Model-independent Parameters Research Articles

Deaggregation is an integral component of the response of platelets to ADP in vitro : kinetic studies of literature and original data

Adenosine diphosphate (ADP) is recognized as an important mediator of platelet aggregation. Transient aggregation at low ( h 1 w M), and sustained aggregation at higher ADP concentrations are consistently observed. Dissociation of platelet aggregates has been described and may explain the reversible component of the aggregation response. We hypothesized that the net aggregation response to ADP in vitro results from the concurrent activation of two opposing processes, aggregation and deaggregation. Different purinergic receptor subtypes may mediate these effects. To test this hypothesis and its generalizability, we performed a kinetic analysis of representative published ADP-induced aggregation responses supplemented with original data from our laboratory. A four-compartment kinetic model was used to estimate k 3 , a rate constant of deaggregation. Two model-independent parameters, the magnitude of the aggregation response ( j OD) and the time to reach maximal aggregation ( t peak ) were also assessed. Greater sustained aggregation at higher ADP concentrations was consistently associated with increased j OD and t peak but decreased k 3 values. These relationships were independent of type of platelet preparation or experimental conditions and not due to ADP receptor desensitization. Conversely, blockade of the P2Y 12 receptor subtype (ticlopidine, clopidogrel or 2-MeS-AMP) decreased j OD and t peak but increased k 3 values. This supports the presence of active deaggregation which is decelerated by activation of the P2Y 12 receptor subtype.

Clinical pharmacokinetics of inhaled budesonide.

The corticosteroid budesonide is a 1:1 racemic mixture of 2 epimers, (22R)- and (22S)-, and is available in 3 different inhaled formulations for the management of asthma: a pressurised metered dose inhaler (pMDI), a dry powder inhaler (DPI) and a solution for nebulised therapy. Inhaled corticosteroids such as budesonide reach the systemic circulation either by direct absorption through the lungs (a route that is much more important than previously recognised) or via gastrointestinal absorption of drug that is inadvertently swallowed. Although the pharmacokinetics of budesonide have been extensively investigated following oral and intravenous administration, relatively few studies have defined the systemic disposition of budesonide after inhalation. Drug deposition in the lungs depends on the inhaler device: 15% of the metered dose of budesonide reached the lung with a pMDI compared with 32% with a breath-actuated DPI. In patients with asthma (n = 38) receiving different doses of budesonide by DPI (Turbuhaler), the pharmacokinetic parameters peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) were dose-dependent after both single dose and repeat dose (3 weeks) administration: time to Cmax (tmax) was short (0.28 to 0.40 hours) and the elimination half-life approximately 3 hours. Both AUC and Cmax were linearly related to budesonide dose. In a small group of healthy male volunteers (n = 9), the pharmacokinetics of budesonide 1,600 microg twice daily via pMDI were assessed on the fifth day of administration. Mean model-independent parameters for (22R)-budesonide were as follows: Cmax 1.8 microg/L, tmax 0.46 hours, elimination half-life 2.3 hours and oral clearance 163 L/h, and there were no enantiomer-specific differences in drug disposition. Budesonide undergoes fatty acid conjugation within the lung, but very limited pharmacokinetic data are available to define the pulmonary absorption characteristics. There is evidence from a population analysis that the pulmonary absorption of budesonide is prolonged and shows wide interindividual variation. Further pharmacokinetic studies are required to define the time-course of budesonide absorption through the lung in specific patient groups, and to investigate the effect of new inhaler devices (especially chlorofluorocarbon-free pMDIs) on the pharmacokinetic profile and systemic drug exposure.

Melting studies of short DNA hairpins: influence of loop sequence and adjoining base pair identity on hairpin thermodynamic stability.

Spectroscopic and calorimetric melting studies of 28 DNA hairpins were performed. These hairpins form by intramolecular folding of 16 base self-complementary DNA oligomer sequences. Sequence design dictated that the hairpin structures have a six base pair duplex linked by a four base loop and that the first five base pairs in the stem are the same in every molecule. Only loop sequence and identity of the duplex base pair closing the loop vary for the set of hairpins. For these DNA samples, melting studies were carried out to investigate effects of the variables on hairpin stability. Stability of the 28 oligomers was ascertained from their temperature-induced melting transitions in buffered 115 mM Na(+) solvent, monitored by ultraviolet absorbance and differential scanning calorimetry (DSC). Experiments revealed the melting temperatures of these molecules range from 32.4 to 60.5 degrees C and are concentration independent over strand concentrations of 0.5 to 260 microM; thus, as expected for hairpins, the melting transitions are apparently unimolecular. Model independent thermodynamic transition parameters, DeltaH(cal), DeltaS(cal), and DeltaG(cal), were determined from DSC measurements. Model dependent transition parameters, DeltaH(vH), DeltaS(vH), and DeltaG(vH) were estimated from a van't Hoff (two-state) analysis of optical melting transitions. Results of these studies reveal a significant sequence dependence to DNA hairpin stability. Thermodynamic parameters evaluated by either procedure reveal the transition enthalpy, DeltaH(cal) (DeltaH(vH)) can differ by as much as 20 kcal/mol depending on sequence. Similarly, values of the transition entropy DeltaS(cal) (DeltaS(vH)) can differ by as much as 60 cal/Kmol (eu) for different molecules. Differences in free energies DeltaG(cal) (DeltaG(vH)) are as large as 4 kcal/mol for hairpins with different sequences. Comparisons between the model independent calorimetric values and the thermodynamic parameters evaluated assuming a two-state model reveal that 10 of the 28 hairpins display non-two-state melting behavior. The database of sequence-dependent melting free energies obtained for the hairpins was employed to extract a set of n-n (nearest-neighbor) sequence dependent loop parameters that were able to reproduce the input data within error (with only two exceptions). Surprisingly, this suggests that the thermodynamic stability of the DNA hairpins can in large part be reasonably represented in terms of sums of appropriate nearest-neighbor loop sequence parameters.

The NLO DGLAP extraction of αs and higher twist terms from CCFR xF3 and F2 structure functions data for νN DIS

We performed the detailed NLO analysis of the combined CCFR xF 3 and F 2 structure functions data and extracted the value of α s , parameters of distributions and higher-twist (HT) terms using the direct solution of the DGLAP equation. The value of α s ( M Z )=0.1222±0.0048(exp)±0.0040(theor) was obtained. The result has larger central value and errors, than the original result of the CCFR collaboration, in view of the incorporation into the fits of the HT terms as the free model independent parameters. The x-shapes of the HT contributions to xF 3 and F 2 are in agreement with the results of other model-independent extractions and are in qualitative agreement with the predictions of the infrared renormalon model. We also argue that the low x CCFR data might have the defects, since their inclusion into the fits led to the following low x-behaviour of the gluon distribution xG(x,9 GeV 2)∼ x 0.092±0.0073, in contradiction with the results of its extraction from low x HERA data.

On the employment of λ carrageenan in a matrix system. III. Optimization of a λ carrageenan–HPMC hydrophilic matrix

The λ carrageenan/HPMC ratio in matrix tablets has been optimized in order to obtain pH-independent release profiles of chlorpheniramine maleate, a freely soluble drug. Release profiles in acidic (pH 1.2) and neutral (pH 6.8) media were fitted according to the Weibull and the power law models. Model independent parameters ( t 50% and the percentage of drug released after 2 h) were also calculated. The Weibull parameters were found suitable to describe the dependence of the release profiles on matrix composition. Preparation and testing of the optimized formulation showed linear and pH-independent release profiles lasting about 24 h, in good accordance with the values predicted by the optimization procedure.

Evaluation of microdialysis sampling of aqueous humor for in vivo models of ocular absorption and disposition

The dynamics of β-adrenergic-associated reductions in aqueous humor production for treatment of elevated intraocular pressure are not well understood. In particular, the relationship between ocular pharmacokinetics and pharmacodynamics has yet to be established. This study was undertaken to develop a procedure for examining the ocular absorption and disposition of topically administered ophthalmic β-adrenergic antagonists in individual animals. Dogs were anesthetized with isoflurane and a microdialysis probe was implanted in the anterior chamber of one eye and perfused with 0.9% saline at a rate of 2 μl min −1. 3H-propranolol was administered by intracameral injection or topically. Each dog received intracameral and topical propranolol, in alternate eyes on separate days, in a randomized cross-over fashion. Microdialysis probe effluent was collected every 5 min for ≥2.5 h; concentrations of propranolol were determined by liquid scintillation spectroscopy and were corrected for probe recovery of the substrate as determined by in vivo retrodialysis (∼46%) to estimate aqueous humor concentrations. In separate experiments in rabbits, microdialysis probes were implanted in each eye. 3H-propranolol was administered topically to one eye; the contralateral eye received intracameral 3H-propranolol. Model-independent pharmacokinetic parameters for each treatment phase were calculated. The mean±S.D. times to peak concentration of propranolol in aqueous humor were 86.6±47.6 min in the dog and 54.1±20.4 min in the rabbit. The terminal rate constant was 0.0189±0.00429 min −1 in the dog vs. 0.00983±0.00546 min −1 in the rabbit. Intraocular tissue availability of propranolol differed markedly between the dog ( n=3) and rabbit ( n=3) (∼0.056 in the dog vs. ∼0.55 in the rabbit). These results demonstrate the utility of microdialysis sampling for examination of ocular pharmacokinetics.

Absorption, Distribution and Excretion of Tacrolimus(FK506) in the Baboon.

The absorption, distribution and excretion of tacrolimus (FK506) was studied in the baboon after intravenous (i.v.) and oral administration of 14C-labeled FK506 (14C-FK506) at respective dose levels of 1 and 10 mg/kg. 1. After i.v. injection of 14C-FK506, both total radioactivity and FK506 were eliminated bi or tri-exponentially from the body. The whole blood levels of radioactivity were higher than those in the plasma, and were almost the same as the FK506 levels in the whole blood, which were much higher than those in the plasma. Model-independent pharmacokinetic parameters of FK506 in the whole blood were as follows: elimination half-life (T1/2), 12.3 hours; total body clearance, 0.265 L/h·kg; and volume of distribution at steady state, 3.93 L/kg. After oral administration, the parameters were as follows: T1/2, 10.4 hours; maximal blood concentration (Cmax), 190 ng/ml; time to reach Cmax, 2 hours; and area under the concentration-time curve (AUC0-∞), 2007 ng·h/ml. The bioavailability of radioactivity and FK506 was 7.0 and 5.1% respectively. The levels of radioactivity and FK506 were much lower in the plasma than those of the whole blood at FK506 level less than 250 ng/ml in the whole blood. 2. Tissue distribution of radioactivity was studied at 1, 24 and 120 hours after dosing with 14C-FK506. After i.v. injection, the radioactivity in all tissues collected was higher than that in the plasma 1 hour after injection, and was highest in the lungs, liver, pancreas, and small intestine. Radioactivity decreased gradually and was not detected in almost any tissues 120 hours after injection, except that maximal radioactivity in the large intestine was observed at 24 hours after injection. After oral administration, the radioactivity was detected in a limited number of the tissues such as thymus, liver, spleen, pancreas, bone marrow, and alimentary tract 1 hour after dosing and was not observed in almost any tissues 120 hours after dosing. The radioactivity in the body was mainly excreted in the bile to the feces after both administrations. 3. For 240 hours after administration of 14C-FK506, 5 and 86% of the dosed radioactivity were excreted in the urine and feces, respectively, after i.v. injection, and 4 and 79% after oral administration. The majority of radioactivity dosed was excreted in the urine and feces during the first 72 hours after both administrations.

Effect of fasting on the uptake of bilirubin and sulfobromophthalein by the isolated perfused rat liver

BACKGROUND & AIMS: Occurrence of hyperbilirubinemia after fasting has been recognized for many years. The pathogenesis of this syndrome is unclear. Although recent studies suggest that increased intestinal deconjugation and reabsorption of bilirubin may play a major role in establishment of hyperbilirubinemia during fasting, other studies have suggested that fasting down-regulates intrinsic hepatocyte transport of bilirubin. The present study was designed to examine this possibility in the isolated perfused rat liver.METHODS: Transport of 3H-bilirubin and 35S-sulfobromophthalein (BSP) was examined in isolated perfused livers from 48-hour fasted or control rats using a multiple indicator dilution technique. Data were analyzed to quantify single-pass extraction (model-independent analysis) and were also fit by computer to the model of Goresky to quantify unidirectional fluxes.RESULTS: Fasting for 48 hours resulted in an approximately 40% reduction in liver weight but had no effect on model-dependent or model-independent parameters of transport. Despite the fact that the liver was smaller, single-pass extraction of bilirubin and BSP by livers from fasted animals did not differ from control, indicating a greater efficiency at uptake of bilirubin and BSP.CONCLUSIONS: Enhanced enterohepatic circulation of bilirubin, not altered hepatic transport, is a major factor in the pathogenesis of fasting-induced hyperbilirubinemia.(Gastroenterology 1997 Nov;113(5):1707-13)

On t-quark decay

An extended electroweak model with second-rank antisymmetric tensor fields was proposed. The effective interactions resulting from the exchange of these fields have a specific dependence on the momentum transfer. This leads to the introduction of new model-independent muon decay parameters (M.V. Chizhov, Mod. Phys. Lett. A 9 (1994) 2979), which can be measured experimentally in SLAC and TRIUMF. The new tensor interactions can affect the three-particle semileptonic meson decays (M.V. Chizhov, Mod. Phys. Lett. A 8 (1993) 2753). In this connection it will be interesting to carry out new experiments on K + → l + νγ, K + → π 0 l + ν decays at DAφNE. The K L-K S mass difference sets constraints to the tensor particles masses. The mass of the lightest tensor particle could be less than the t-quark mass. Therefore, the lightest tensor particle may give an additional W-boson contribution to the t-quark decay with the same signature. In this Letter we have calculated the contribution of the new tensor particles to the t-quark decay.

Inhibitory synaptic transmission in isolated patches of membrane from cultured rat spinal cord and medullary neurons.

1. To quantify the variability in the characteristics of inhibitory glycinergic and GABAergic currents at single synaptic connections between cultured rat embryonic spinal cord or medullary neurons, we have used patch-clamp techniques to record miniature inhibitory postsynaptic currents (mIPSCs) in cell-attached patches. Experiments were performed with the patch pipette containing either a low-calcium internal saline to allow comparison with subsequent whole cell recordings or external saline with tetrodotoxin, DL-2-amino-5-phosphonovaleric acid, and 6-cyano-7-nitroquinoxaline-2,3-dione, a solution that is more appropriate for bathing a nerve terminal. 2. The mIPSCs recorded from the synapses restricted to the cell-attached patches were characterized by their times to peak, amplitudes, and time constants of decay. The degree of variability in these characteristics was quantified with the use of the following model-independent parameters: the coefficient of variation, skewness, and kurtosis. The distribution of time to peak values has a mean value of 5.6 +/- 0.5 (SE) ms, has the lowest coefficient of variation (0.33 +/- 0.01), is fairly symmetrical, and has a Gaussian shape with respect to peakedness. On the other hand, both the amplitude and decay time constant distributions are highly skewed and more peaked than Gaussian distributions. The mean amplitude is -6.6 +/- 0.6 pA with a coefficient of variation of 0.60 +/- 0.05, whereas the mean decay time constant is 22.8 +/- 1.0 ms with a coefficient of variation of 0.81 +/- 0.03. 3. The amplitude distributions for spontaneous inhibitory currents recorded from cell-attached patches are best fitted by the sum of multiple Gaussians. The coefficient of variation for the first Gaussian peak fitted to the amplitude distributions is 0.290 +/- 0.028. 4. Decay time distributions were consistently best fitted by the sum of four Gaussians with decay constants as follows: D1 = 5.7 +/- 0.2 ms (n = 12), D2 = 11.2 +/- 0.7 ms (n = 11), D3 = 20.6 +/- 0.8 ms (n = 12), and D4 = 43.8 +/- 2.3 ms (n = 16). These mean values are essentially identical to those reported in the preceding paper for mIPSCs recorded in the whole cell configuration. 5. In eight neurons we were able to record mIPSCs both in cell-attached patches and in subsequent whole cell configurations. The properties of mIPSCs recorded from single synapses (i.e., times to peak, amplitude, and time constants of decay) show as much variability as those of mIPSCs recorded subsequently in the whole cell mode; that is, there are no statistically significant differences in the coefficients of variation, skewness, or kurtosis for the three different distributions.

Application of model-independent and model analysis for the investigation of effect of drug solubility on its release rate from hydroxypropyl methylcellulose sustained release tablets

The effect of drug solubility on the dissolution from the sustained release (SR) matrix tablet prepared with hydroxypropyl methylcellulose (HPMC) 2910 4000 cps was investigated using model-independent moment analysis and Higuchi-type model analysis. In this study, seven model drugs which have various solubilities in the dissolution medium were used for preparation of tablets and dissolution studies were then performed. To determine the mechanisms behind the sustained release, the infiltration rate of the medium into the matrix tablet and the erosion rate of the matrix tablet were also investigated. The model-independent moment parameters i.e. mean dissolution time (MDT), mean medium infiltration time (MIT), mean tablet erosion time (MET), mean swelling time (MSWT) and mean diffusion time (MDFT) as well as Higuchi-type model analysis which, based on release mechanisms, were demonstrated for optimization of HPMC matrix tablets. Both in the model-independent and model analyses, the relationships obtained between drug solubility and release characteristics were similar. Regarding the poorly soluble drug, U-78875, the observed dissolution rate is slower than the erosion rate of the matrix tablet, which indicates that the main rate limiting factor for the dissolution is erosion of the matrix tablet. In the case of drugs whose solubilities are between 0.5 mg/ml and 5 mg/ml (methyl-paraben, ethyl-paraben and propyl-paraben), dissolution rates are observed between the erosion rate of the matrix tablet and the infiltration rate of medium into the matrix tablet, and. the dissolution rate increases with increasing drug solubility. Regarding highly soluble drugs, whose solubilities are more than 5 mg/ml (procaine hydrochloride, acetaminophen, and theophylline), the dissolution rates are not influenced so much by drug solubility but show a similar rate of medium infiltration into matrix. In the latter two cases, the primary rate limiting factor of dissolution is infiltration of medium into the matrix tablet. The reported MDT and MDFT values were within the range 3.16-8.75 h and 1.11-6.70 h, respectively, except for U-78875. Also, MIT, MET and MSWT values as device matrix characteristics were 2.05, 12.05 and 10.00 h, respectively. The model-independent moment parameters, MDT, MIT, MET, MSWT and MDFT are directly comparable to each other. Further, these parameters would be applicable in comparing the device and dissolution characteristics of different types of formulation. These model-independent analytical approaches allow us to optimize the SR matrix formulation at the development stage.

Effect of food on the bioavailability of SDZ DJN 608, an oral hypoglycemic agent, from a tablet and a liquid-filled capsule in the dog.

The effect on food on the bioavailability of SDZ DJN 608, a D-phenylalanine derivative, was investigated in three mature, male beagle dogs. Each dog received, under fasting and postprandial conditions, a 30 mg oral dose as a tablet (T) and a liquid-filled capsule (LC). Additionally, a 5 mg intravenous dose was given in the fasting state. Doses in the same dog were separated by 1-week washout periods. Serial plasma samples were collected for 24 h postdose and analyzed for SDZ DJN 608 using HPLC. Model-independent pharmacokinetic parameters were compared between treatments by 3-way ANOVA: In vitro dissolution profiles of T and LC were generated using the USP paddle method. In addition, the transport of SDZ DJN 608 through a Caco-2 cell monolayer was examined at concentrations of 0.1 and 1 mM, in the absence and presence of an aromatic amino acid, L-alpha-methyldopa, the transport of which is mediated by the large neutral amino acid (LNAA) carrier. In the dog, SDZ DJN 608 was rapidly absorbed. The peak plasma concentration (Cmax) averaged higher, and the peak time (tmax) shorter, after LC than T, though the differences were not statistically significant. This finding is consistent with in vitro dissolution data showing that, at both pH 1.2 and pH 6.8, the dissolution rate of LC was faster than that of T. No significant difference in the area under curve (AUC) was observed between LC and T, the absolute bioavailability of both being complete in the fasting state. Whereas the presence of food showed little effect on the tmax and Cmax of either dosage form, it significantly reduced the AUC, the effect (ca -20%) being not different between LC and T. In the Caco-2 model, the mucosal-to-serosal permeability of SDZ DJN 608 was independent of concentration and unaffected by L-alpha-methyldopa, suggesting passive diffusion of the former. Food had little effect on the absorption rate but significantly reduced the bioavailability of SDZ DJN 608 regardless of the dosage form. This effect is unlikely to be caused by inhibition of the transepithelial transport of SDZ DJN 608 by amino acids in the diet.

Bioavailability of pseudoephedrine from controlled release formulations in the presence of guaifenesin in human volunteers

A multiple-dose bioequivalence study with six healthy human volunteers was conducted. The bioavailability of an experimental controlled release tablet containing pseudoephedrine was compared with a marketed controlled release pseudoephedrine capsule in a three-way crossover study. Plasma samples, collected serially after oral drug administration, were analyzed for pseudoephedrine content using a specific HPLC method with UV detection. The bioavailability parameters, area under the concentration-time curve (AUC), maximum plasma concentration Cmax, and time to peak (Tmax) were obtained from the plasma concentration-time data. Additionally, model independent pharmacokinetic parameters were estimated. Analysis of variance of the data revealed no statistically significant differences between the test and the reference formulation. The presence of guaifenesin in the sustained release tablet did not influence pseudoephedrine bioavailability. The relative bioavailability of the tablet dosage form with respect to the capsule was found to be 100.8%. Classical and Westlake 95% confidence limits as well as the two one-sided t test, proposed by Schuirmann, and the Anderson-Hauck power analysis supported the inference that the two formulations demonstrated comparable bioavailabilty, even in the presence of guaifenesin. Using a non-linear regression program, it was found that the pharmacokinetics of pseudoephedrine followed a simple one-compartment disposition model with no lag time. Additionally, an in vitro-in vivo correlation, based on the estimation of cumulative relative fraction absorbed, was developed between the absorption of pseudoephedrine in humans and the in vitro dissolution time.

Application of a population pharmacokinetic modeling to bioavailability/bioequivalence study of cefadroxil preparations

The bioavailability of cefadroxil after administration of two immediate-release preparations, Cedrox and Duricef, to 12 healthy volunteers was studied. Bioequivalence of the preparations was assessed using model-independent parameters and a non-parametric confidence interval method. No difference in the extent of bioavailability and in the absorption rate was detected. However, after applying pharmacokinetic models and a population approach to estimate their parameters, significant differences in absorption kinetics were evident. A one-compartment model with a time lag and two consecutive first-order absorption steps were found to be consistent with the data, and the first step absorption rate constant was greater in the case of Cedrox while in the second step Duricef demonstrated more rapid absorption. No significant differences in the absorption time lag were found. Despite the fact that the difference in the absorption kinetics of cefadroxil for these two formulations is clinically insignificant, the study clearly demonstrated the usefulness of a population approach in determining the intimate details of the drug absorption process.

Absolute Bioavailability and Absorption Characteristics of Aerosolized Tobramycin in Adults with Cystic Fibrosis

Administration of antibiotics by the inhalational route has become part of standard protocols for treatment of and prophylaxis for Pseudomonal pneumonias in patients with cystic fibrosis. For tobramycin, however, limited data are available on the aerosol absorption patterns, and no absolute bioavailability data for tobramycin exist. The purpose of this study was to measure the absolute bioavailability and systemic absorption characteristics of tobramycin when administered in high doses by a nebulizer. Multiple serum concentrations of tobramycin were measured after administration of an intravenous dose (mean, 2.9 mg/kg every 6 hours) and after an inhalational dose (5.6 mg/kg over 1 hour). Inhalational doses were superimposed over the "tail" of a steady-state intravenous dose to improve the sensitivity of the assay procedure (Abbott-TDX). Absolute bioavailability (F) was determined from AUC ratios normalized for dose. Model-independent pharmacokinetic parameters (volume of distribution [Vss] and total clearance [CLt]) were determined for each subject. Absorption characteristics (absorption rate constant [Ka] and mean absorption time [MAT]) were assessed after calculation of the cumulative fraction of drug absorbed, amount of bioavailable drug, and percent remaining to be absorbed per unit time using the Loo-Riegelman method. Three men and three women completed the study, and all received concurrent doses of ceftazidime. Mean absolute bioavailability (+/- standard deviation) was 9.13% (+/- 3.82), and the rate of absorption into the systemic circulation was consistent with a zero-order model profile for all subjects. Mean absorption time values reflected a wide degree of subject variability and ranged from approximately 15 to 150 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved measurements of the neutral current from hadron and lepton production at LEP

We present an update with increased statistics to our published analysis of hadronic and leptonic cross sections and of the leptonic forward-backward asymmetries ine + e − collisions. The published results were based on a total 454 000 hadronic and 58 000 leptonic events. This analysis adds 733 000 hadronic and 88 000 leptonic events recorded at theZ 0 peak in 1992 by the OPAL experiment at LEP. A model independent analysis ofZ 0 parameters based on an extension of the improved Born approximation leads to tests of lepton universality and gives an interpretation of the results within the Standard Model framework. We also present a model independent test for new physics.

Experimental pharmacokinetics of biologically active plant phenolic compounds III. Pharmacokinetics of dihydroquercetin

AbstractThe pharmacokinetics of dihydroquercetin (DHQ) was studied by HPLC in rats after intravenous injection of the compound in single doses of 1,3, 10 and 30 mg/kg and after oral administration in single doses of 50 and 500 mg/kg. Nonlinear pharmacokinetic behaviour was demonstrated for DHQ when administered intravenously to rats; after oral administration DHQ can be detected in blood plasma only in trace amounts. Model independent parameters for intravenous administration of DHQ were calculated, and the description of the dynamics of the change in concentration of DHQ as a two‐compartmental model were given for blood plasma.

Pharmacokinetics of acridine-4-carboxamide in the rat, with extrapolation to humans

The pharmacokinetics of N-[2-(dimethyl-amino)ethyl]acridine-4- carboxamide (AC) were investigated in rats after i.v. administration of 18, 55 and 81 mumol/kg [3H]-AC. The plasma concentration-time profiles of AC (as measured by high-performance liquid chromatography) typically exhibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mean (+/- SD) model-independent pharmacokinetic parameters were: clearance (Cl), 5.3 +/- 1.1 1 h-1 kg-1; steady-state volume of distribution (Vss), 7.8 +/- 3.0 l/kg; mean residence time (MRT), 1.5 +/- 0.4 h; and terminal elimination half-life (t1/2Z), 2.1 +/- 0.7 h (n = 10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1-8 h after AC administration. By 6 h, plasma radioactivity concentrations were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometric equations were developed from rat and mouse pharmacokinetic data that predicted a Cl value of 0.075 (range, 0.05-0.10; 95% confidence limits) 1 h-1 kg-1 and a Vss value of 0.63 (range, 0.2-1.1) l/kg for total drug concentrations in humans.

A novel method for the observation of membrane transporter dynamics

A new method is proposed for measuring the dynamic properties of a membrane transporter by means of steady-state fluxes. Any voltage-sensitive transporter will give a flow of substrate in the presence of a steady-state periodic membrane potential. The periodic steady-state flow, averaged over one period, is a flux that can be measured by traditional steady-state techniques, such as the radioactive tracer method. The average flux, solely due to the periodic field, is described by a set of Lorentzian functions that depend on the applied periodic field amplitude and frequency. The normal mode amplitudes and frequencies of these Lorentzians are model-independent parameters of the transport mechanism. Measurement of the average flux as a function of the applied periodic frequency permits determination of system relaxation times as the reciprocals of the midpoints of the Lorentzian curves, which in turn can be used to estimate individual rate constants of specific models. It was found by simulation of a six-state model of the electrogenic Na+/glucose cotransporter, using published estimates of the model rate constants, that the periodic field effects can be large and rich with measurable details that can be used to study the mechanism thoroughly. The new method serves in this case to complement and expand on the information obtainable by means of the voltage clamp method. It was also found by means of simulations of a nonelectrogenic six-state cotransporter model that experimentally measurable effects are expected and that results can be used to distinguished among alternative kinetic models as well as to estimate individual rate constants. The range of dynamic information available with this method is not accessible by voltage clamp or other pre-steady-state methods presently in use.

Pharmacokinetics of Rapamycin

The pharmacokinetics of rapamycin was investigated in five New Zealand white rabbits following intravenous administration of 0.05 and 0.5 mg/kg rapamycin in a randomized crossover fashion. Whole blood concentrations of rapamycin were analyzed by high-performance liquid chromatography (HPLC). Model-dependent and -independent parameters were calculated. The volume of distribution at steady state and total body clearance increased significantly as the dose increased. Rapamycin pharmacokinetics appear to be nonlinear. The whole blood volume of distribution, especially at the higher dose, indicated distribution out of the blood component. The drug is not cleared rapidly, with a terminal half-life of > 13 hours as calculated by model-independent parameters. The 24-h whole blood trough concentrations of the drug are well within the analytical range of the HPLC procedure. This should permit trough level monitoring for therapeutic range studies involving the drug.