneously hypertensive rats (SHR) and in old Sprague-Dawley rats. In adult SHR, there was a significant increase in theB_max values of [³H](+)-PN 200-110 binding in the hippocampus when compared to the values obtained in WKY. There was no difference in theB_max values between young (3 weeks) prehypertensive SHR and age-matched WKY. In senescent (26 months) Sprague-Dawley rats, theB_max values of [³H](+)-PN 200-110 binding were significantly reduced (30%) in the frontal cerebral cortex and the hippocampus, as compared with the number of DHP binding sites found in mature Sprague-Dawley rats (15 weeks).     

Filtration of fentanyl is not the cause of the elevation of arterial blood pressure associated with post-bypass ultrafiltration in children

Modified ultrafiltration after cardiopulmonary bypass in children has been shown to be associated with an increase in arterial blood pressure. As part of a series of studies to investigate the possible causes of this blood pressure elevation, the hypothesis that if filtration was removing a significant amount of fentanyl, then the increase in blood pressure might be due to pain was proposed. Ten children, aged between 0.5 and 9.3 years (median 3.8 years), weighing 5.9 to 25..5 kg (median 15.7 kg), underwent corrective cardiac surgery (incorporating modified ultrafiltration). A standard anesthetic protocol was followed, with up to 78 μg/kg of fentanyl given prebypass for analgesia. After completion of cardiopulmonary bypass, modified ultrafiltration was commenced at 100 mL/min until a hematocrit of 35% was reached. Samples were taken of arterial blood (prefiltration, 3, 10, and 20 minutes postfiltration), the venous reservoir blood (prefiltration) and the filtrate (5 and 10 minutes into filtration). Hemodynamic data were recorded both prefiltration and postfiltration. The hemodynamic data showed the expected rise in both systemic arterial pressure and cardiac index after ultrafiltration. The plasma fentanyl concentrations did not significantly change after ultrafiltration: 1.59 to 12.39 ng/mL (median 6.27 ng/mL) prefiltration and 2.05 to 15.59 ng/mL (6.29 ng/mL) at 3 minutes, 2.22 to 12.64 ng/mL (6.87 ng/mL) at 10 minutes, and 1.83 to 11.52 ng/mL (5.85 ng/mL) at 20 minutes postfiltration. The concentration of fentanyl in the venous reservoir, 2.06 to 11.64 ng/mL (7.04 ng/mL), was not significantly different from the plasma levels. The level of fentanyl in the filtrate was significantly less than the plasma levels, 0.243 to 1.87 ng/mL (0.894 ng/mL) at 5 minutes and 0.385 to 1.688 ng / mL (0.952 ng / mL) at 10 minutes into filtration; (P < 0.02 by the Wilcoxon signed-rank method). The data show that the plasma fentanyl concentration was not significantly reduced by modified ultrafiltration. The fentanyl levels found prefiltration were maintained postfiltration, and the observed changes in systemic arterial pressure were not due to an acute fall in the plasma concentration of analgesic drug.     

Regional left atrial voltage in patients with atrial fibrillation

BACKGROUND: Regional differences in fibrosis, particularly related to the posterior wall and septum, may be important in atrial fibrillation (AF). Using electroanatomic mapping, voltage can be used as a measure of fibrosis. OBJECTIVES: The purpose of this study was to determine if patients with AF have disproportionately lower voltage in the septal and posterior walls of the left atrium. METHODS: Sinus rhythm left atrial electroanatomic maps were used in serial patients presenting for left atrial ablation of AF (8-mm tip). Patients undergoing left atrial mapping for focal atrial tachycardia (AT) were used as a comparison group (4-mm tip). Animal experiments were performed to assess the influence of ablation catheter tip size on voltage amplitude. RESULTS: The posterior and septal walls exhibited the lowest voltages in both groups. Compared with the anterior wall, there was a 3.78-fold greater odds of finding a low-voltage point (<0.5 mV) in the septum (P <.001) and a 3.37-fold greater odds of finding a low-voltage point in the posterior wall (P <.001) in the AF patients; the proportion of low-voltage points by region were not significantly different in the AT group. In the animal model, the mean voltage obtained from an 8-mm ablation catheter was significantly higher (0.30 +/- 0.17 mV) than that obtained from the same points using a 4-mm catheter (0.22 +/- 0.17, P = .05). CONCLUSION: Regional differences in voltage are present in patients with atrial arrhythmias, with AF patients exhibiting significantly more low-voltage areas in the septum and posterior walls.     

Deep dermal burn injury results in scarless wound healing in the ovine fetus

Early to mid-term fetuses heal cutaneous incisional wounds without scars; however, fetal response to burn injury has not been ascertained. We present a fetal model of thermal injury and subsequent analysis of fetal and lamb response to burn injury. A reproducible deep dermal burn injury was created in the fetus by application of water at 66 degrees C for 7 seconds, and at 82 degrees C for 10 seconds to the lamb. Macroscopically, the area of fetal scald was undetectable from day 7 post injury, while all lamb scalds were readily identified and eventually healed with scarring. Using a five-point histopathology scoring system for alteration in tissue morphology, differences were detected between control and scalded skin at all stages in lamb postburn, but no difference was detected in the fetal model after day 7. There were also large differences in content of alpha-smooth muscle actin and transforming growth factor-beta1 between control and scalded lamb and these differences were statistically significant at day 14 (P < 0.01). This novel model of fetal and lamb response to deep dermal injury indicates that the fetus heals a deep burn injury in a scarless fashion. Further elucidation of this specific fetal process of burn injury repair may lead to improved outcome for patients with burn injury.     

Extracorporeal membrane oxygenation for postcardiotomy mechanical cardiovascular support in children with congenital heart disease

Extracorporeal membrane oxygenation (ECMO) is increasingly used to support postcardiotomy cardiorespiratory failure in children with congenital heart disease. We report on survival outcomes and factors associated with survival for postcardiotomy ECMO patients.     

Improvement in quality of life after initiation of lamotrigine therapy in patients with epilepsy in a naturalistic treatment setting.

Quality of life is impaired in patients with epilepsy and can be improved by effective therapy. Randomised clinical trials have shown that lamotrigine treatment is associated with improved quality of life. However, little information is available on quality of life or treatment effects in patients with epilepsy in the general population. The objective of this study was to estimate the impact of lamotrigine on quality of life in a naturalistic treatment setting. The study included adult patients with epilepsy in whom lamotrigine therapy was initiated. Each subject completed the Quality of Life in Epilepsy Inventory (QOLIE)-31 quality of life questionnaire at inclusion and at a follow-up visit in the next 4 months. Demographic information and medical history were provided by the investigator. These were evaluated as potential determinants of change in quality of life using logistic regression. Three hundred and forty-one patients were evaluated, 192 starting lamotrigine in combination with another drug, 90 as a first-line monotherapy, 45 as a switch from another drug and 14 as a reduction to monotherapy from a previous combination. Baseline scores on the QOLIE-31 ranged from 53.8 in the combination group to 69.5 in the first-line group. 34.6% of patients were considered to be responders, with no significant differences between treatment regimen. Most improvement was seen for the energy-fatigue and medication effects subscales and, for the first-line group, seizure worry. Seizure type was the only determinant of improvement of quality of life identified. In conclusion, lamotrigine treatment is associated with improved quality of life, regardless of treatment regimen.