The use of antiplatelet medication in hospitalised elderly patients.

BACKGROUND: The use of antiplatelet agents is strongly recommended for the secondary prevention of ischemic events such as myocardial infarction, stroke/transient ischemic attack (TIA). OBJECTIVES: The aim of our study was to analyse the use of antiplatelet medication in patients after myocardial infarction, stroke/TIA, and patients with both conditions and to identify patient-related characteristics, which determine the use of such drugs in elderly patients. METHODS: Study sample (n=372) was derived from 2,157 patients admitted to long-term care departments of three municipal hospitals. The study included patients aged ≥65 years after myocardial infarction, stroke/TIA or both. RESULTS: Antiplatelet medications were prescribed in 54.8 % and 68.5 % of patients at hospital admission and discharge, respectively. Hospitalisation led to a significant increase in the use of antiplatelet medication in patients after myocardial infarction and in those with the combination of both events. However, in patients after only stroke/TIA, we did not find any significant difference comparing the use of antiplatelet medication at the time of hospital admission and discharge, respectively. CONCLUSION: Our study revealed that physicians are more aware of the benefits of antiplatelet medication in elderly patients after myocardial infarction or those after both myocardial infarction and stroke/TIA in comparison with patients after only stroke/TIA (Tab. 3, Ref. 32).

Effects of ionizing radiation on the blood brain barrier permeability to pharmacologically active substances.

Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultra-structural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physico-chemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding 10-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. Either an increase or a decrease of BBB permeability, or both, occurring in a certain time sequence, was observed. The mechanism of hyperpermeability after irradiation is not fully understood, but the activation of vesicular transport offers one possible explanation. Even less understood is the mechanism of decreased permeability. The response of the BBB to ionizing radiation is most probably nonspecific and its nature may be assumed to be similar to its responses to other physical or chemical noxious factors.

Bile-independent absorption of cyclosporine from a microemulsion formulation in liver transplant patients.

A microemulsion formulation of CsA, which was anticipated to be independent of bile for oral absorption, was compared with the currently marketed formulation in liver transplant patients with external biliary drainage. Eleven patients aged 47.6 +/- 13.1 years and weighing 75.8 +/- 5.7 kg received single 400-mg oral doses of each formulation in a randomized, crossover protocol on days 4 and 6 after transplant. Serial venous blood samples were collected over a 12-hr period after each administration and whole blood CsA concentrations were determined by a validated RIA specific for the parent compound. Systemic exposure to CsA was consistently higher from the microemulsion formulation in all patients, as judged by the peak concentration and the area under the curve. Specifically, the area under the concentration-time curve was 943 +/- 400 vs. 2378 +/- 911 ng.hr/ml, indicating an average 156% higher bioavailability from the microemulsion compared with the currently marketed formulation in liver transplant patients in the absence of bile.

Lack of interaction between fluvastatin and oral hypoglycemic agents in healthy subjects and in patients with non-insulin-dependent diabetes mellitus.

Human drug interaction studies in vivo are conducted when in vitro and/or animal interactions suggest clinical relevance. Studies in vitro have indicated that the new, entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin affects the metabolism of the nonsteroidal anti-inflammatory drug diclofenac and the oral hypoglycemic tolbutamide. Diclofenac and tolbutamide are both model substrates of the CYP2C isozymes, suggesting that this enzyme could be involved in the underlying mechanism of interaction. The concomitant use of lipid-lowering drugs with oral hypoglycemic agents has been recommended in patients with non-insulin-dependent diabetes mellitus (NIDDM). Therefore, 2 studies were initiated to explore potential pharmacokinetic and pharmacodynamic interactions between fluvastatin, simvastatin, or placebo and the oral hypoglycemic agents tolbutamide (study I) and glyburide (study II), each in 16 healthy subjects. These compounds were selected because of a demonstrated in vitro interaction with tolbutamide and widespread clinical use of glyburide. A further study (study III) was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between fluvastatin and glyburide under therapeutic conditions in 32 patients with NIDDM. Single and multiple coadministration of fluvastatin 40 mg or simvastatin 20 mg increased the mean maximum plasma concentration and area under the concentration-time curve of glyburide by about 20%. The pharmacokinetics of tolbutamide were influenced to only a minor extent. Fluvastatin concentration-time profiles were unaffected by tolbutamide or glyburide coadministration. However, the pharmacokinetic interactions between fluvastatin or simvastatin and tolbutamide and glyburide were not associated with clinically relevant changes in blood glucose and insulin concentrations and, therefore, are not considered to be relevant in therapeutic practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of orally administered cyclosporine in patients with Crohn's disease.

Cyclosporine pharmacokinetics were reported to be influenced in patients with Crohn's disease. To explore the relationship between Crohn's disease and cyclosporine pharmacokinetics, this investigation was performed in 20 patients with varying Crohn's Disease Activity Index (CDAI). A single oral dose of 300 mg of cyclosporine was given and serial blood samples were obtained over 52 hours. Cyclosporine whole blood concentrations were determined by a specific monoclonal radioimmunoassay. Pharmacokinetic parameters were comparable with those of healthy volunteers. No statistically significant difference between the pharmacokinetic parameters of the patients with CDAI values less than 150 and those with CDAI values 150 or greater could be shown. Although several factors associated with the pathology of Crohn's disease theoretically could influence the pharmacokinetics of orally administered cyclosporine, this investigation did not identify statistically significant differences in cyclosporine pharmacokinetics in Crohn's disease patients with different disease activities or different localization of inflammation as compared with healthy volunteers. However, if large parts of the small bowel were removed, a decrease of absorption of cyclosporine could be observed. In any case, it is important to be aware of the clinical variability of Crohn's disease and its potential implications in cyclosporine absorption.

Concentration-guided strategies in drug development: experience with a cyclosporine analog in transplantation.

A concentration-guided study was designed to maintain adequate immunosuppression and avoid excessive drug exposure while determining steady-state relative bioavailability of two cyclosporine G (CyG) oral formulations in stable renal transplant patients. In period I (week 1), 26 patients taking cyclosporine A (CyA)-based immunosuppressive regimens entered the study. Doses were titrated to maintain trough concentrations within a predefined range, as measured by fluorescence polarization immunoassay (FPIA). Patients were given an oral solution of CyG in period II (weeks 2-3), and a microemulsion capsule formulation of CyG in period III (weeks 4-5), with dose titration as necessary to achieve trough concentrations in a predefined range, as measured by FPIA. Full pharmacokinetic profiles were obtained on the last day of each study period. Treatment with CyA was reinitiated in period IV (week 6) at the same doses as at study entry. All blood samples were analyzed at the conclusion of the study using CyG- and CyA-specific high-performance liquid chromatography (HPLC). When changing from oral solution to capsule for CyG, an average 19% dose reduction was necessary to compensate for the elevated trough concentrations resulting from the increased bioavailability of the capsule formulation. The concentration-guided strategy was successful in avoiding over-exposure, and resulted in comparable values for area under the concentration-time curve (AUC) for both formulations of CyG. Dose normalization of the pharmacokinetic parameters subsequently allowed calculation of the relative bioavailability. Specifically, a faster rate and greater extent of CyG absorption from the capsule than the oral solution were manifested as a slightly earlier time to peak concentration (tmax), an average 44% increase in the maximum concentration (Cmax), and an average 29% increase in AUC. This experience demonstrated that a concentration-guided trial design allowed a drug development question for a compound with a narrow therapeutic index to be addressed safely and directly in the target patient population.

Pharmacokinetic study of stobadine.

The aim of this paper is to provide a brief overview of most important results of stobadine kinetic studies in rats, dogs, and human volunteers. In these studies, stobadine dihydrochloride and stobadine dipalmitate was used for intravenous and oral administration, respectively. To evaluate kinetic properties of stobadine and its metabolites, TLC, HPLC, GLC, GC-MS, radiometric, and fluorometric methods were developed and used.

Determination of pentoxifylline in serum by high-performance thin-layer chromatography.

An analytical method to study the bioavailability of newly developed pentoxifylline sustained-release tablets has been developed and assessed in experiments on dogs. For the isolation of pentoxifylline and its metabolites from serum solid-liquid extraction was applied by involving the internal standard probe. HPTLC plates with a preconcentration zone were used for separation of the analysed substances, using chloroform-methanol (95:5, v/v). Quantification was by densitometric detection. The detector response was linear in the concentration range investigated for pentoxifylline: 0.02-1.5 micrograms ml-1 of serum.

Effect of gamma-irradiation on disposition of the local anaesthetic, carbisocaine in rabbits.

14C Labelled carbisocaine, a local anaesthetic agent, has been administered intravenously in a dose of 2 mg kg-1 to rabbits 7 days after whole-body 60Co gamma-irradiation with a dose of 5 Gy (1.9 Gy min-1) and to control rabbits. The plasma carbisocaine concentration-time courses were approximated by biexponential equations. The estimated pharmacokinetic parameters obtained when the data were fitted to an open two-compartment model were significantly different for the irradiated group relative to control animals, indicating a radiation-induced slower elimination rate of carbisocaine: AUC: 0.37 vs 0.29% dose min mL-1, CLtot: 109.8 vs 155.4 mL min-1, Vdss: 27.6 vs 33.2 mL kg-1, kel: 0.0259 vs 0.0307 min-1, MRT: 251.7 vs 214.6 min. The total excreted amount of 14C radioactivity in the irradiated group was lower in comparison with controls: 6.5 vs 8.7% in bile and 18.3 vs 23.7% in urine. However, lower carbisocaine concentrations were recorded in the heart, lungs, liver, and kidneys of irradiated rabbits compared with controls.

Model of distribution of anticancer agents transplanted into the brain tissue using the random walk method.

A Monte-Carlo approach to analysis of dispersion in the tissue of a locally administered drug is presented. The distribution of a drug in the tissue is simulated as a distribution of randomly walking particles. The approach is demonstrated on a simple situation for which both experimental results and an analytical solution are known. The approach can be used in situations, where common numeric methods are difficult to use, especially for analyses of drug transport in an inhomogeneous space, and problems with complex boundary conditions, e.g. in analyses of dispersion of anticancer agents locally applied into tumours.

The rate and extent of calcium bioavailability from two oral dosage forms in rats.

The purpose of the present work was to compare oral bioavailability of calcium from two calcium preparations, Calcium Sandoz forte 500 mg and Calcium Spofa effervescens. The pharmacokinetic study was carried out on rats, and plasma levels of 45Ca after administration of labelled calcium solutions were determined. Appropriate equations describing the two-compartment open model and the one-compartment model with first order absorption were fitted to the observed i.v. and oral data, respectively, using weighted nonlinear least-squares regression analysis. The extent and the time profile of the rate of 45Ca systemic bioavailability were assessed. Both parameters suggested identical bioavailability of calcium from the two dosage forms compared.

Pharmacokinetics of ethimizol in man.

The pharmacokinetics of ethimizol were studied in healthy volunteers given 1 mg/kg i.v. or 2 mg/kg orally. The serum concentrations of ethimizol were determined by HPLC. After i.v. infusion the kinetics of ethimizol could be described by a one-compartment model in 4 and by a two-compartment model in 1 subject. The elimination half-lives ranged from 34.1 to 79.2 min and the apparent volumes of distribution from 0.4 to 1.3 l/kg. After oral administration, the absorption half-lives ranged from 7.3 to 57.1 min. The absolute bioavailability varied between 3.6 and 22.2%. The binding of ethimizol to plasma proteins was less than 10%.

Clinico-biochemical aspects of guanidine compounds in uraemic toxicity.

"Uraemia" literally means "urine in blood". With the advancement of basic medical sciences, it is being better understood. The clinical syndrome of uraemia is due to the failure of not only the excretory but also the metabolic, regulatory and endocrine functions of the kidney. Apart from the "retained toxic metabolites", a number of guanidine derivatives had been found which are now considered to be more important in the causation of the uraemic syndrome. Cohen had hypothesised that nitrogen retention in uraemia causes an aberration in the urea cycle that in turn leads to the production of guanidinosuccinic acid (GSA) in large amounts. However, it appears that methylguanidine (MG) is produced from the degradation of creatinine by the gut flora in uraemics. Both GSA and MG are proved to be toxic. The role of GSA in uraemic neurotoxicity and coma is still controversial and needs further investigation. It is possible that the combined effects of a number of compounds are responsible for the development of the uraemic syndrome.

Pharmacokinetics of carbisocaine in rats and mice.

[14C]carbisocaine, N-(2-(2-[1-14C]-heptyloxyphenylcarbamoyloxy)-propyl)-diethylammoni um chloride was administered to male Wistar rats, weighing 180-210 g IV in doses of 0.425, 1.425, 2.425 or 4.425 mg/kg or orally in a dose of 2.425 mg/kg. Extraction of carbisocaine from alkaline media into n-heptane was used for assessment of the unchanged drug in plasma, organs and excreta in predetermined time intervals. The two-way analysis of variance confirmed the insignificant effect of subject variability of experimental animals (p greater than 0.05) on plasma data after IV administration. Plasma data following the IV administration were approximated by a linear open two-compartment model with elimination from the central compartment. Regression analysis indicated linearity between carbisocaine plasma AUC and the IV administered dose within the range tested. The following model parameters were obtained: elimination half-life 161.2 +/- 37.5 min, total body clearance 59.5 ml/min/kg, distribution volume in steady state 5616.2 ml/kg and mean residence time 96.7 min. The systemic availability of the orally given carbisocaine was 45.2%, assessed by AUCpo/AUCiv (0-360 min). The brain uptake index of carbisocaine in relation to 3H2O was 57.7 +/- 3.9%. Whole body autoradiographs of mice injected with [14C]carbisocaine documented accumulation of 14C in gall and urinary bladder and in the gut contents and the effective placental barrier against carbisocaine and its metabolites.

Pharmacokinetics of stobadin and of the sum of its metabolites in rats during repeated administration.

Stobadin dihydrochloride was administered p.o. to rats at a dose of 1 mg kg-1 once daily for 25 consecutive days. The peak and trough concentrations of the sum of stobadin metabolites, determined from Days 6-16 of treatment, demonstrated a steady-state. The mean daily excretion of 3H-radioactivity during this period was 43 per cent and 52 per cent of the administered dose into urine and faeces, respectively. The terminal half-life of stobadin in plasma following a 25-day chronic treatment was 78.3 min, which was shorter than the value of 95.3 min, determined in a single dose experiment. The data indicate that no accumulation of stobadin and of its labelled metabolites occurs in the course of repeated administration of 3H-stobadin.