Increase In Mean Residence Time Research Articles

The effect of mixing particles with different characteristics on the residence time distribution of particles in two-phase flow in a tubular system

The residence time distribution of large solid particles in fluid suspensions was determined in a tubular continuous processing system. Different flow conditions covering both laminar and transient flow regimes were studied for particles with different diameter and density. Experiments were performed for single particles and for suspensions with 1% v/v concentration. The results showed that even for low particle concentrations, particle interactions promote an increased mean residence time and dispersion. Residence time distribution of mixtures of two different types of particles were also measured for different flow conditions. It was concluded that mixing particles with different characteristics often promotes a decrease both in the mean and minimum residence time of each type of particle, although in some situations the opposite was observed.

Experimental ovine fasciolosis: antipyrine clearance as indicator of liver damage

Antipyrine clearance was used to assess microsomal oxidative function in eight female Churra breed sheep at 20, 30, 40, 60, 80 and 100 days after infection by an oral administration of 150 metacercariae of Fasciola hepatica. Experimental infection was ascertained by an ELISA test and by faecal analysis. A significant increase in plasma glutamate dehydrogenase (GLDH) activity from 20 days post-infection and in gamma-glutalmyltransferase (GGT) activity from 40 days post-infection was found Both enzyme activities reached maximum levels in plasma of infected sheep at 80 days post-infection, progressively decreasing thereafter. A significant reduction in the total plasma clearance of antipyrine occurred from 60 to 100 days post-infection and a significant increase in mean residence time occurred by 80 days post-infection. The decrease of antipyrine metabolism coincided with the entrance of parasites in bile ducts and the highest liver damage caused by migrating juvenile flukes.

Species difference in the disposition of liposomes among mice, rats, and rabbits: allometric relationship and species dependent hepatic uptake mechanism.

The species difference in the pharmacokinetics of liposomes was investigated in mice, rats and rabbits. Liposomes were intravenously injected at doses of 1, 10 and 100 (nmol/g body weight), and the time courses of liposomes in blood, liver and spleen were measured. Pharmacokinetic parameters were regressed as a function of body weight (BW) and dose of liposomes (D). The uptake mechanism of liposomes was also examined with the isolated perfused liver between rats and mice. Mean residence time increased with the increase of BW and D of liposomes. This increase of mean residence time resulted from the decreased total body clearance, which was principally explained by the species difference in the hepatic uptake clearance (CLh) of liposomes. The parameter CLh was regressed well by a multiple regression as a function of BW and D. In this analysis, an exponent for BW was around 0.5, which clearly indicates that smaller animals have higher uptake clearance per unit BW. Immunohistochemical analysis revealed that there was no significant difference in the density of Kupffer cells among these species. This suggest that the species difference in CLh resulted not from the density of Kupffer cells but from the uptake ability of Kupffer cells among species. In the isolated perfused liver, the hepatic uptake of liposomes was mainly explained by opsonin dependent uptake in rats, while opsonin independent uptake in mice. These quantitative and qualitative information on the species difference of liposome disposition will provide an useful information for constructing a drug delivery system using liposomes.

The effect of colestipol and cholestyramine on ibuprofen bioavailability in man

The purpose of this study was to determine whether a concomitant single oral dose of one of the anion exchange resins colestipol hydrochloride (10 g) or cholestyramine (8 g) administered with ibuprofen (400 mg) would alter the bioavailability of this non-steroidal anti-inflammatory agent. The study was performed according to a randomized three-way crossover design in six healthy male volunteers. After dosing, serial blood samples were collected for a period of 10 h. Plasma harvested from blood was analysed for ibuprofen by a sensitive high-performance liquid chromatographic method. There were no significant differences between colestipol treatment and control for peak plasma concentration (Cmax), time to peak concentration (Tmax), area under the plasma concentration-time curve (AUC), mean residence time (MRT), elimination rate constant (Kel), or elimination half-life (t1/2). Cholestyramine treatment resulted in a significant decrease in AUC (26%, p < 0.05) and Cmax (34.4%, p < 0.01) and a significant increase in Tmax (80%, p < 0.01) and MRT (20.2%, p < 0.05). Cholestyramine administration showed no significant effect on the Kel and t1/2 values. A significant correlation was obtained between the increase in MRT and the increase in Tmax. The confidence intervals (90%) of the mean values of the pharmacokinetic parameters (AUC0-infinity and Cmax) for the colestipol: control ratio were well within the acceptable range of 100 +/- 20, whereas those for the cholestyramine: control ratio were outside it. Colestipol treatment was found to be bioequivalent to the control treatment by Schuirmann's two one-sided t tests, while cholestyramine treatment was found to be bioinequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of meropenem and its metabolite in young and elderly healthy men

The pharmacokinetics of meropenem and its ring-opened metabolite (ICI 213,689) were investigated with eight young (20- to 34-year-old) and eight elderly (67- to 80-year-old) healthy male volunteers given single 30-min intravenous infusions of 500 mg of meropenem. All subjects had normal age-correlated glomerular function. The mean terminal half-life of meropenem was 1.27 h in the elderly subjects versus 0.81 h in the younger subjects (P less than 0.001). This and similar increases in mean residence time and area under the concentration-time curve were explained by a reduction in total [139 versus 203 ml/(min.1.73 m2); P less than 0.001], renal, and nonrenal clearances in subjects at advanced ages. The apparent volume of distribution and urinary recovery over 8 h were not significantly altered. With the metabolite, prolonged serum half-life and mean residence time, enlarged area under the concentration-time curve, and lower renal clearance but no significant changes in peak plasma concentration or urinary recovery were found in the elderly. The reduction in the renal excretion rate of meropenem and its metabolite corresponds to the age-associated physiological decline in renal function. The capacity to metabolize meropenem may also be slightly impaired in people at advanced ages. Dose reduction of meropenem should be considered for elderly patients.

Analgesic and Thermic Responses to Intravenously Administered Morphine in 8- and 24-Week-Old Rats

The analgesic and thermic responses to morphine (5 and 10 mg/kg) injected intravenously to 8- and 24-week-old male Sprague-Dawley rats were determined. Greater analgesic and lower hyperthermic responses to morphine in 24-week-old rats in comparison to 8-week-old rats were observed. The pharmacokinetic parameters of morphine administered intravenously were also determined. Cmax for 5 and 10 mg/kg doses of morphine were smaller in 24-week-old rats in comparison to 8-week-old rats; however, AUC0----infinity was smaller only for 5 mg/kg dose. For 10 mg/kg dose, mean residence time (MRT) and the apparent steady state volume of distribution (Vss) for the older rats were higher than for the younger ones, but for 5 mg/kg dose the values did not differ. The enhanced responses to morphine in older age group of rats for 5 mg/kg dose cannot be explained solely on the basis of pharmacokinetics. However, for 10 mg/kg dose of morphine, the greater responses in 24-week-old rats could probably be related to increases in MRT and Vss. Factors other than serum kinetics, like kinetics of morphine in the brain as well as the brain opiate receptors, may also be involved in the differential effects of morphine in rats of different ages.

Loperamide Hydrochloride

Artemether and lumefantrine are World Health Organization (WHO) approved combinational therapy for antimalarial action, which exhibits low aqueous solubility and poor oral bioavailability. The present work intended to perform the comparative antimalarial and pharmacokinetic studies for newly designed combinational formulations using carriers such as dry suspension containing nanosponges (ADS) and microneedles (AMN). The nanosponges required for formulation ADS were prepared using the solvent evaporation method, whereas AMN by solvent casting method. The antimalarial test (percentage inhibition test) revealed that formulations showed significant activity towards chloroquine-resistant strain (RKL-9) in comparison to sensitive strain (MRC-2). Rane's test showed that formulations ADS and AMN increased the mean survival time of mice in contrast with the untreated groups. The pharmacokinetic study revealed that the formulation ADS demonstrated similar kinetic profile with increased mean residence time (MRT) of actives, in comparison with marketed preparation (Riamet). However, formulation AMN showed lesser Cmax and AUC but increased MRT, which demonstrated the prolonged presence of actives in the systemic circulation. Thus, the results of antimalarial and pharmacokinetic studies revealed the excellent action of formulations ADS and AMN towards resistant strains and tremendous potential of formulation ADS in escalating the oral bioavailability of actives with improved efficacy, respectively.

Model for the Kinetics of Imipramine and Its Metabolites in Adolescents

A kinetic model for imipramine (IMI) has been developed, based upon a study of 16 teenagers who received IMI 4-5 mg/kg/day for treatment of a major depressive disorder. Serial measurements of plasma concentrations of IMI, desmethylimipramine (DMI), 2-hydroxy-IMI, and 2-hydroxy-DMI were made. Mean residence times, volumes of distribution, clearances of IMI and DMI, and rate constants for formation and elimination of the hydroxy metabolites were determined from a multicompartment model fitted to the concentration-time data. Mean residence time for DMI was significantly longer than for IMI (47.1 +/- 21.2 vs. 13.4 +/- 4.8 h, p less than 0.001). A different volume of distribution for IMI and DMI was not supported by the data. Clearance of DMI was considerably slower than that of IMI (0.67 +/- 0.45 vs. 2.18 +/- 1.33 l(kg.h), p less than 0.001). A statistically significant increase in mean residence time with increasing age during adolescence was found (r = 0.57, p less than 0.05).

Study on the continuous loop tubular reactor for emulsion polymerization of styrene

AbstractA continuous loop tubular reactor (CLTR) with a Bodenstein number of 100 and a recycle ratio of 0.992 (obtained under the conditions of a mean residence time of 25.0 to 59.95 min and a stirring rate of 418 rpm) was used for studying the emulsion polymerization of styrene (St). The recipe used in the study is 76.8 g St/l‐water, 3.73 g sodium lauryl sulfate (SLS)/l‐water, and 2.30 g potassium persulfate (KPS)/l‐water. The effects of the mean residence time on the performance of emulsion polymerization were studied. The overshoots in the monomer conversion and the particle number concentration were found to be higher as the mean residence time increased. The overshoots diminished at about 3 times the mean residence time. The steady state particle number concentration was independent of the mean residence time, while the steady state monomer conversion increased with increasing mean residence time.

A preliminary pharmacokinetic study of 111In-labeled 260F9 anti-(breast cancer) antibody in patients.

The pharmacokinetics of 111In-labeled 260F9, a murine monoclonal antibody directed against a breast-cancer-associated antigen, was determined in seven patients with advanced breast cancer. Six patients were administered 1 mg antibody containing 1 mCi 111In. The seventh patient was administered 20 mg unlabeled antibody followed by 1 mg 111In-labeled antibody all via a peripheral vein. Immunoprecipitation, HPLC and SDS-PAGE gels demonstrated the stability of radiolabel on the antibody. The serum clearance of the radiolabel closely fits (r2 greater than 0.95) a two-compartment model for the first six patients. The apparent volume of distribution of the radiolabel approximated to the plasma volume (31) and its mean residence time was 23.7 h. The radiolabel had an average t 1/2 beta of 22.9 +/- 12.21 h at the 1-mg dose. At the 20-mg dose one-compartment elimination kinetics were observed with the radiolabel and antibody showing similar mean residence times (36-41 h) and a t 1/2 beta of 26-28 h. Whole-body imaging showed that the blood-pool: liver ratio of radioactivity increased fourfold (at 48 h postinfusion) at the higher dose and the percentage of the injected dose of radioactivity in the liver decreased from 25% to 8% (24 h postinfusion). In one patient 7-14 times more radioactivity was localized in a breast tumor than in fat (normal breast). Over the first 25 h an average (cumulative) 7.5% of the total dose was excreted in urine. A study of 260F9 in CDF-1 mice demonstrated that the radiolabel remained associated with the antibody in serum. The antibody, however, cleared 60-fold slower in mice than in patients and showed an increased mean residence time of 191 h. The disparity in the pharmacokinetics of the antibody seen in the mouse and in the clinic, points to the different behavior shown by murine monoclonal antibodies in humans. This points to the need for preliminary studies of antibodies in patients for preclinical evaluations of their effectiveness as drug-targeting agents.

Incidence of a subclinical fascioliasis on antipyrine clearance and metabolite excretion in sheep.

1. The pharmacokinetics of i.v. antipyrine (25 mg/kg) used as a model compound, were determined in young male sheep, before and each month after an oral infestation by 150 metacercariae of Fasciola hepatica, and 8 weeks following a flukicidal treatment. 2. The parasitic pathology was ascertained by the clinical observation of animals and the increase in plasma antibodies directed against liver flukes. 3. A significant decrease in the total plasma clearance of the drug occurred by week 4 to 16, and a 1.7 fold increase in mean residence time occurred by week 12 post-infection. 4. Urinary excretion of antipyrine metabolites was determined before and 8 weeks following the infestation. 4-Hydroxyantipyrine was the major urinary metabolite and its excretion was decreased by 30% in infected sheep, whereas there was no change in the excretion of norantipyrine, 3-hydroxymethylantipyrine or unmetabolized drug. 5. It is concluded that the impairment of antipyrine clearance in the course of fascioliasis could be related to the decrease in liver microsomal cytochrome P-450-dependent mono-oxygenases observed in sheep with a similar parasitic burden.

Deposition of Monodisperse Insoluble Aerosol Particles in the 0.005 to 0.2 &lt;italic&gt;μ&lt;/italic&gt;m Size Range Within the Human Respiratory Tract

Abstract In 4 subjects with normal lung function total deposition of monodisperse, hydrophobic, uncharged silver particles in the 0.005 to 0.08 μm size range was investigated for a variety of breathing patterns during steady state mouth- and nose breathing. The evaluation of deposition was based upon measurements of mean particle number concentration in inspired and expired air by means of a condensation nucleus counter. Owing to the diffusional particle transport, total deposition increases with decreasing particle size and increasing mean residence time of the aerosol in the lungs. With decreasing particle size the time dependence becomes less and the effect of tidal volume more significant. A semi-empirical formula is derived which fits the experimental data.

Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol

The effects of ketoconazole and methylprednisolone on endogenous cortisol were studied in eight normal subjects. Intravenous methylprednisolone sodium succinate was given alone in doses of 15 or 30 mg. The methylprednisolone dose was reduced by 57% when ketoconazole was administered chronically for 1 week to seek equivalent methylprednisolone AUCs by compensating for the expected reduction in methylprednisolone clearance. Ketoconazole decreased clearance by 46% and increased mean residence time by 37%. The ratio of the cortisol AUC during each drug treatment compared with baseline conditions was used to assess the net extent and duration of cortisol suppression. This cortisol AUC ratio was reduced from 0.45 (methylprednisolone) to 0.39 (methylprednisolone plus ketoconazole), suggesting that ketoconazole modestly enhanced (P less than 0.01) cortisol suppression. Based on the reduction in methylprednisolone clearance and cortisol AUC by ketoconazole, a 50% lower dose of methylprednisolone during concomitant therapy with ketoconazole is recommended.

Intercomparison of lung deposition data for aerosol particles

There are considerable discrepancies between published lung deposition data. Therefore, the aerosol groups of GSF at Frankfurt/M and of CNEN at Bologna devoted a two week workshop to the understanding of the reasons for some of these discrepancies. This paper reports on the workshop and describes the intercomparison procedures. For all particle sizes and breathing patterns investigated total deposition values for mouthbreathing evaluated with the methods and techniques used in the two laboratories agree satisfactorily and exhibit an intersubject variability. Electrostatic deposition was found to rise with increasing number of charges carried by the particles and with increasing mean residence time of the aerosols in the respiratory tract.