Furazolidone disposition after intravascular and oral dosing in the channel catfish

1. The pharmacokinetics, tissue distribution and excretion of the nitrofuran drug furazolidone have been examined in the channel catfish. [14C]Furazolidone was administered by intravascular or oral routes in a single dosage of 1 mg/kg body weight. 2. A two-compartment pharmacokinetic model best described parent furazolidone concentrations in the plasma after intravascular dosing. Elimination of parent compound was extremely rapid, with a terminal half-life of 0.27h and total body clearance of 1901 ml/h/kg. 3. After oral dosing, furazolidone concentrations in the plasma were highest at 1 h and were below the limit of determination (< 20 ng/ml) at 5 h. The oral bioavailability of parent furazolidone administered in solution was 58%, compared with 28% in a feed mixture. 4. Concentrations of furazolidone and its metabolites were highest in the excretory tissues and lowest in the muscle after oral dosing. Parent furazolidone comprised 10% of the total 14C in the muscle at 8 h and was not detectable (< 1 ng/g) at 24 h; total 14C concentrations declined from 274 to 59 ng furazolidone equiv./g between 8 and 168 h. Non-extractable (bound) residues comprised 18% of total 14C in muscle at 8 h and 33% at 168h. 5. Renal excretion was the primary route of elimination of 14C residues and accounted for nearly 55% of the oral dose.     

Immunomodulator polysaccharides: chemistry, disposition and metabolism

This work was carried out to decide whether a non-specific perturbation of the platelet membrane with exogenous amphiphiles affects protein phosphorylation in platelets, especially phosphorylation mediated by PKC. Effects of amphiphiles per se on protein phosphorylation were also recorded. (i) Sublytic concentrations of the differently charged model surfactants cetyltrimethylammonium bromide (CTAB), Zwittergent 3-16, sodium tetradecyl sulphate, and octaethyleneglycol hexadecyl ether, as well as chlorpromazine, and Triton X-100, did not affect the thrombin-induced, PKC-mediated phosphorylation of pleckstrin, whereas sphingosine blocked this phosphorylation. (ii) The sphingosine-mediated phosphorylation blockade is not related to a non-specific perturbation of the membrane, but can instead be attributed to specific properties of sphingosine. (iii) The amphiphiles, per se, had differential effects on protein phosphorylation at sublytic concentrations: a treatment with CTAB, Zwittergent 3-16, and sodium tetradecyl sulphate for 1 min led to phosphorylation of a 49-kDa protein, while treatment with sphingosine for 1 min led to a transient phosphorylation of the myosin light chain as well as a weak phosphorylation of pleckstrin.     

Metabolism and disposition of 14C-granisetron in rat, dog and man after intravenous and oral dosing

1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0.25 and 5 mg/kg in rat and 0.25 and 10 mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man. 4. In rat and dog, 35-41% of the dose was excreted in urine and 52-62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5-25% of dose). 5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.     

Hyperthermia following MDMA administration in rats: effects of ambient temperature, water consumption, and chronic dosing

In two experiments it was found that the hyperthermia which follows MDMA ("Ecstasy") results from an interaction of direct pharmacological effect of the drug and the prevailing environmental conditions in which it is administered. In Experiment 1, rats given fixed doses of either 2.5, 5.0 or 7.5 mg/kg MDMA or saline were injected on different days at ambient temperatures (Ta's) of 11, 24, and 30 degrees C. At each Ta drinking water was freely available following dosing on one session and temporarily unavailable on a second. The hyperthermic and hyperkinetic responses were monitored using remote biotelemetry. Experiment 2 used a between-subject design in which each group of rats received a standard 7.5 mg/kg dose of MDMA administered at only one of the three levels of Ta(24 degrees C) and at only one level of the water-availability factor. Dosing in some groups was continued for a further 13 days to test for tolerance or sensitization effects. Ambient temperature significantly affected the magnitude of the hyperthermia but not the hyperkinesis. Water deprivation during the drugged period significantly augmented the hyperthermia, but only in the high Ta (30 degrees C.) condition. Chronic dosing produced sensitization of both hyperthermic and hyperkinetic responses. The findings indicate that ambient temperature, water consumption and frequency of drug use affect the hyperthermia which follows MDMA administration.     

Bronchodilator response to salbutamol after chronic dosing with salmeterol or placebo

OBJECTIVES: We report the occurrence of cardiac events during long-term follow-up in patients with hypertrophic cardiomyopathy (HCM) after cardioverter-defibrillator implantation. BACKGROUND: The identification of patients at high risk for sudden death and the prevention of recurrence of sudden death in HCM represents a difficult problem. METHODS: We retrospectively analyzed the occurrence of cardiac events during follow-up of 13 patients with HCM who received an implantable cardioverter-defibrillator (ICD) because of aborted sudden death (n = 10) or sustained ventricular tachycardia (n = 3) (group I). Findings were compared with those in 215 patients with an ICD and other structural heart disease or idiopathic ventricular fibrillation (group II). RESULTS: After a mean (+/-SD) follow-up period of 26+/-18 months, 2 of 13 patients in group I received appropriate shocks. The calculated cumulative incidence of shocks was 21% in group I and 66% in group II after 40 months (p < 0.05). We observed a low incidence of recurrence of ventricular tachycardia/fibrillation during follow-up in patients with HCM. No deaths occurred. CONCLUSIONS: Our data suggest that ventricular tachyarrhythmias may not always be the primary mechanism of syncope and sudden death in patients with HCM. The ICD seems to have a less important impact on prognosis in patients with HCM than in patients with other etiologies of aborted sudden death.     

Tenoxicam: acute dose-dependent disposition studies in rats

Single intravenous bolus doses of tenoxicam of 2.5, 5, and 10 mg/kg were administered to male Wistar rats to determine the effects of dose on tenoxicam pharmacokinetics. Predicted apparent volume of distribution at steady state (Vdss) and total plasma clearance (CL) were, respectively, 42 and 45% higher in the animals given 10-mg/kg dose than the animals given 2.5- and 5-mg/kg doses. Binding of tenoxicam to plasma proteins showed saturability, with a 33% higher unbound fraction of tenoxicam in plasma when total drug concentration in plasma was 36 mg/L (high dose group) in comparison with animals given the low doses (12 and 20 mg/L). The blood-to-plasma concentration ratio of tenoxicam was concentration independent and therefore did not account for the observed dose-dependent changes in Vdss and CL.     

Psychopathology and mood during heroin use: acute vs chronic effects

In the context of evaluating the effects of a narcotic antagonist on opiate acquisition, 14 detoxified addicts self-administered increasing doses of unblocked heroin intravenously over a ten-day period. Early in the addiction cycle, subjects experienced tension relief and euphoria but this was followed shortly by a shift in the direction of increasing dysphoria and psychopathology. Nonetheless, individual injections of the drug continued to induce brief episodes of positive mood, an effect enhanced by frequent injection. Heroin self-administration was sharply reduced when subjects were blocked with naltrexone, a narcotic antagonist, and the negative effects observed during unblocked drug use were not observed.     

Diltiazem disposition and metabolism in recipients of renal transplants

Owing to increasing evidence showing the importance of lipid peroxidation in oxidative stress in vivo, the role and evaluation of antioxidants have received much attention. Ginkgo biloba extract (GBE), well-known as an efficient drug against diseases induced by free radicals, has been suggested to exert its effect by antioxidant action. A method was established to determine the activity of GBE as a hydrogen donor by stoichiometric and kinetic studies, and GBE was compared with several other antioxidants such as alpha-tocopherol, propyl gallate, and two kinds of flavonoids which are found in GBE, quercetin, and kaempferol. It was found that there were 6.62 x 10(19) active hydrogens in 1 g of GBE. Stoichiometric studies showed that one molecule of alpha-tocopherol reacted with one molecule of galvinoxyl radical. For quercetin, kaempferol and propyl gallate, the experimental stoichiometric numbers were 4.0, 1.9, and 3.1, respectively. The rates of reaction of antioxidants with galvinoxyl in ethanol were determined spectrophotometrically, using a stopped-flow technique. The second-order rate constant, k2, obtained at 25 degrees C was 0.13 (g/L)(-1)s(-1) for GBE and 5.9 x 10(3), 2.1 x 10(3), 1.2 x 10(4), and 2.4 x 10(3) M(-1)s(-1) for quercetin, kaempferol, propyl gallate, and alpha-tocopherol, respectively. The second-order rate constant, k2', on the molar basis of active hydroxyl groups in the tested substances obtained at 25 degrees C decreased in the order of propyl gallate > alpha-tocopherol > quercetin > GBE approximately kaempferol. This is the first study on GBE as an antioxidant which reports both stoichiometric and kinetic results.     

Effects of Plasmodium berghei infection on arteether metabolism and disposition

Arteether (AE) is primarily deethylated to dihydroqinghaosu (DQHS) in rats and humans. Conversion of AE to DQHS was impaired in microsomes from rats infected with Plasmodium berghei. The Km for AE was 175.1 +/- 49.1 and 124.4 +/- 115.1 mumol/l, and Vmax was 2.24 +/- 0.45 and 1.22 +/- 0.67 nmol AE formed/mg protein/min in control and infected microsomes (p < 0.05), respectively. Calculated intrinsic clearance (CLint = initial Vmax/Km) for AE was only 4% lower in infected microsomes. Apparent pharmacokinetic parameter estimates for AE using the isolated perfused rat liver demonstrated no differences (p > 0.05) in volume of distribution, clearance, and half-life between normal and infected animals. Malaria infection resulted in decreased biliary excretion of free AE and DQHS. The majority of AE is eliminated via biliary excretion of conjugated DQHS, which is approximately 500-fold higher than free DQHS and 75-fold higher than free AE on a molar basis.     

Phospholipid metabolism during renal regeneration after acute tubular necrosis

Renal function, structure, and membrane metabolism were studied during regeneration of proximal tubular cells in rats. A reversible syndrome of nonoliguric acute renal failure was induced by the intravenous administration of a low dose of mercuric chloride (1.0 mg Hg/kg). At day 1 there was a marked increase in serum urea nitrogen concentration (SUN), decrease in food intake, and a zone of proximal tubular cell necrosis in the inner cortex. By day 3 low cuboidal epithelial cells were seen, indicating that regeneration had been initiated despite decreased food intake and increasing SUN. Phospholipid synthesis for new membrane formation in regenerating cells was studied by using [14C] choline as a precursor of phosphorylcholine and cytidine diphosphocholine (CDP-choline), which are intermediates in the synthesis of renal choline-containing phospholipid. The rate of [14C]choline incorporation into phospholipids in inner cortical slices was lowest 1 day after mercury administration, then increased constantly for the next 4 days to reach a maximal value 104% above control. The rate declined slowly for the next 11 days and returned to normal by 28 days. The increased rate represented choline phosphoglyceride synthesis, since degradation was unchanged. The entire increment in choline radioactivity in regenerating tissue 2 and 3 days after mercury administration was in phospholipid or CDP-choline, which suggests that the increased number of choline molecules entering the growing cells were trapped in these two forms. The results indicate that renal regeneration is associated with a specific enhancement of the synthesis of choline-containing phospholipids. This anabolic response of the kidney occurs in the presence of systemic catabolism and progressive renal functional insufficiency.     

Behavioral differences between acute and chronic schizophrenics: Course of psychosis, effects of institutionalization, or sampling biases?

Notes that scores of studies have been reported which demonstrate behavioral differences between acute and chronic schizophrenics. These data have most often been interpreted as reflecting changes in psychological functioning due to processes intrinsic to the schizophrenic disorder and/or the effects of institutionalizaton. Examination of the construct of chronicity and of the design of these studies suggests that (a) the existence of perceptual and cognitive changes during the course of schizophrenia has not been demonstrated and (b) the observed acute-chronic differences may primarily reflect sampling biases. (60 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Repeated dosing with oral cocaine in humans: Assessment of direct effects, withdrawal, and pharmacokinetics.

Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1–4 & Days 9–12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5–8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13–40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of LY293558, an AMPA receptor antagonist, on acute and chronic morphine dependence

A modified mE medium (mEI) containing the chromogenic substrate indoxyl-beta-D-glucoside to detect beta-D-glucosidase activity was evaluated with respect to specificity and recovery of enterococci from environmental waters. Extending incubation from 24 to 48 h improved enterococci recovery but 77% of the colonies classified as non-target were confirmed as enterococci. Randomly chosen enterococcal isolates from sewage, exposed in microcosms containing 0.22 micron membrane filtered fresh or estuarine water, exhibited differences in persistence as a function of exposure treatment. Decreasing the concentration of or eliminating indoxyl-beta-D-glucoside from mE did not significantly affect recovery of purified isolates.     

Liposome disposition in vivo: effects of pre-dosing with lipsomes

The effect of a high, intravenous dose of extruded multilamellar liposomes (1.1 g lipid/kg body weight) upon the subsequent ability of mouse tissues to take-up or bind a second intravenous dose of similar liposomes encapsulating 14C-inulin has been studied in vivo. The first and second doses were separated by either 1,5 or 24 hours. All tissue levels were measured one hour after the second dose. Controls received only the second dose. When the two doses were separated by one hours, 14C-levels in liver were depressed 6-fold and blood levels rose 29-fold relative to controls. However spleen uptake of lipsomes increased to three times control levels. When the two doses were separated by 24 hrs, the first dose had only a minimal effect on the disposition of the second dose. The results are consistent with a reversible blockade of hepatic, but not spleenic uptake and/or binding sites, by the first dose and indicate that adjusting a liposome dose (i.e. number of lipsomes) or use of a drug-free liposome pre-dose may be a useful technique for reducing hepatic uptake, increasing the circulation life time and/or modifying the tissue disposition properteries of therapeutic liposomes without changing liposome composition or size.