18FDG PET/CT imaging of adenovirus-associated acute interstitial nephritis after allogeneic bone marrow transplantation.

Adenovirus-associated acute interstitial nephritis (AAIN) should always be considered in the differential diagnosis of acute kidney failure following allogeneic bone marrow transplant. Although not intended for the definitive diagnosis of AAIN, 18FDG PET/CT can be a helpful noninvasive diagnostic tool, especially when a biopsy is not feasible.

Clinical pharmacokinetics and delivery of bovine superoxide dismutase.

Experimentally, superoxide dismutase (SOD) protects against cytotoxological and histotoxological effects of superoxide anions, which play a fundamental role where inflammatory processes are involved. Currently, only bovine copper containing SOD (Cu-SOD) is available for clinical application in the treatment of patients with various arthritic diseases. The intramuscular route is the principal route to administer usual dosages of bovine Cu-SOD 4 to 32mg, 2 or 3 times weekly. A single dose corresponds to an optimal dose ranging from 30 to 200 micrograms/kg, determined from an established dose-response curve. After intramuscular injection of bovine Cu-SOD 8, 16 and 32mg the peak plasma concentration occurs 4 to 8 hours postdose and is 0.05, 0.16 and 0.39 mg/L, respectively. Clinically this metallo-protein is particularly effective for the treatment of inflammation and toxicity resulting from ionising irradiations, ischaemia and tumours. The major advantages of liposomally encapsulated bovine Cu-SOD are its improved pharmacokinetic characteristics, leading to a longer plasma half-life and a slower release of free bovine Cu-SOD. In humans, bovine Cu-SOD (free or liposomal), although a foreign protein, is well tolerated and produces no acute or delayed toxic effects.

Effect of crilvastatin, a new cholesterol lowering agent, on unesterified LDL-cholesterol metabolism into bile salts by rat isolated hepatocytes.

1. The aim of these experiments was to determine the effect of crilvastatin, a new cholesterol lowering agent, on the metabolism of unesterified low density lipoprotein (LDL)-cholesterol by rat freshly isolated hepatocytes. This preclinical model was developed as an alternative to in vivo experiments, to mimic the metabolic effects of a molecule on its target cells and to define optimal conditions for future experimentation on human hepatocytes. 2. Cells were obtained from normolipidaemic or hypercholesterolaemic rats, hypercholesterolaemia was nutritionally induced. Incubations were performed in a medium containing 600 microM taurocholate and 50 microM or 300 microM crilvastatin. 3. This molecule was shown in vitro to be carried by physiological transporters, i.e., albumin-bile salt micellar associations and LDL. Crilvastatin induced a significance increase in the synthesis and secretion by hepatocytes of bile salts resulting from the metabolism of unesterified LDL-cholesterol in both normolipidaemic and hypercholesterolaemic rats. Stimulation involved non-conjugated as well as tauro- and glyco-conjugated bile salts. These findings corroborate preliminary studies showing in vivo that crilvastatin enhances the secretion of bile acids by stimulating the uptake and incorporation of LDL-cholesterol by the liver.

Differences in hypolipidaemic effects of two statins on Hep G2 cells or human hepatocytes in primary culture.

1. The objective of this study was to compare in cultured human hepatocytes or Hep G2 cells, changes in the fate of unesterified low density lipoprotein (LDL)-cholesterol induced by crilvastatin, a new cholesterol lowering drug and a reference statin, simvastatin. 2. The experiments were carried out for 20 h, each well contained 4.2 x 10(5)/cm2 Hep G2 cells or 0.5 x 10(5)/Cm2 human hepatocytes, 130 microM ursodeoxycholate, 0.68 microCi or 1.59 microCi unesterified human [14C]-LDL-cholesterol, crilvastatin or simvastatin at 0 or 50 microM (both cell types) or 300 microM (Hep-G2 cells). Incubation with the two drugs resulted in increased amounts of unesterified [14C]-LDL-cholesterol taken by the two cell types, compared to control. 3. Crilvastatin 50 microM led to significantly higher quantities of [14C]-glyco-tauro-conjugated bile salts, compared to simvastatin. Statins reduced the apo B100 level secreted by the two cell types (simvastatin) or human hepatocytes (crilvastatin). Crilvastatin enhanced both the level of apo A1 secreted by the Hep G2 cells and the level of APF, a high density lipoprotein (HDL) and biliary apoprotein. 4. Crilvastatin not only acts by stimulating LDL-cholesterol uptake by hepatocytes, but also by enhancing the catabolism of LDL-cholesterol in bile salts and probably by stimulating HDL and/or bile component secretion. Such a mechanism was not previously described for HMG CoA reductase inhibitors. Our results on APF show that this apoprotein could be considered also as an indicator of changes in bile and/or HDL compartments. 5. The human hepatocyte model appeared to be a suitable and relevant model in the pharmacological-metabolic experiments carried out in this study. It led to more consistent data than those obtained with Hep G2 cells.

Anti-inflammatory activity of various superoxide dismutases on polyarthritis in the Lewis rat.

The anti-arthritic activity of four superoxide dismutases (SODs) has been compared by using the adjuvant-induced polyarthritis rat model. Many of the clinical signs observed in the rat closely resemble those of human rheumatic diseases and the Fiessinger-Leroy-Reiter syndrome. An original protocol and various approaches allowed study of the evolution of long term (30-90 days) SOD treatment. Results are relevant to clinical application: human and bovine Cu-SODs are fully active during secondary and tertiary arthritic reaction; homologous rat Cu-SOD is active only transiently at the end of the secondary reaction; human Mn-SOD is active only on the second stage of arthritic reaction. It should be noted that bovine and human SODs slightly delay the appearance of bony damage. These data were confirmed by the scintigraphic study. Finally it is noteworthy that drug pharmacological activity decreases when the blood level of anti-SOD antibodies increases. This indicates the existence of an immunological reaction following SOD administration.

Pharmacokinetic and anti-inflammatory properties in the rat of superoxide dismutases (Cu SODs and Mn SOD) from various species.

The comparison of the anti-inflammatory properties (carrageenan paw edema in the rat) of exogenous Cu SODs from various species and human Mn SOD administered at doses corresponding to clinical schedules, shows that human and bovine Cu SOD are fully active, whereas rat Cu SOD and Mn SOD are inefficient. This difference does not correspond to the similarity of pharmacokinetic properties (blood levels, subcellar location in kidney cortex) of the Cu proteins or to the increased circulating life time of Mn SOD. The pharmacological activity of exogenous SOD is limited to heterologous Cu SODs in the rat. A similar problem may occur in man. The true mechanism of action of Cu SOD remains to be elucidated.

Superoxide dismutase treatment reduces [3H]flunitrazepam affinity in cortex and hippocampus of the rat.

Superoxide dismutases (SOD) are essential enzymes involved in the cellular defense against oxidative processes occurring with the generation of the superoxide anion. In this work, we have investigated in the rat the effects of a subchronic administration of liposomal SOD from bovine erythrocytes, on benzodiazepine (BZD) 'central-type' receptor sites in cortex and hippocampus. Animals were treated for 15 days with an i.p. injection of liposomal SOD, and binding parameters were determined using [3H]flunitrazepam. BZD receptor affinity was found decreased, while no change was observed in the maximal binding capacity. With regard to previously reported data, our results show that the superoxide anion radical is involved in the modulation and/or the stability of 'central-type' BZD receptor sites.

Sodium valproate: kinetic profile and effects on GABA levels in various brain areas of the rat.

1. The kinetic profile of sodium valproate (VPA) and the GABA levels were studied in discrete brain areas of the rat after an i.p. injection of 200 mg/kg. The results were discussed comparatively with GABA-T and GAD activities reported in the literature. 2. VPA was rapidly distributed in brain areas; its concentrations, its kinetic parameters and the GABA levels after the drug administration were not uniform in the different brain areas studied. 3. The results showed a particular relation of the VPA to the olfactory bulbs; in this specific area the VPA effect on GABA level was stronger; the VPA apparent half life of elimination was longest; the VPA apparent disappearance rate constant was smallest; the initial GABA level was higher; the activities of GABA-T and GAD were higher than in other brain areas studied except the hypothalamus. 4. These data were correlated with the role of the olfactory bulbs in the behaviour of the rodents.

Valproate increases diazepam impregnation selectively in CNS of the rat after subchronic administration.

Valproate-Diazepam association is not unusual in the treatment of epilepsies. The present paper investigates in an experimental study the effect of sodium valproate (VPA) on the regional cerebral level of diazepam (DZP), and the relationship with plasma or erythrocytes amounts after subchronic administration. The VPA addition increases the DZP levels in peripheral and central compartments. The results shows a linear correlation between the drug concentration in all areas studied and the plasmatic or erythrocytic amounts during the CNS - impregnation phase. The VPA influence is greater in the CNS where the DZP impregnation is selectively increased, specially in cortex and cerebellum.

Effects of a subacute treatment in rats by a fresh cola extract on EEG and pharmacokinetics.

The compared effects of an acute and subacute treatment by fresh cola extract and caffeine on the caffeine pharmacokinetics and on cortical activities by spectral analysis of the electroencephalogram (EEG) are studied in rats. After acute cola administration, we observed an increase in half-life elimination of caffeine and a stabilization of its plasma/erythrocyte ratio. Chronic administration revealed differences in cola-caffeine penetration in erythrocytes and a reduction of the area under the curve (AUC) and plasma/erythrocyte ratio. We also noted a significant difference in the binding of the caffeine on plasma proteins after subacute administration of cola seed extract. Cola seed treatment induces an increase in the cortical activity with a widening of the dominant frequency spectrum 7- to 10-Hz band of EEG, whereas caffeine alone induces a shift of the dominant frequency band toward higher frequencies. The observed delay to obtain the greatest EEG effect related to the caffeine contained in cola seeds can be partially explained by the pharmacokinetic data.

Behavioral effects resulting from sub-chronic treatment of rats with extract of fresh stabilized cola seeds.

The aim of our study was to compare the effects of a sub-chronic treatment with fresh cola seed extract and pure caffeine in the male rat. The activity tests (open-field) and reactivity (tail-tap, resistance to capture), show that fresh cola has an effect on behavior similar to that of caffeine. However, the effects of cola are more gradual than those of caffeine. Furthermore, cola administration leads to an increase in the fall latency observed during the grasping test. These results suggest that the fresh cola seed has both psychostimulating properties similar to those of caffeine, and an original effect on muscular tonus.

Circadian changes in procainamide and N-acetylprocainamide kinetics in the rat.

The aim of this study was to investigate the possible influence of the time of administration on procainamide and N-acetylprocainamide (NAPA) kinetics in the rat. A single 50 mg kg-1 i.p. dose of procainamide was given to Wistar AF SPF adult male rats maintained under controlled environmental conditions (LD: 06.00h-18.00h) at four different fixed times i.e. 10.00, 16.00, 22.00 and 04.00h. Procainamide and NAPA plasma levels were determined by an immunoenzymatic method. Our data showed significant 24 h variation of the following pharmacokinetic parameters: highest elimination half-lives at 10.00h (t1/2 beta = 0.736 +/- 0.020h) for procainamide and at 04.00h (t1/2 beta = 3.55 +/- 0.08h) for NAPA (P less than 0.001); highest apparent volume of distribution at 04.00h for procainamide (Vd = 2.35 +/- 0.17 litre) (P less than 0.05); highest ratio AUC NAPA/AUC procainamide at 04.00h (1.039 +/- 0.056) (P less than 0.001). Procainamide clearance and Cmax and AUC for procainamide and NAPA were not significantly dependent on time of day. These data indicate a 24 h variation in the metabolism of procainamide which is converted to NAPA, the N-acetylation being greatest at 04.00h.

Effects of the 1,5-benzodiazepine clobazam on pituitary hormones in the male rat.

The aim of this study is to evaluate the effects of the acute and subchronic administration of the benzodiazepine clobazam (20 mg/kg orally) on the plasma levels of the pituitary hormones (prolactin, FSH and LH) in the male rat. This 1.5 benzodiazepine did not induce any variation of the hormone levels either after acute or subchronic administration. These negative data are discussed as compared to the effects of other benzodiazepines of GABA and GABA receptor agonists and antagonists on the pituitary hormone levels according to particular experimental conditions.

[Alpha 1-acid glycoprotein and carbamazepine]. / Alpha 1-glycoprotéine acide et carbamazépine.

Levels of alpha 1-acid glycoprotein (alpha 1-AGP) were determined in 40 epileptic patients who had been also treated with carbamazepine (CBZ) and, in some patients, phenobarbital (PB) for at least 3 months. alpha 1-AGP levels were also determined in 28 controls. CBZ dit not alter blood levels of alpha 1-AGP while CBZ-PB decreased them. Such results are at variance with recent studies which suggested an increase of alpha 1-AGP in epileptic patients treated either with phenytoin or phenytoin + PB, or + CBZ, or + primidone.

Diazepam: kinetic profiles in various brain areas, plasma and erythrocytes after chronic administration in the rat.

The regional distribution of diazepam (DZP) was established in eleven discrete brain areas in the rat after i.m. chronic treatment (15 days; 5 mg/kg/day). In addition, the kinetic profiles of this drug were investigated in plasma, eryhtrocytes, and three CNS regions (nucleus caudatus, hippocampus, and cerebellum) upon which the pharmacokinetic study was focused. The modifications occuring in plasma-protein binding and erythrocytes binding were reported. In the CNS, the DZP was rapidly distributed; its concentrations and its kinetic profiles were not uniform in the different brain areas studied. The highest amount of DZP was noted in the hypothalamus, while nucleus caudatus and colliculi also presented important DZP levels. Concerning the kinetic parameters after chronic administration, an increase in the elimination half-life time value in central and peripheral compartments, as compared to values reported after acute administration, was observed. The study of cerebral DZP levels as compared with those in the erythrocytes or in plasma suggests a linear correlation in the three CNS areas investigated. These experimental results demonstrate the interest of such studies for psychotropic drug monitoring.

Effect of the hour of administration on the pharmacokinetics of lidocaine in the rat.

The aim of the present study was to investigate an eventual influence of the hour of administration on lidocaine kinetics in the rat. 280 Wistar AF-SPF adult male rats were used for this study and maintained under controlled environmental conditions (LD: 06.00-18.00) during the month of October. A single 50 mg X kg-1 dose of lidocaine was given by intramuscular route, at four different fixed time points of a 24 hour period (i.e.: 10.00, 16.00, 22.00 and 04.00) to 70 rats. Blood samples were taken at the following time points: 5, 15, 30 min., 1, 2, 4 and 6 hours after the drug administration. Lidocaine plasma levels (free and bound) were determinated according to a specific gas chromatographic method. The data showed circadian variations of pharmacokinetic parameters:--Elimination half-life: max. 2.12 +/- 0.05 h at 10.00, min. 1.50 +/- 0.03 h at 16. --Initial concentration: max. 5.05 +/- 0.65 micrograms X ml-1 at 16.00; min. 2.97 +/- 0.29 micrograms X ml-1 at 04.00.--Elimination constant rate: max. 0.4618 +/- 0.0094 h-1 at 16.00, min 0.3279 +/- 0.0079 h-1 at 10.00.--Area under curve (experimental): max. 11.11 +/- 1.07 micrograms X kg-1 X h-1 at 16.00, min. 7.45 +/- 0.84 micrograms X kg-1 X h-1 at 04.00.--Apparent volume of distribution: max. 16.67 +/- 1,67 L X kg-1 at 04.00, min. 9.75 +/- 1.04 L X kg-1 at 16.00. The lidocaine-free fraction varied with time and the protein binding of lidocaine showed a circadian variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian effect on carbamazepine kinetics in rat.

The purpose of the present study was to investigate whether the time of day (24 h) at which carbamazepine is administered influences its pharmacokinetics in the rat. The pharmacokinetics of a single, 100 mg . kg-1 bodyweight per os, dose of carbamazepine were studied at four different fixed time points of a 24-hour period (i.e. 10.00, 16.00, 22.00 or 04.00 h) in Wistar AF-SPF adult male rats maintained under controlled environmental conditions (LD: 18.00 - 06.00h) during October 1978. The total plasma levels and the unbound fraction were measured according to an immunoenzymatic method (EMIT). The effects of fasting were also investigated. The data shows circadian variations of pharmacokinetic parameters: the maximum peak concentration and the maximum time to reach this peak was observed when the drug was given respectively at 16.00h and at 10.00h. The elimination half-life varied from 15.15 hours at 16.00h to 10.48 hours at 22.00h. The observed variations may be related to: daily fluctuations of absorption or binding of the drug; diurnal variations of the hepatic drug metabolizing enzymes responsible for the inactivation; and/or diurnal variations in excretion rate of the drug.

[Use of calcium inhibitors in neuropsychiatric pathology]. / Utilisation des inhibiteurs calciques en pathologie neuropsychiatrique.

The use of calcium channel blockers is usual in cardiology today, but seem to spread to others specialties, particularly in the field of neuropsychiatry. The authors report the major clinical studies in neurology (treatment of migraines, epilepsia, dizziness and ischemic stroke) where flunarizine and nimodipine seem to have an important role. In psychiatry, their introduction is more recent. However, some encouraging results have been noted in the treatment of panic disorder, Gilles de la Tourette disease and mania.

[Serum beta-glucuronidase activity in patients with epilepsy]. / Etude de l'activité de la bêta-glucuronidase sérique chez le malade épileptique.

Little information is available on the effect produced by antiepileptic drugs on the serum beta-glucuronidase activity. According to recent findings, beta-glucuronidase serum levels are increased in patients with epilepsy just before the beginning of seizures and remain increased during several weeks; this it is suggested that determination of this enzyme could be important in the provision and the treatment of seizures. The purpose of the present study attempts to understand these changes. Our study was carried out on 49 adult healthy subjects and 48 adult epileptic patients receiving anticonvulsant therapies. Serum beta-glucuronidase activity was determined by a simplified procedure employing phenolphtalein glucuronic acid as substrate. The mean +/- SEM of serum beta-glucuronidase activity in treated patients (40.93 +/- 5.01 MSU/ml) was significantly higher than those of the healthy subjects (25.04 +/- 3.40 MSU/ml). In conclusion, the relationship between changes in serum enzyme activity, seizures and anticonvulsant therapies suggests that the determination of serum beta-glucuronidase activity presents a weak interest in predicting or treating seizures.

[Lipid peroxidation in aged patients. Influence of an antioxidant combination (vitamin C-vitamin E-rutin)]. / Etude de la lipidoperoxydation chez le malade âgé. Influence d'une association antioxydante (vitamine C - vitamine E - rutine).

Lipoperoxidation has an important role in the normal processes of the cell-life. The induction is produced by oxygen-derived free radicals which attack the membrane phospholipids. Such an attack is modulated by an enzymatic protection system (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase) and by a non-enzymatic one (vitamin C, vitamin E...). In various pathologic conditions, a dispoise takes place between radical attack and antiradical protection. The place taken by lipoperoxidation in the ageing process seems to be fundamental. We report here the results of a study carried out in aged and sick patients who were given an antioxidant medicamentous combination made from Vitamin C, Vitamin E and Rutin. Our results evidence that such a synergistic combination does modify both enzymatic protection system and lipoperoxidation, this latter showing a decrease under treatment.