Meta-analysis of the relationship between dose and benefit in phase I targeted agent trials.

Background: To date, the primary objective of phase I trials has been to safely select the maximum tolerated dose (MTD) of a drug or drug combination for utilization in subsequent trials. Although conventional cytotoxic chemotherapy is generally more effective at the MTD than molecularly targeted agents (MTAs), recent single-institution data suggest that molecularly targeted agent may not require an MTD for efficacy. We analyzed patient outcome results in MTA phase I trials at multiple institutions throughout North America sponsored by the National Cancer Institute's Cancer Therapy Evaluation Program.

Dose-response study of recombinant human soluble thrombomodulin (ART-123) in the prevention of venous thromboembolism after total hip replacement.

Background: Recombinant human soluble thrombomodulin (ART-123) is composed of the active, extracellular, domain of thrombomodulin. ART-123 binds to thrombin and this complex converts protein C into the natural anticoagulant activated protein C. This study was performed to identify an effective and safe dose of ART-123 for prevention of venous thromboembolism after elective, unilateral total hip replacement.

Evaluation of succinimidoethyl and pivaloyloxyethyl esters as progenitors of methyldopa in man, rhesus monkey, dog, and rat.

The succinimidoethyl (Sm) and pivaloyloxyethyl (P) esters of methyldopa were evaluated as progenitors of the latter. Experiments in spontaneously hypertensive (SH) rats and humans demonstrated that a radioactive dose of progenitor was well absorbed. The metabolism of these progenitors appeared to be comparable in the SH rat; the urinary excretion of [3H]methyldopa was similar after oral administration of [3H]Sm or [3H]P.

Some clinical pharmacological studies with indoramin, with observations on its therapeutic usefulness.

In the treatment of fifteen patients with essential hypertension, in open trial indoramin caused a mean blood pressure fall from 180/115 mmHg to 159/98 mmHg. No reversal of antihypertensive effect was seen in four patients after additions of the tricyclic antidepressant drug desipramine. Blood pressure did not begin to rise in these four patients for at least 5 weeks after stopping indoramin.