Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double-blind study.

BACKGROUND: Prophylaxis is recommended following total joint replacement because of the high risk of venous thromboembolism (VTE). Postoperative low-molecular-weight heparin (LMWH) reduces the incidence of venographically detected deep vein thrombosis (DVT) to about 10-15% in total hip replacement (THR) patients. Ximelagatran is a novel, oral direct thrombin inhibitor that selectively and competitively inhibits both free and clot-bound thrombin. We compared the efficacy and safety of ximelagatran with those of enoxaparin for the prevention of VTE in patients undergoing THR. METHODS: This was a prospective, randomized, multicenter, double-blind study conducted principally in the USA and Canada. Patients received fixed-dose oral ximelagatran 24 mg bid or subcutaneous enoxaparin 30 mg bid and matched placebo for 7-12 days; both regimens were initiated the morning after surgery. The incidence of VTE (by postoperative day 12) included thrombosis determined by mandatory venography of the leg on which surgery was performed and symptomatic, objectively proven DVT or pulmonary embolism (PE). VTE and bleeding events were interpreted by an independent central adjudication committee for primary analysis. RESULTS: Of the 1838 patients randomized, 1557 had either adequate venography or symptomatic, proven VTE (efficacy population). Overall rate of venography acceptable for evaluation was 85.4%. Overall rates of total VTE were 7.9% (62 of 782 patients) in the ximelagatran group and 4.6% (36 of 775 patients) in the enoxaparin group, with an absolute difference of 3.3% and a 95% confidence interval for the difference of 0.9% to 5.7%. Proximal DVT and/or PE occurred in 3.6% (28 of 782 patients) in the ximelagatran group and 1.2% (nine of 774 patients) in the enoxaparin group. Major bleeding events were observed in 0.8% (seven of 906) of the ximelagatran-treated patients and in 0.9% (eight of 910) of the enoxaparin-treated patients (P > 0.95). Non-inferiority of ximelagatran 24 mg bid based on a prespecified margin of 5% was not met, resulting in superiority of the enoxaparin regimen. CONCLUSIONS: Both ximelagatran and enoxaparin decreased the overall rate of VTE compared with that reported historically. However, in this study, enoxaparin 30 mg bid was more effective than ximelagatran 24 mg bid for prevention of VTE in THR. Oral ximelagatran was used without coagulation monitoring, was well tolerated, and had bleeding rates comparable to those of enoxaparin. Further refinement by testing a higher dose of ximelagatran in the patients undergoing THR is warranted.

Hormonal effects on tirilazad clearance in women: assessment of the role of CYP3A.

This study assessed whether the previously reported difference in tirilazad clearance between pre- and postmenopausal women is reversed by hormone replacement and whether this observation can be explained by differences in CYP3A4 activity. Ten healthy women from each group were enrolled: premenopausal (ages 18-35), postmenopausal (ages 50-70), postmenopausal receiving estrogen, and postmenopausal women receiving estrogen and progestin. Volunteers received 0.0145 mg/kg midazolam and 3.0 mg/kg tirilazad mesylate intravenously on separate days. Plasma tirilazad and midazolam were measured by HPLC/dual mass spectrophotometry (MS/MS) assays. Tirilazad clearance was significantly higher in premenopausal women (0.51 +/- 0.09 L/hr/kg) than in postmenopausal groups (0.34 +/- 0.07, 0.32 +/- 0.06, and 0.36 +/- 0.08 L/hr/kg, respectively) (p = 0.0001). Midazolam clearance (0.64 +/- 0.12 L/hr/kg) was significantly higher in premenopausal women compared to postmenopausal groups (0.47 +/- 0.11, 0.49 +/- 0.11, and 0.53 +/- 0.19 L/hr/kg, respectively) (p = 0.037). Tirilazad clearance was weakly correlated with midazolam clearance (r2 = 0.129, p = 0.02). Tirilazad clearance is faster in premenopausal women than in postmenopausal women, but the effect of menopause on clearance is not reversed by hormone replacement. Tirilazad clearance in these women is weakly related to midazolam clearance, a marker of CYP3A activity.

Comparison of the pharmacokinetics of tirilazad mesylate in healthy volunteers and stable subjects with mild liver cirrhosis.

OBJECTIVE: The pharmacokinetics of tirilazad mesylate and an active reduced metabolite, U89678, were studied in 7 volunteers with mild cirrhosis of the liver, and seven age, sex, weight and smoking status matched healthy normal volunteers. Subjects received a single intravenous infusion of 2.0 mg.kg-1 tirilazad mesylate over 10 min. RESULTS: Mean tirilazad AUCzero-infinity was 8.83 mumol h.l-1 and 18.6 mumol h.l-1 in healthy volunteers and cirrhotic subjects, respectively. Mean tirilazad clearance in cirrhotics (12.7 l.h-1) was approximately 2.1 fold lower than in healthy volunteers (27.8 l.h-1). The differences were statistically significant. Mean U-89678 AUCzero-infinity in cirrhotic subjects (3.88 mumol h.l-1) was 2.5 fold higher than in healthy controls (1.53 mumol h.l-1), but the difference was marginally significant. CONCLUSION: These results indicate that clearance of both tirilazad mesylate and U89678 is decreased in subjects with hepatic impairment. This observation may be attributed either to decreases in liver blood flow and/or intrinsic clearance. The results of this study thus suggest that increased monitoring and or a reduction in tirilazad dosing may be necessary in patients with hepatic impairment.

Comparison of intraosseous and intravenous routes of anticonvulsant administration in a porcine model.

During status epilepticus, rapid IV access for the administration of anticonvulsant drugs can be a very difficult and time-consuming procedure. Our study evaluated whether therapeutic serum levels of phenobarbital and phenytoin could be obtained by the intraosseous route. Twenty domestic swine weighing 10 to 20 kg were divided into two groups (ten each). In one group, phenobarbital 20 mg/kg was administered either intravenously (five) or intraosseously (five). The second group received phenytoin 15 mg/kg either intravenously (five) or intraosseously (five). All animals had samples for anticonvulsant levels drawn from an indwelling arterial cannula at one, three, five, seven, ten, 15, and 30 minutes after dosing. Anticonvulsant levels were found to be statistically significantly higher with IV administration (P less than .01). However, phenobarbital levels were therapeutic by the intraosseous route, while phenytoin levels were below the therapeutic range after the ten-minute interval. Bone marrow levels 45 minutes after infusion were 13.5 micrograms/mL (phenobarbital) and 11.5 micrograms/mL (phenytoin). Our study demonstrates that current IV dosing of phenobarbital 20 mg/kg given intraosseously obtains and maintains therapeutic serum levels. Phenytoin 15 mg/kg does not maintain therapeutic levels and cannot be recommended for intraosseous administration.

The effects of cefmetazole and latamoxef on platelet function in healthy human volunteers.

This study has compared the effects of normal saline (placebo), cefmetazole, and latamoxef (moxalactam) on platelet function in healthy human volunteers. Twenty-nine volunteers were randomized to receive placebo (n = 10), cefmetazole 2 g (n = 9) or latamoxef 2 g (n = 10) intravenously every 6 h for six days. Under double-blind conditions template bleeding time and ex-vivo adenosine diphosphate (ADP) induced platelet aggregation were measured before drug dosing, after the first, ninth, and last drug doses and one and three days after the last drug dose. Latamoxef caused progressive impairment of platelet function with statistically significant increases in the mean bleeding time to 7.4 +/- 3.7 min (P = 0.02) and the amount of ADP (0.2 mM) required to induce 50% platelet aggregation to 77.3 +/- 91.1 microliters (P = 0.03) on day 6 of treatment compared with values before drug administration (4.2 +/- 0.7 min; 3.7 +/- 22 microliters, respectively). These changes were reversible following discontinuation of drug dosing. Cefmetazole and placebo had no significant effects on either measure of platelet function at any time during the study.

Effects of a fish oil concentrate in patients with hypercholesterolemia.

The effects of a fish oil supplement on lipid and lipoprotein levels, platelet function, and vital signs were investigated in 31 hypercholesterolemic patients. Thirteen patients took 5 g of encapsulated fish oil per day and 18 patients took 5 g of encapsulated safflower oil "placebo" per day for 28 days. Diet and exercise patterns were kept as constant as possible during the study. The fish oil group had significant increases in several lipid/lipoprotein values at the end of the treatment, including an increase of total cholesterol of 14% (P = 0.0001), LDL of 16% (P = 0.003), HDL of 13% (P = 0.015) and HDL2 of 36% (P = 0.009). The triglyceride level fell 24%, a nonsignificant change (P = 0.217). The ratios of total cholesterol/HDL and LDL/HDL were increased at the end of fish oil treatment, and returned to baseline 30 days after fish oil was stopped. The placebo group had no significant changes in any of the lipid/lipoprotein values. Neither the fish oil nor the placebo group had significant changes in vital signs or platelet function tests (bleeding time, thromboxane B2, platelet factor 4 and beta-thromboglobulin) during the study. These results suggest that fish oil supplements may have an adverse effect on lipid/lipoprotein values in hypercholesterolemic patients.

Influence of chloroplast development on the activation of the diphenyl ether herbicide acifluorfen-methyl.

The activity of acifluorfen-methyl (AFM); methyl 5-(2-chloro-4-[trifluoromethyl] phenoxy)-2-nitrobenzoate in excised cucumber cotyledons (Cucumis sativus L.) was examined. AFM induced membrane disruption, was significantly greater when etiolated cotyledons were illuminated 16 hours at 150 microeinsteins per square meter per second photosynthetically active radiation versus incubation under illumination of 4-fold greater intensity. These results were unexpected since the loss of membrane integrity is initiated by photodynamic reactions. Untreated, etiolated cotyledons were not able to accumulate chlorophyll under the higher light intensity while control and herbicide treated cotyledons greened significantly under the lower intensity illumination suggesting that some process associated with greening stimulated AFM activity. Inhibition of greening by cycloheximide also reduced AFM activity. Intermittent lighting induced greening in AFM treated cotyledons without causing any detectable loss of plasmalemma integrity. Utilization of this system for pretreatment of cotyledons prior to continuous illumination revealed that activity was greater when tissue was greened in the presence of AFM than when herbicide treatments were made after a greening period of the same duration. The results indicate that the pigments in situ in etiolated tissue are sufficient, without greening, to initiate membrane disruption by AFM. However, greening increases the herbicidal efficacy greatly. Furthermore, the stimulation appears to be due to specific interactions between AFM and the developing plastid and is not attributable solely to an increase in endogenous photosensitizers.

Treatment of paracoccidioidomycosis with itraconazole in a murine model.

A new triazole, itraconazole, was studied as oral therapy of paracoccidioidomycosis in a murine model. The Paracoccidioides brasiliensis isolate, susceptible to itraconazole in vitro, was given by intranasal challenge, producing acute pulmonary and disseminated disease. Therapy was given twice daily over 4 weeks, and animals observed over 2 months. The infection was lethal for 70-80% of controls (untreated or polyethylene glycol diluent), whereas all treated animals, given 10-200 mg kg-1 day-1, survived. Itraconazole was ineffective in eradicating lung disease in survivors, though effective in treatment of disseminated sites. Since the highest doses did not give a better response than the lower doses, pharmacokinetic studies were performed. These showed irregular curves and small increases in peak serum concentrations and total area under the serum concentration-time curves, which were not proportional to the dose. This non-linearity appears to be best explained by poor absorption. Itraconazole, from these studies, appears to have promise for the therapy of human paracoccidioidomycosis but possibly with a different formulation.