PubMed Health⌕ Search

Biomedical subjects

W J Jusko

Publications and source records attributed to W J Jusko.

At least 109 records · Page 6Linked to original sources
PubMed1994

Prednisolone pharmacodynamics: leukocyte trafficking in the rat.

Leukocytes circulate throughout the body patrolling for foreign antigens and facilitating immune responses. Corticosteroids exert their immunosuppressive actions, in part, by inhibiting the normal trafficking of these cells. The rat was used to investigate corticosteroid-induced changes in circulating total lymphocytes, CD4+ cells, and granulocytes. Prednisolone doses of 5, 25, and 50 mg/kg or saline were given i.v. Blood was taken over 24 hr for analysis of cell subsets by flow cytometry. Steroid exposure was assessed by assaying plasma prednisolone by HPLC. Response profiles were complicated, possibly by opposing effects on the recirculation of cells to blood. This prospect was investigated using pharmacodynamic cell trafficking models. Steroid-like effects in saline treated animals that may be due to stress or other factors limited data interpretation. As an animal model to characterize cell trafficking actions, the rat is an imperfect model.

Animals↗
PubMed1994

Inhibition of rat splenocyte proliferation with methylprednisolone: in vivo effect of liposomal formulation.

The effect of a liposomal formulation of methylprednisolone (MPL) on the inhibition of lymphocyte proliferation in spleen cells was investigated following IV dosing in rats. Liposomes do not alter the suppressive action of MPL when placed in lymphocyte culture. Rat splenocytes were found to have greater sensitivity to MPL (EC50 = 7.9 nM) than do human peripheral blood lymphocytes (EC50 = 28 nM). In vivo studies in rats utilized 2 mg/kg IV bolus doses of liposomal MPL compared to drug in solution. Animals were sacrificed at various times post-dosing until 120 h, spleen was excised and, after incubation of lymphocytes with PHA, splenocyte blastogenic responses were assessed by measuring cellular incorporation of 3H-thymidine. The suppressive effect of liposomal MPL in comparison with free drug was significantly prolonged (> 120 h vs < 18 h). Inhibition effects versus time were described by a pharmacodynamic model using MPL concentrations in plasma as an input function. A nonlinear relationship was found between suppression of splenocyte proliferation and the concentration of bound glucocorticoid receptors in spleen. Only partial receptor occupancy accompanied complete lymphocyte suppression. The suppression of endogenous corticosterone in plasma for both treatments was similar with values from L-MPL rats returning to baseline after 24 h. These results demonstrate enhanced efficacy of local immunosuppression by targeting spleen with liposomal MPL.

Animals↗
PubMed1994

Effects of acute and chronic inflammation on the pharmacokinetics of prednisolone in rats.

The effects of acute and chronic stages of carrageenan-induced air-pouch inflammation on the pharmacokinetics of prednisolone were studied in male Wistar rats. Chronic inflammation produced a significant increase in the area under the curve (AUC) of prednisolone compared to control animals (6594 +/- 2144 vs 3530 +/- 2164 micrograms.hr/L). The effect of acute inflammation was not significant (AUC = 4996 +/- 3813). Both acute and chronic inflammation also reduced the in vitro plasma protein binding of prednisolone, the reduction being much greater after chronic inflammation. The AUC of free prednisolone after chronic inflammation was 3141 micrograms.hr/L, compared to 1121 micrograms.hr/L in the control group and 1823 micrograms.hr/L after acute inflammation. The mean values of half-life and apparent volume of distribution at steady-state in each group were similar. These results indicate that prednisolone must be used with caution in the treatment of inflammatory diseases because of higher free concentrations of the steroid.

Acute Disease↗
PubMed1994

Physiologic indirect response models characterize diverse types of pharmacodynamic effects.

A family of four basic physiologic indirect response models has been proposed to account for the pharmacodynamics of drugs that act by way of inhibition or stimulation of the production or loss of endogenous substances or mediators. Such models were applied previously to account for the anticoagulant effects of warfarin, adrenal suppression by corticosteroids, cell trafficking effects of corticosteroids, antipyretic effects of ibuprofen, and aldose reductase inhibition. Additional responses that can be readily characterized with such models include muscular contraction from pyridostigmine, diuresis from furosemide, bronchodilation from terbutaline, prolactin secretion after cimetidine, and potassium suppression by terbutaline. This report shows that indirect response models, rather than "link" or "hypothetical effect compartment" models, may be more appropriate for diverse drugs when time lags exist between plasma or biophase drug concentrations and the time course of pharmacodynamic responses.

Adrenal Cortex Hormones↗
PubMed1994

Concomitant etodolac affects neither the unbound clearance nor the pharmacologic effect of warfarin.

Potential interactions between the nonsteroidal anti-inflammatory etodolac and the anticoagulant warfarin were studied in 18 healthy subjects by use of a randomized, three-period crossover design. Each treatment lasted 2 1/2 days and consisted of warfarin, etodolac, or both drugs. Prothrombin time was determined daily during each warfarin period to measure pharmacologic effect. Total serum concentration and unbound fraction of both drugs were determined over the dose interval after the last dose of the study drug(s). Concomitant etodolac did not affect the prothrombin time response or the unbound clearance of warfarin. During concomitant etodolac administration, the median peak concentration of total warfarin was significantly decreased by 19% (p = 0.005), median total clearance was significantly increased by 13% (p = 0.0123), and the unbound fraction tended to increase (median unbound fraction of warfarin, 1.245% with etodolac and 1.045% without etodolac; p = 0.0979; not statistically significant). These observations suggest a small displacement of warfarin from serum protein by etodolac or a metabolite of etodolac. No etodolac pharmacokinetic parameter was significantly affected by concomitant warfarin administration. Thus etodolac does not appear to alter the unbound clearance of warfarin or augment its pharmacologic effect. Nevertheless, it is prudent that clinical monitoring be done for individuals taking these two compounds concomitantly.

Adult↗
PubMed1994

Multicenter comparison of tacrolimus (FK 506) whole blood concentrations as measured by the Abbott IMX analyzer and enzyme immunoassay with methylene chloride extraction.

A multicenter comparison was made between the Abbott IMX and enzyme-linked immunosorbent assay (ELISA) procedures for analysis of tacrolimus (FK 506) in whole blood. Proficiency samples and 853 patient specimens obtained after various organ transplantations were assayed by 13 laboratories. Both groups of test samples yielded slightly lower (7 and 13%) values by the IMX method, but the difference is not clinically meaningful. The type of organ transplant was not a factor that contributed to assay variation. The Abbott IMX results were essentially equivalent to ELISA and considerably facilitates monitoring of FK 506 therapy.

Enzyme-Linked Immunosorbent Assay↗
PubMed1994

Pharmacokinetics in the infant.

Processes controlling the absorption, distribution, metabolism, excretion, and pharmacologic effects of drugs are likely to be immature or altered in neonates and infants. Absorption may be affected by differences in gastric pH and stomach emptying rate. Low serum protein concentrations and higher body water composition can change drug distribution. Drug metabolism enzyme activity is typically reduced in the neonate, but rapidly develops over the first year of life. Renal excretion mechanisms are low at birth, but mature over a few months. Limited data are available on the pharmacodynamics of drugs; infants show greater sensitivity to d-tubocurarine. Developmental changes are rapid during the first weeks and months of life, thus requiring continual modification of drug dosage regimens designed for treating pediatric patients.

Body Composition↗
PubMed1994

Inhibition of phytohaemagglutinin-induced lymphocyte proliferation by immunosuppressive drugs: use of whole blood culture.

A whole blood lymphocyte proliferation assay was compared to a standard method requiring the isolation of lymphocytes from blood. Both methods were used to measure inhibition of proliferative responses of phytohaemagglutinin (PHA1)-stimulated human peripheral blood lymphocytes by tacrolimus (FK 506(1)), cyclosporine A (CsA1), rapamycin (RA1), dexamethasone (DEX1), prednisolone (PR1), and methylprednisolone (MP1). Three of the drugs studied (FK 506, CsA, and DEX) yielded similar IC50 values with both methods. The whole blood proliferation assay produced modestly lower IC50 values for RA, PR and MP. The whole blood lymphocyte proliferation method is simple and can be used when only limited volumes of blood can be obtained or isolation of cells gives unsatisfactory yields.

Cells, Cultured↗
PubMed1994

Pharmacokinetic and pharmacodynamic effects of coadministration of methylprednisolone and tacrolimus in rabbits.

Tacrolimus (FK 506) is used for treatment of various organ transplantations in combination with corticosteroids. Rabbits are a good animal model for pharmacokinetic studies of these drugs. The i.v. administration of methylprednisolone (MP; 1.25 mg/kg) (sodium succinate) at 0.5 hr after tacrolimus (0.15 mg/kg) did not influence the disposition of these drugs in rabbits. Clearances of MP were 0.45 liters/hr/kg after given alone and 0.48 liter/hr/kg after tracrolimus. The plasma and whole blood clearances of tacrolimus were 2.18 and 0.21 and 2.35 and 0.19 liters/hr/kg after separate and joint administration with the steroid. The concentrations of corticosterone were variable in all groups and was not useful as a pharmacodynamic parameter. Whole blood histamine concentrations as a marker for basophils did not change after drug administration, but increased over several weeks of experiments. Helper-T cells in rabbits as in humans show a circadian rhythm with an acrophase at 1:00 A.M. MP and tacrolimus decreased the number of circulating helper-T cells with IC50 values of 23 ng/ml for MP and 6.7 ng/ml for tacrolimus. After coadministration of these drugs, an interaction occurs, but the nature (additive or antagonistic) of this interaction was not clear. The IC50 of tacrolimus for in vitro inhibition of lymphocyte proliferation was 0.39 ng/ml (0.47 nM) and 1.02 ng/ml (2.73 nM) for MP. The maximum percentage of inhibition was 94.6% for tacrolimus and 64.9% for MP. The interaction between low concentrations of tacrolimus (0.1-0.3 ng/ml) and MP was additive, but mild antagonism was observed at higher concentration of tacrolimus (1 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of liposomal methylprednisolone on heart allograft survival and immune function in rats.

Liposomal methylprednisolone (L-MPL) applied in monotherapy prolonged cardiac allograft survival in rats in comparison with the same dosage regimen of drug in solution (Solu-Medrol). The most efficacious treatment consisted of a 2-mg/kg i.v. dose of L-MPL twice a week (group III), producing survival up to 30 days, followed by a 4-mg/kg/week dose of L-MPL (group IV) and a single 2-mg/kg dose of L-MPL (group II). Survival in animals receiving Solu-Medrol as a 2-mg/kg dose twice a week (group V) did not differ from untreated animals. Only daily 4-mg/kg doses of methylprednisolone (MPL) in solution (group VI) were as effective as group III. The concentrations of MPL in liver and spleen were detectable for 26 days after the last dose of L-MPL, showing tissue selective sequestration of drug. Treatment at these low doses did not suppress endogenous corticosterone determined 24 hr or later in plasma. The administration of steroid caused significant immunosuppression in most animals as measured by inhibition of splenocyte blastogenesis induced with phytohemagglutinin. Cellular immunity data did not differ significantly between groups, but alterations occurred at day 14 to 15 after surgery: CD3, CD4 and ratio CD4:CD8 subsets of cells showed minimum values; CD8, CD4CD8, CD25 and white blood cell counts were at maximum at this time. Slight but significant differences between Immunoglobulin M suppression in group II compared to group I or V were found, whereas Immunoglobulin G values were unchanged. The transplantation and treatment with steroid decreased the total body weight of animals but increased weights of internal organs, particularly spleen, similarly for all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Receptor-mediated pharmacodynamics of corticosteroids.

Major conclusions from these studies are that receptor occupancy usually directly governs biologic responses to corticosteroids and that the slow onset of effects is caused not by pharmacokinetic factors but by the time needed for mRNA and protein synthesis. The slow dissipation of steroid effects is governed by steroid elimination (time to decline below KD values), the KD for receptor binding, and the time required for mRNA and the TAT enzyme to readjust to baseline conditions. These studies provide insight concerning the integrated role of drug, receptors, and biologic response mediators in determining the role of dose, time, type of corticosteroid, and drug-disease interactions in governing the pharmacodynamics of these agents. The models are of more general value in pharmacology as well, for these cascade models should be relevant to the quantitation of any type of gene-mediated drug effect.

Adrenal Cortex Hormones↗
PubMed1994

Selected tissue distribution of liposomal methylprednisolone in rats.

The distribution of methylprednisolone (MPL) in various rat tissues following 2 mg/kg IV bolus doses of liposomal drug (L-MPL) and drug in solution was investigated. Animals were sacrificed at selected times post-dosing until 120 h. Liver, spleen, thymus, heart, lungs, muscle, kidney and brain were excised and the concentrations of MPL were measured using HPLC after homogenizing organs in buffer. The incorporation of MPL in liposomes did not alter the uptake of drug by heart, lung and muscle. Drug concentrations in brain were undetectable. In the kidney the MPL concentrations after 1 h were higher for liposomal drug and not detectable at later time points. Tissue to plasma partition coefficients were close to unity in lung, heart, and muscle at 1-2 h after the dose of drug in solution and increased by 7.5 times for spleen and 6 times for thymus after the dose of L-MPL. There were no significant differences between the weights of organs expressed in percent of body weight. These results demonstrate that, while the sequestration of L-MPL by lymphatic tissues occurred, the uptake of drug by the other tissues did not increase. This may be beneficial for preferential targeting of the immune system.

Animals↗
PubMed1993

Pharmacokinetics of methylprednisolone hemisuccinate and methylprednisolone in chronic liver disease.

The disposition of methylprednisolone (MP) and its prodrug hemisuccinate (MPHS) was assessed in six middle-aged patients with chronic liver disease (CLD) and compared with six younger, healthy subjects after a single IV dose of 25.4 mg of MPHS. Blood and urine samples were collected over 12 hours. Plasma and urine concentrations of MPHS and MP and plasma cortisol were measured by HPLC. MPHS clearance (CL) was significantly reduced in the CLD group (495 vs. 1389 mL/hr/kg) whereas volume of distribution (Vss) of MPHS (about 0.35 1/kg) did not differ. The elimination half-life, t1/2 beta, was significantly longer in CLD (0.61 vs. 0.32 hr). The percent recovery of unchanged MPHS in urine was similar (about 9%) in both groups. The kinetic parameters of MP did not differ between the two groups for: clearance (about 370 L/hr/kg IBW), Vss (about 1.3 L/kg), and t1/2 beta (about 3.0 hr). The suppression t1/2 of cortisol after MPHS was longer (3.9 vs. 1.9 hr) indicating metabolic pathways for cortisol and MP are affected differently in CLD. Reduction in MPHS CL may reflect altered hepatic blood flow due to both cirrhosis and age effects. However, good availability of MP from MPHS and lack of perturbation of MP pharmacokinetics in CLD patients may provide therapeutic advantages in selection of this glucocorticoid. This is the first study that characterizes the disposition of the prodrug MPHS and the formation of MP simultaneously in CLD patients.

Adult↗
PubMed1993

Plasma protein binding of tacrolimus in humans.

An ultracentrifugation method was used for the determination of the tacrolimus (FK 506) free fraction in plasma. Samples of 400 microL were centrifuged for 6 h at 160,000 x g, and concentrations of [3H]tacrolimus were measured in the original plasma and in the second layer of the supernatant. The binding of tacrolimus in normal plasma averaged 73% and was independent of the drug concentration. Albumin (3.5%) binding averaged 44.4-57.0%, and alpha 1-acid glycoprotein (100 mg/L) binding averaged 39%. Hepatic transplant patients exhibited 72.0% +/- 3.6% binding of tacrolimus. Plasma protein binding is probably not an important factor in the disposition of tacrolimus.

Blood Proteins↗