In vitro metabolism of the specific endothelin-A receptor antagonist ZD4054 and clinical drug interactions between ZD4054 and rifampicin or itraconazole in healthy male volunteers.

ZD4054 is an oral specific endothelin-A receptor antagonist in development for the treatment of hormone-resistant prostate cancer. Both renal and metabolic processes contribute to its overall clearance. Two preclinical in vitro studies investigated the metabolism of ZD4054 using human liver microsomes, individual cytochrome P450 (CYP) isozymes, and flavin-containing monooxygenase isoforms. Two Phase I open-label crossover volunteer studies subsequently investigated in vivo drug interactions between ZD4054 and the CYP450 inducer rifampicin or CYP3A4 inhibitor itraconazole. The most abundant metabolite produced in in vitro incubations accounted for 12.8% of radioactivity after ZD4054 was incubated with CYP3A4. No significant flavin-containing monooxygenase metabolism of ZD4054 was observed. In the in vivo studies, rifampicin co-administration reduced the area under the concentration-time curve and maximum plasma concentration of ZD4054 by 68% and 29%, respectively, whilst co-administration with itraconazole was associated with an increase in ZD4054 area under the curve of approximately 28%. While co-administration of CYP450 inducers might be associated with reduced efficacy of ZD4054, dose reduction is unlikely to be required with concomitant administration of CYP3A4 inhibitors.

A comparison of the pharmacokinetics of meropenem after intravenous administration by injection over 2, 3 and 5 minutes.

The pharmacokinetics of meropenem were determined in 9 healthy volunteers after the administration of 1 g dose by injection over 2, 3 or 5 min. Peak plasma concentrations were not significantly different across the three rates of administration and, due to the finite time required for complete mixing of the blood in the central compartment, did not always occur at the end of the injection. Overall exposure to meropenem was unchanged by the more rapid rates of administration. Plasma clearance, terminal half-life and volume of distribution were virtually unchanged. Within 10 min after the start of the injection, the plasma concentrations from all three injections were very similar indicating that dosing over 2, 3 or 5 min would result in similar antimicrobial cover and, therefore, comparable efficacy. Comparison of the data derived from the three injections indicated that rapid administration of meropenem did not appreciably alter its disposition pharmacokinetics. Tolerability of meropenem was unchanged with the more rapid administration rate.

Effects of surgical technique on bone. A preliminary study.

The authors compared the use of the power saw with bone-cutting forceps for excision of bone. A total of 44 digits were studied in 12 patients. The study was performed on patients requiring bilateral digital arthroplasties of the proximal and distal interphalangeal joints. The authors examined the differences in healing: pain, inflammation, and fibrosis. Digits on which the power cuts were made showed a slight advantage with regard to inflammation and pain, until 1 week after surgery. By week 12, neither technique demonstrated superiority. Overall results demonstrated no significant digit (p > 0.2) or treatment effect (p = 0.11). The authors believe that the study showed that the technique used for bone excision may have little effect on inflammation and healing in the long-term management of a surgical patient.

Sternal fractures associated with spinal injury.

Twenty-eight cases of sternal fractures and/or dislocations were reviewed for the presence of associated spinal injury. Patient records and radiographs were studied. Sixteen cases had inadequate radiographs to rule out spine fracture. Three cases had known direct injuries to the sternum. Of the remaining nine patients, eight had spine fractures. All of the spine fractures were consistent with a flexion injury mechanism. Three patients had spine fractures at the thoracic level and four at the lumbar level. One patient had lower cervical and thoracic injuries. In the patients with spine injury, the proximal manubrial fragment tended to displace posteriorly. Similarly, the manubrium would move posteriorly in manubriosternal dislocations. A case of spontaneous sternal fracture in a patient with osteoporosis and multiple thoracic compression fractures is described. One patient had open reduction of the manubriosternal joint. Three patients who were admitted for their sternal injuries had spine fractures which were not recognized during the hospitalization. There were no cases of mediastinal injury in the patients with combined sternal and spinal injuries. Flexion injury to the spine may cause buckling of the sternum. However, indirect sternal injury continues to be overlooked. Careful evaluation for spine injuries should be done on all patients with sternal fractures and vice versa.