At optimized steady state, individual sensitivity to warfarin is determined by CYP2C9 genotype and age with no effect of vitamin K. Prospective studies will determine the impact of these findings in clinical practice.

The dimerization equilibrium of deuteroporphyrin IX and of mesoporphyrin IX in aqueous solutions were studied by fluorimetric techniques over the 0.01-1 microM concentration range, where dimerization is the dominant aggregation process. Deuteroporphyrin IX was studied at several temperatures over the range 22-37 degrees C, and mesoporphyrin at 25 and 37 degrees C. The magnitudes determined for the dimerization equilibrium constants (25 degrees C, neutral pH, phosphate-buffered saline) are 2.3 X 10(6)M-1 and 5.4 X 10(6)M-1 for the deutero and meso derivatives respectively. The meso, deutero and haemato species tested show a similar temperature effect, namely dimerization decreasing with increasing temperature, indicating the involvement of a negative enthalpy change. Van't Hoff isochore of the dimerization constants determined for deuteroporphyrin IX was linear within the temperature range of 22-37 degrees C, allowing the calculation of the thermodynamic parameters. For deuteroporphyrin dimerization, those were found to be delta G0 = -36. 4kJ X mol-1; delta H0 = -46. 0kJ X mol-1 and delta S0 = -32.2J X K-1 X mol-1 (at neutral pH, 25 degrees C, phosphate-buffered saline), showing the process to be enthalpy-driven. Similar trends have been found for porphyrin species other than those studied here. Our data fit with a hypothesis giving a major role to the solvent in driving porphyrins to aggregate in aqueous solution. The magnitudes and directions of the energetic changes fit better with the expectation of the ' solvophobic force' theory predicting enthalpy-driven association, than with the classic hydrophobic bonding, predicting the association to be entropy-driven.

No abstract

Mercury an important therapeutic substance in Tibetan Medicine undergoes complex ''detoxification'' prior to inclusion in multiingredient formulas. In an initial cross-sectional study, patients taking Tibetan Medicine for various conditions were evaluated for mercury toxicity. Two groups were identified: Group 1, patients taking ''Tsothel'' the most important detoxified mercury preparation and Group 2, patients taking other mercury preparations or mercury free Tibetan Medicine. Atomic fluorescence spectrometry of Tibetan Medicine showed mercury consumption 130 mg/kg/day (Group 1) and 30 mg/kg/day (Group 2) (P 0.001), levels above EPA (RfDs) suggested threshold (0.3 mg/kg /day) for oral chronic exposure. Mean duration of Tibetan Medicine treatment was 9 AE 17 months (range 3-116) (Group 1) and 5 AE 1.96 months (range 1-114) (Group 2) (NS) with cumulative days of mercury containing Tibetan Medicine, 764 days AE 1214 (range 135-7330) vs. 103 days AE 111 (range 0-426), respectively (P 0.001). Comparison of treatment groups with healthy referents (Group 3) not taking Tibetan Medicine showed no significant differences in prevalence of 23 non-specific symptoms of mercury toxicity, abnormal neurological, cardiovascular and dental findings and no correlation with mercury exposure variables; consumption, cumulative treatment days, blood/ urine Hg. Liver and renal function tests in treatment groups were not significantly increased compared to referents, with mean urine Beta 2 Microglobulin within the normal range and not significantly associated with Hg exposure variables after correcting for confounding variables. Neurocognitive testing showed no significant intergroup differences for Wechsler Memory Scale, Grooved Pegboard, Visual Retention, but Group1 scores were better for Mini-Mental, Brief Word Learning, Verbal Fluency after correcting for confounding variables. These results suggest mercury containing Tibetan Medicine does not have appreciable adverse effects and may exert a possible beneficial effect on neurocognitive function. Since evidence of mercury as a toxic heavy metal, however, is well known, further analysis of literature on mercury use in other Asian traditional systems is highly suggested prior to further studies.

Porphyrin binding to serum albumin was studied at the molecular level probing the effects of: porphyrin self‐aggregation, porphyrin species, temperature and protein‐bound fatty acids. Human serum albumin was found to have a single high‐affinity site for porphyrin monomers, with binding constants of 2 x 106, 5 x 107 and 3 x 108 (37o C, neutral pH, M−1), for hemato‐, deutero‐ and protoporphyrins, respectively. Three equilibria models for the dimer binding were developed and tested. The data were found to fit best with a model proposing a single high‐affinity binding site for the dimer, independent of and different than the monomer site. The binding constants of the hematoporphyrin and deuteroporphyrin dimers to human serum albumin (37o C, neutral pH, M−l) being 4 x 10* and 5 x 108 respectively. The temperature dependence (Dp and HSA, 22‐37o C) of the monomer binding showed the process to be entropy‐driven (δGo= ‐45 kJ mol−1; δSo=+146 kJ mol−1; δHo= 0 kJ mol−1). For the dimer binding, the enthalpy change was found to be highly temperature‐dependent implying continuous changes in the heat capacity of the system over the entire temperature range, the trend at the 37o C region fitting an entropy‐driven process. The monomer vs dimer differences in temperature dependence strongly support separate and independent binding sites for these species. Similar thermodynamics were determined for fatty‐acid carrying as well as for fatty‐acid free HSA, with mild quantitative (but not qualitative) shifts.