Relative frequencies of constrained events in stochastic processes: An analytical approach.

The stochastic simulation algorithm (SSA) and the corresponding Monte Carlo (MC) method are among the most common approaches for studying stochastic processes. They relies on knowledge of interevent probability density functions (PDFs) and on information about dependencies between all possible events. Analytical representations of a PDF are difficult to specify in advance, in many real life applications. Knowing the shapes of PDFs, and using experimental data, different optimization schemes can be applied in order to evaluate probability density functions and, therefore, the properties of the studied system. Such methods, however, are computationally demanding, and often not feasible. We show that, in the case where experimentally accessed properties are directly related to the frequencies of events involved, it may be possible to replace the heavy Monte Carlo core of optimization schemes with an analytical solution. Such a replacement not only provides a more accurate estimation of the properties of the process, but also reduces the simulation time by a factor of order of the sample size (at least ≈10(4)). The proposed analytical approach is valid for any choice of PDF. The accuracy, computational efficiency, and advantages of the method over MC procedures are demonstrated in the exactly solvable case and in the evaluation of branching fractions in controlled radical polymerization (CRP) of acrylic monomers. This polymerization can be modeled by a constrained stochastic process. Constrained systems are quite common, and this makes the method useful for various applications.

Plasma protein binding of APD: role of calcium and transferrin.

The bisphosphonate drug APD (pamidronate, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate) has been shown to bind to human plasma proteins. This was an unexpected observation since this hydrophilic, anionic drug is not typical of molecules that exhibit this characteristic. At a concentration of 5 micrograms/ml the extent of binding of APD to fresh human plasma in vitro was variable between subjects 30.2% +/- 8.5% (mean +/- S.D., n = 10). Binding was not influenced by the time or concentration of APD over the range 0.05-10.0 micrograms/ml. At 20 and 50 micrograms/ml some precipitation of APD occurred. Both calcium and iron play a role in the binding of APD to plasma proteins, addition of calcium to plasma increased the degree of binding of APD, whereas the calcium chelators EDTA and EGTA reduced the binding of APD. Similarly, addition of iron to plasma increased the binding and the inclusion of the iron chelator desferrioxamine diminished the binding of the drug. The effects of iron and desferrioxamine were less pronounced than those of calcium and EDTA, indicating that the majority of the binding involves calcium ions and a smaller contribution is made by ferric ions. The equilibrium dissociation constants (Kd) for APD binding to calcium and iron binding sites on plasma proteins were estimated to be 852 microM and 29 microM, respectively. Calcium binding sites were of high capacity but low affinity and the iron binding sites were of lower capacity and higher affinity. Electrophoresis of plasma proteins following incubation with [14C]APD revealed binding to the transferrin and globulin fractions. However, there was some dissociation of protein bound APD during the electrophoresis. The consequences of hypercalcaemia on the pharmacokinetics of APD are discussed.

Disposition and nephrotoxicity of 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD), in rats and mice.

The purpose of this study was to investigate the disposition and the nephrotoxicity of 3-amino-1-hydroxypropylidene-1, 1-bisphosphonate (APD-pamidronate) in order to elucidate the mechanism of the non-linearity of the renal elimination of this drug. The fate of APD labelled with [14C]APD was studied in mice and rats for a range of doses (0.5-40 mg/kg) and indicators of renal function were monitored. In both species, the percentage of dose excreted during the first 24-h after treatment fell dramatically as a function of the dose. However, the renal burden of APD rose linearly for doses of APD below 10 mg/kg and increased non-linearly over this threshold. In contrast the concentration of APD in both bone and liver, which together account for a large proportion of the dose, appeared to increase proportionally with dose. There was no evidence, therefore, that the non-linear renal elimination of APD was due to an increased uptake of APD by tissues. Conversely, the significant fall in the renal excretion of APD was paralleled by a striking loss in body weight, and for high doses, by a fall in the creatinine clearance. An increased enzymuria suggested the loss of brush border membranes and the release of lysosomal contents by proximal tubular cells. Morphological studies confirmed this and revealed a focal proximal tubular necrosis 6 days post dosing. We conclude that the nephrotoxicity of APD accounts for the non-linear renal elimination of this drug.

[Chronobiology and renal physiopathology]. / Chronobiologie et physiopathologie rénale.

This review presents our recent knowledge in renal chronobiology, considering physiology, pathology, pharmacology and toxicology. In a first part, are described renal chronophysiological data, pointing out particularly urinary excretion rhythms, largely described for last century. Such physiological observations lead to conclude that renal structures and functions present large temporal variations. Endogenous and exogenous origins of these rhythms are widely discussed. Evidence of such circadian and circannual variations in these renal structures and functions permit to understand why different agents, pathogeneous, toxic or medicamentous, will present time-dependent effects at renal level. So, a second part presents some recent experimental and clinical data in chrononephrology, chronopharmacology and chrononephrotoxicity. Finally, the concept of renal chronesthesy is presented and discussed, in order to explain these temporal variations in renal target susceptibility to different substances acting at this level.

Circadian rhythm in gamma glutamyltranspeptidase and leucine aminopeptidase urinary activity in rats.

Urinary gamma glutamyltranspeptidase (GGT) and leucine aminopeptidase (LAP), renal tubular brush border enzymes, have been shown to be sensitive indicators of renal tubular functions. This study documents circadian rhythms in the urinary activity of GGT and LAP, statistically validated and quantified by the cosinor method, in 15 male Wistar rats standardized to a LD 12:12 illumination schedule (light from 0800 hr to 2000 hr) and fed ad libitum. The acrophase of the circadian rhythms in urinary GGT and LAP activity occurred at the end of the rest span of the animals: between 1730 and 1915 for GGT (depending on the mode of expression of the activity) and between 1700 and 1910 for LAP. Of striking resemblance in their timing, both these rhythms were also of large amplitude (about 50% of the mesor for urinary GGT activity and about 45% for LAP one). The circadian acrophases of urinary GGT and LAP activity led in timing the circadian rhythms in urine volume and creatinine excretion by about 13 hr. Such findings consistent with the circadian variations found by other investigators in GGT in kidney homogenates or in LAP in human urine thus reflect a periodicity in renal tubular function. The reasons for these circadian variations, still unknown at this time, are discussed. The influence recently demonstrated of the hormonal context on protein and enzyme synthesis at the tubule, and its phase relations to urinary enzyme excretion emphasize how much the circadian rhythm in urinary GGT and LAP activity is well included in the murine time structure.(ABSTRACT TRUNCATED AT 250 WORDS)

[Chronotoxicity of amikacin]. / Etude de la chronotoxicité de l'amikacine.

This study addresses circadian variations in the tolerance of mice to a single lethal dose of amikacin. Female mice placed in cages providing constant thermal conditions and lighted from 8 h to 20 h were given a single intraperitoneal injection of 1.6 to 1.9 g/kg amikacin at different times over the 24 hours (8 h, 14 h, 20 h and 2 h) and in two different seasons (november/december and march/april). The number of dead mice was determined every day for seven consecutive days. For a given dose, mortality rate was influenced by the time and season of administration of amikacin. Amikacin toxicity exhibited a peak at 2 h (mean 60%) and nadir at 14 h (mean 47.75%) in november/december, whereas the opposite was true in spring (means 36.6% and 23.3% respectively at 14 h and 2 h). Thus, acute toxicity of amikacin in mice varies throughout the circadian cycle and from season to season. These findings encourage further research in view of achieving optimal use of antibiotics in human clinical practice.

[Circadian variations of the mortality of mice due to cadmium sulfate]. / Etude des variations circadiennes de la mortalité de la souris vis-à-vis du sulfate de cadmium.

If circadian variations in tolerance to drugs have been often demonstrated, such observations about heavy metals are still very scarce. The present study proposes to determine if circadian variations occur in the tolerance of Mice to single lethal dose of cadmium sulphate. 400 female mice, kept in cages on a 8.00-20.00 L/D cycle, received IP a single cadmium sulphate injection at different doses (2.5, 3, 3.5 and 4 mg/kg) at different hours in the day (8.00, 14.00, 20.00 and 2.00 hrs.). Death number was determined each day during 10 consecutive days. The mortality percentage is a function of the time of the cadmium administration, varying between 3.3 and 21.7% for 2.5 mg/kg, between 16.7 and 43.3% for 3 mg/kg, between 33.3 and 71.7% for 3.5 mg/kg and between 73.3 and 96.7% for 4 mg/kg. The metal is the most toxic at 20.00 hr (mean: 58.3%) and the least at 2.00 hr. (mean: 33.7%). A circadian susceptibility to cadmium sulphate in Mice thus clearly appears, as has been recently described with mercury and platinum.

[Ciradian variation in the lethal dose 50 of mercuric chloride in mice]. / Etude des variations circadiennes de la dose léthale 50 du chlorure mercurique chez la Souris.

If circadian variations in tolerance to drugs have been often demonstrated, such observations about heavy metals are still very scarce. The present study proposes to determine if circadian variations occur in the tolerance of Mice to single lethal dose of mercuric chloride. 360 female Mice, kept in cages on a 8.00 - 20.00 L/D cycle, receive I.P. a single mercuric chloride injection at different concentrations (100 to 300 X 10(-6)) at different hours in the day (8.00 - 14.00 - 20.00 or 2.00). Death number is determined each during 10 consecutive days. For the highest doses causing death (from 200 x 10(-6)), the mortality percentage is a function of the time of the mercury administration. The metal is the most toxic at 20.00 (LD50: 4,14 +/-0,47) mg/kg) and least at 2.00 (LD50: 5,54 +/- 0,18 mg/kg). Moreover, death occurs later at 2.00 than at other times. So a susceptibility to mercuric chloride in Mice clearly appears.