BßArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes.

Both type 2 diabetes (T2DM) and Bß448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BßArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BßArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BßArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BßArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bß448Lys was longer than Bß448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bß448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bß448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bß448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BßArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies.

The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.

AIMS: Voriconazole is a new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. These studies evaluated the pharmacokinetics and safety of intravenous voriconazole in healthy male volunteers. METHODS: Two single-blind, placebo-controlled studies were conducted. In Study A, 12 subjects were randomized to voriconazole (3 mg kg-1) or placebo, administered once daily on days 1 and 12, and every 12 h on days 3-11. In Study B, 18 subjects were randomized to voriconazole or placebo, with voriconazole being administered as a loading dose at 6 mg kg-1 twice on day 1, then at 3 mg kg-1 twice daily on days 2-9, and once at 3 mg kg-1 on day 10. RESULTS: In both studies, the plasma concentrations of voriconazole increased rapidly following the initiation of dosing. Minimum observed plasma concentration (Cmin) values at steady state were above the in vitro minimum inhibitory concentrations (MICs) for most fungal pathogens (Cmin > 0.8 micro g ml-1). The use of a loading dose in Study B resulted in a shorter time to steady-state Cmin values than was observed in Study A. Values of the final day plasma pharmacokinetic parameters in Studies A and B were similar: maximum observed plasma concentration (Cmax) 3621 and 3063 ng ml-1; areas under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCtau) 16 535 and 13 245 ng.h ml-1, and terminal elimination phase half-lives (t1/2) 6.5 and 6.7 h, respectively. On multiple dosing, voriconazole accumulated (AUCtau accumulation ratio 2.53-3.17, Study A) at a level that was not predictable from single-dose data. The mean concentration-time profiles for voriconazole in saliva were similar to those in plasma. Multiple doses of voriconazole were well tolerated and no subject discontinued from either study. Seven cases of possibly drug-related visual disturbance were reported in three subjects (Study B). CONCLUSIONS: Administration of a loading dose of 6 mg kg-1 i.v. voriconazole on the first day of treatment followed by 3 mg kg-1 i.v. twice daily achieves steady state by the third day of dosing. This dosage regimen results in plasma levels of the drug that rapidly exceed the minimum inhibitory concentrations (MICs) against important fungal pathogens, including Aspergillus spp.

Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety.

AIMS: Voriconazole is a potent new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing. METHODS: Sixty-four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg-1 twice daily, 4 mg kg-1 once daily, 2 mg kg-1 three times daily, or 3 mg kg-1 twice daily. Eleven subjects received 1.5 mg kg-1 three times daily, and 21 subjects were administered placebo. RESULTS: Voriconazole exhibited nonlinear (dose- and time-dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing kel values on multiple dosing, with a consequent increase in the terminal phase t1/2. There was also notable intersubject variability in Cmax and AUCtau. The absorption of voriconazole was rapid (mean tmax= 0.9-1.7 h) after single and multiple dosing and the decline in plasma concentration-time curves after tmax was generally biphasic. By day 12, the Cmax, AUCtau, tmax, and t1/2 values for the 3 mg kg-1 twice-daily group were 2356 ng ml-1, 11 170 ng.h ml-1, 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single-dose data. Accumulation ratios for Cmax and AUCtau, which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg-1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of Cmin values together with statistical analyses of Cmax and AUCtau values suggest that steady-state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens (Cmin > 0.8 micro g ml-1). Voriconazole was well tolerated: most treatment-related adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing. CONCLUSIONS: The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg-1 twice daily.

Effect of food on the pharmacokinetics of multiple-dose oral voriconazole.

AIMS: Voriconazole is a new triazole antifungal agent with activity against a range of clinically important and emerging pathogens. This study determined the effect of food on the pharmacokinetics of voriconazole in healthy volunteers. METHODS: This was an open, randomized, two-way crossover, multiple-dose study in male volunteers. Twelve subjects received voriconazole 200 mg twice daily for 6.5 days. Each dose was administered either with food or in the fasted state, i.e. not within 2 h of food. Treatment periods were separated by a minimum 7-day washout period. Plasma samples were taken for the estimation of voriconazole plasma concentrations on days 1 and 7. Safety and toleration were assessed by monitoring of both laboratory safety tests and adverse events. RESULTS: Administering voriconazole with food significantly decreased both day 7 AUCtau and Cmax by approximately 35% (9598-7520 ng.h ml-1; P = 0.003) and 22% (2038-1332 ng ml-1; P = 0.008), respectively. Administering voriconazole with food statistically significantly delayed absorption, evident from tmax values; the mean difference for tmax on day 7 was 1.1 h. The terminal phase rate constant was unchanged by administering voriconazole with food. The fasted terminal phase half-life was 7.3 h compared with 6.6 h for the fed state. Visual inspection of Cmin values suggests that steady state was achieved after 5 days in both dietary states. Voriconazole accumulation, as assessed by ratios of Cmax and AUCtau on days 1 and 7, was statistically significantly greater when administered with food (Cmax, P = 0.010, AUCtau, P = 0.006). Mean Cmax accumulation in the fasted state was 2.1-fold compared with 3.5-fold in the fed state. AUCtau accumulation in the fasted state was 3.1-fold compared with 4.2-fold in the fed state. There were no discontinuations due to adverse events or laboratory abnormalities. Treatment-related mild-to-moderate visual disturbances were experienced by six out of 12 subjects. CONCLUSIONS: The bioavailability of twice-daily 200 mg voriconazole is reduced by approximately 22% as measured by AUCtau after multiple dosing when taken with food, compared with fasting.