Field test comparison of two dermal tolerance assessment methods of hand hygiene products.

This study aimed to compare the sensitivity and workload requirement of two dermal tolerance assessment methods of hand hygiene products, in order to select a suitable pilot testing method for field tests. An observer-rating method and a self-assessment method were compared in 12 voluntary hospital departments (autumn/winter of 2005-2006). Three test-periods of three weeks were separated by two-week intervals during which the routine products were reintroduced. The observer rating method scored dryness and irritation on four-point scales. In the self-assessment method, the user rated appearance, intactness, moisture content, and sensation on a visual analogue scale which was converted into a 10-point numerical scale. Eleven products (soaps) were tested (223/250 complete reports for observer rating, 131/251 for self-assessment). Two products were significantly less well tolerated than the routine product according to the observers, four products according to the self-assessments. There was no significant difference between the two methods when products were classified according to tolerance (Fisher's test: P=0.491). For the symptom common to both assessment methods (dryness), there is a good correlation between the two methods (Spearman's Rho: P=0.032). The workload was higher for observer rating method (288 h of observer time plus 122 h of prevention team and pharmacist time compared with 15 h of prevention team and pharmacist time for self-assessment). In conclusion, the self-assessment method was considered more suitable for pilot testing, although further time should be allocated for educational measures as the return rate of complete self-assessment forms was poor.

Influence of plasma protein binding on the brain uptake of an antifungal agent, terbinafine, in rats.

The intracarotid injection technique has been used to determine the unidirectional brain uptake of an antifungal, lipophilic agent, terbinafine (Lamisil, Sandoz Basle), in the rat. Ultrafiltration showed it to be highly bound to human plasma, human serum albumin (HSA), alpha 1-acid glycoprotein (AAG) and lipoproteins (VLDL, LDL, HDL). The effect of plasma protein binding of the drug on brain uptake was also examined with the technique. The lowest brain uptake was observed in the presence of plasma (6%); it varied from 23 to 30% with physiological concentrations of VLDL, LDL and HSA and was significantly higher (43-45%) in the presence of physiological concentrations of AAG and HDL. The free fraction as determined in-vitro and the brain uptake of the drug varied inversely with the plasma protein concentrations; however, the brain uptake was higher than expected from in-vitro measurements. These data indicate that the amount of circulating Lamisil available for brain penetration exceeds its free fraction; they also show that plasma proteins differently reduce the brain transport of the drug.

Comparison of fluvastatin and lovastatin blood-brain barrier transfer using in vitro and in vivo methods.

We measured the permeability of fluvastatin, lovastatin, and its pharmacologically active hydroxy acid (HA) across the blood-brain barrier (BBB) with three different techniques. The brain uptake index (BUI) technique yielded values for fluvastatin and HA below the limit of detection of this method; in contrast, brain extraction of lovastatin was high: 57 and 7% with addition of buffer and human plasma, respectively. Brain perfusion studies in rats indicated that when fluvastatin and HA were exposed for a longer time to the BBB, small but measurable brain uptake occurred, with permeability coefficients of 2.5 x 10(-4) and 1.4 x 10(-4) cm/min, for fluvastatin and HA, respectively, whereas the permeability coefficient of lovastatin was 2.3 x 10(-2) cm/min. An in vitro BBB model consisting of a primary culture of confluent monolayers of bovine brain microvessel endothelial cells yielded very similar values: 7.2 x 10(-4) cm/min for fluvastatin and 1.3 x 10(-3) cm/min for HA and a permeability coefficient of 1.1 x 10(-2) cm/min for lovastatin. The results of the different methods show that lovastatin crosses the BBB to a much greater extent than does fluvastatin or HA. Although lovastatin undergoes hydrolytic conversion to HA, it subsists in blood for sufficient time to cross the BBB. Therefore, lovastatin and fluvastatin are expected to be different in their central side effect profile, as was observed in patients treated for hypercholesterolemia. This finding supports the hypothesis that sleep disturbances due to some cholesterol biosynthesis inhibitors might be correlated with their abilities to cross the BBB.

Microdialysis sampling to determine the pharmacokinetics of unbound SDZ ICM 567 in blood and brain in awake, freely-moving rats.

The free concentrations of the serotoninergic 5-HT3 antagonist SDZ ICM 567 in blood and in the central nervous system were examined in awake, freely-moving rats using blood and brain microdialysis coupled to liquid chromatography. Microdialysis probes were implanted in the jugular vein and in the frontal cortex and dialysis samples were simultaneously collected from both sites. Pharmacokinetic parameters were calculated after a 10 mg/kg intravenous dose of [14C]SDZ ICM 567. The elimination half lives measured in whole blood, brain and blood microdialysates were similar (congruent to 1.7 h). The AUC0-5h corresponding to the unbound drug was 462 +/- 142 ng.ml-1.h in blood dialysate, not significantly different from the AUC corresponding to the free concentration in whole blood, i.e. 586 +/- 63 ng.ml-1.h. The free fraction in blood obtained in vitro by equilibrium dialysis (21%) or by microdialysis (19%) was not statistically different from that obtained in vivo (17%) in microdialysis experiments. The unbound concentrations (AUC0-5h) of SDZ ICM 567 in the brain cortex were 86 +/- 24 ng.ml-1.h, lower than those expected from unbound blood concentrations, suggesting an active transport out of the central nervous system. Finally, microdialysis sampling allowed the determination of pharmacokinetic parameters of SDZ ICM 567 in blood and brain as well as the estimation of the free fraction of drug in blood.

Absorption and disposition of SDZ IMM 125, a new cyclosporine derivative, in rats after single and repeated administration.

The absorption and disposition of SDZ IMM 125, a new derivative of the cyclosporine family, were studied in rats after oral, subcutaneous, or intravenous dosing. The absolute bioavailability of 53% observed after a single oral dose of 10 mg/kg was variable and similar to that observed with cyclosporine A. The bioavailability was not modified during 21 days of daily treatment. The fraction of SDZ IMM 125 bound to plasma proteins was moderate (70% vs. 95% for cyclosporine A), whereas the uptake by blood cells was considerably higher than that of cyclosporine A varying from 80% at 50 ng/ml to 30% at 10,000 ng/ml. SDZ IMM 125 distributes extensively in most tissues except in brain; multiple oral administration does not modify the tissue distribution and indicates that there is no drug accumulation. The tissue distribution of SDZ IMM 125 is lower than that of cyclosporine A; the volume of distribution of this drug (2.6 liters/kg) is roughly half that of cyclosporine A, which is consistent with the lower lipophilicity of this compound. The systemic clearance of SDZ IMM 125 is relatively low (1.3 ml/min) and comparable to that of cyclosporine A. The excretion of SDZ IMM 125 occurs essentially through the liver via the bile; biliary and urinary excretion of unchanged drug represents 18% and 7% of the dose, respectively. The significant excretion of unchanged drug in both bile and urine represents a major difference compared with cyclosporine A, which is not excreted as unchanged drug to any extent.

Pharmacokinetic evaluation of the blood-to-lymph transfer of cyclosporin A in rats.

The blood-to-lymph transfer kinetics of cyclosporin A (CyA) were investigated in thoracic duct cannulated rats after a 3 mg kg-1 i.v. bolus injection of tritium-labelled drug. Blood CyA concentrations declined bi-exponentially with a terminal half-life of 13.1 +/- 1.8 h. The appearance rate of CyA in the lymph was also bi-phasic, initially rising and then declining in parallel with the concentrations of CyA in the blood. A pharmacokinetic model describing the blood-to-lymph transfer kinetics of CyA is presented. From the slopes of graphs relating the appearance rate of CyA in the lymph to the corresponding midpoint blood drug concentration, the estimated blood-to-lymph clearance rate of CyA (ClL)b was 0.262 +/- 0.132 ml h-1. (ClL)b was positively correlated with the average lymph flow rate (QL) but was significantly less than QL. On the other hand, the plasma-to-lymph clearance rate of CyA (ClL)p of 0.393 +/- 0.198 ml h-1 was positively correlated and similar to QL. Lymph concentrations of CyA were approximately 40-60 per cent of the corresponding blood concentrations. The results of this investigation showed the existence of an intervening compartment between the blood and lymph fluids which would be consistent with the presence of lymph nodes. It was shown that the blood-to-lymph transfer of CyA was dependent on the flow rate of the lymph and that CyA appeared to be cleared from the plasma (or serum) fraction of the blood.

Apparent dose-dependent oral absorption of cyclosporin A in rats.

The oral absorption of cyclosporin A (CyA) was studied in rats after 6, 12, 18, and 23 mg kg-1 doses were given in an olive oil solution to determine if CyA absorption from the gastrointestinal tract was dose-dependent. Using serial blood samples obtained at various times after the respective doses, analysis of the resultant blood CyA concentration-time curves suggested that the rate of CyA absorption for all four doses was an apparent zero-order process. Moreover, the rate of CyA absorption appeared to be dose-dependent, increasing as the dose of CyA increased. Similarly, the extent of CyA absorption (F) also exhibited dose-dependent characteristics in this study. F increased from 0.13 after the 6 mg kg-1 dose to 0.22 with the 18 and 23 mg kg-1 doses (p less than 0.05). In the present investigation, the observed values for the duration of drug absorption (T), terminal first-order rate constant (beta) and corresponding elimination half-life (T 1/2 beta) of approximately 4-5 h, 0.030 h-1 and 21-28 h, respectively, were similar for all CyA doses. Moreover, no difference in beta was observed after oral or intravenous drug administration. Absorption lag times of 1-2 h were found. The results suggested that the dose-dependent absorption of CyA observed in the present study was possibly related to the effects of olive oil on gastric emptying and that CyA might be unstable in the gastric fluids and/or metabolized by the gastric mucosa.