Pharmacokinetic-pharmacodynamic modeling of the anticonvulsant and electroencephalogram effects of phenytoin in rats

In this study a pharmacokinetic-pharmacodynamic model is proposed for drugs with nonlinear elimination kinetics. We applied such an integrated approach to characterize the pharmacokinetic-pharmacodynamic relationship of phenytoin. In parallel, the anticonvulsant effect and the electroencephalogram (EEG) effect were used to determine the pharmacodynamics. Male Wistar-derived rats received a single intravenous dose of 40 mg . kg-1 phenytoin. The increase in the threshold for generalized seizure activity (TGS) was used as the anticonvulsant effect and the increase in the total number of waves in the 11.5 to 30 Hz frequency band was taken as the EEG effect measure. Phenytoin pharmacokinetics was described by a saturation kinetics model with Michaelis-Menten elimination. Vmax and Km values were, respectively, 386 +/- 31 microg . min-1 and 15.4 +/- 2.2 microg . ml-1 for the anticonvulsant effect in the cortical stimulation model and 272 +/- 31 microg . min-1 and 5.9 +/- 0.7 microg . ml-1 for the EEG effect. In both groups, a delay to the onset of the effect was observed relative to plasma concentrations. The relationship between phenytoin plasma concentrations and effect site was estimated by an equilibration kinetics routine, yielding mean ke0 values of 0.108 and 0.077 min-1 for the anticonvulsant and EEG effects, respectively. The EEG changes in the total number of waves could be fitted by the sigmoid Emax model, but Emax values could not be estimated for the nonlinear relationship between concentration and the increase in TGS. An exponential equation (E = E0 + Bn . Cn) derived from the sigmoid Emax model was applied to describe the concentration-anticonvulsant effect relationship, under the assumption that Emax values cannot be reached within acceptable electric stimulation levels. This approach yielded a coefficient (B) of 2.0 +/- 0.4 microA . ml . microg-1 and an exponent (n) of 2.7 +/- 0.9. The derived EC50 value of 12.5 +/- 1. 3 microg . ml-1 for the EEG effect coincides with the "therapeutic range" in humans.     

Frozen Storage of Unwashed Cod (Gadus morhua) Frame Mince with and without Kidney Tissue

Removal of kidney material was essential for a higher quality cod frame mince. The removal of kidney tissue before deboning eliminated typical “chemical” and “petroleum” type flavors and resulted in a white, less red, and higher quality unwashed frame mince. Those samples without kidney tissue had good frozen storage stability, (particularly at -40°C) and could be used as an ingredient in apropriate meat products. The length of iced storage of frames or whole cod had little effect on frame mince quality during frozen storage.     

Fluorine-18-fluorodeoxyglucose assessment of glucose metabolism in bone tumors

In our study, we investigate the glucose metabolism of various types of bone lesions with 18F-fluorodeoxyglucose (FDG) PET. METHODS: Twenty-six patients showing clinical and radiographic symptoms of a malignant bone tumor were included. Histological examination after the PET study revealed 19 malignant and 7 benign tumors. PET images were corrected for attenuation. Arterial blood samples were taken to establish the input function. The metabolic rate of glucose consumption (MRglc) was calculated for the whole tumor, for the 10 pixels with maximum activity and for contralateral normal muscle tissue. RESULTS: All lesions were clearly visualized with 18F-FDG PET except for a small infarction of the humerus. All the other lesions had increased glucose metabolism compared to surrounding and contralateral muscle tissue. Both maximum and average MRglc for benign, as well as malignant, lesions were significantly higher than for contralateral normal tissue. The maximum and average MRglc were not higher for malignant as opposed to benign lesions. There was a large overlap between the MRglc of benign and malignant lesions. CONCLUSION: Fluorine-18-FDG PET appears suitable to visualize bone tumors. With the quantification of glucose metabolism, it is not possible to differentiate between benign and malignant bone tumors. There does not seem to be a clear correlation between the MRglc and the biologic aggressiveness of the neoplasms.     

Changes in reactivity of the middle cerebral artery caused by cerebral circulation disturbances of ischemic and hemorrhagic types in rats

Reactivity of the middle cerebral artery (MCA) to serotonin was attenuated in vitro in vessels taken from rats following an audiogenic stress. The MCA reactivity to endothelin remained unchanged. Chronic cerebral ischemia diminished the 5-HT-induced contraction and the contractile responses to endothelin were enhanced. Preliminary hypoxic adaptation decreased the artery sensitivity to endothelin in ischemic animals. The findings suggest that a progressing ischemia may involve changes in reactivity of cerebral vessels whereupon hypoxic adaptation may prove to be protecting the brain from ischemia development.     

Technique of lymphatic mapping and sentinel node biopsy for melanoma

AIM: To evaluate the effect of PD Plus on weekly Kt/Vurea and creatinine clearance (Kcr) among patients undergoing CAPD/CCPD (continuous ambulatory peritoneal dialysis/continuous cyclic peritoneal dialysis). METHODS: The kinetic studies of 92 CAPD and 18 CCPD patients who transferred to PD Plus were analyzed. All patients underwent CAPD/CCPD and PD Plus for a minimum of 3 months. Standard collection methods were used and kinetic indices calculated with the Pack PD Kinetic Modeling program. 57 patients had transport data and were modeled for a target weekly Kt/Vurea >/=2.1 using PD Plus with /=2.1 and 47% a Kcr >/=60 liters/1.73 m2 with PD Plus, but only 20% did so with CAPD/CCPD. A close correlation between the supervised patients and modeled therapy was observed. CONCLUSIONS: Adequate dialysis is possible by using higher fill volumes, the supine position, and optimal dwell times (PD Plus) in most patients. The discrepancy between modeled and achieved dose is likely due to poor compliance with therapy, inadequate training, or poor specimen collection.