Anaplastic thyroid carcinoma is a rare, lethal disease with no effective systemic therapies. Preclinical studies demonstrated antineoplastic activity of paclitaxel. This prompted a prospective phase 2 clinical trial to determine activity of paclitaxel against anaplastic thyroid carcinoma in patients with persistent or metastatic disease despite surgery or local radiation therapy. Twenty patients, entered through 6 of 12 study sites, were treated with 96-hour continuous infusion paclitaxel every 3 weeks for 1 to 6 cycles; the first 7 patients received 120 mg/m2 per 96 hours and the rest received 140 mg/m2 per 96 hours. Total responses to therapy were assessed using modified criteria with response durability acceptable at 2 or more weeks, due to the exceedingly rapid growth rate of this tumor. Plasma samples were obtained for pharmacokinetic analyses. Off-protocol, data showed that 9 patients were later treated with 225 mg/m2 paclitaxel as weekly 1-hour infusions. Nineteen evaluable patients demonstrated a 53% total response rate (95% confidence interval, 29%-76%) with one complete response and nine partial responses (including one off protocol). Results of historical review off-protocol showed 2 of 7 patients, with prior partial responses to the 96-hour infusion, had subsequent partial responses to weekly treatment and 1 of 2 prior nonresponders gained a partial response to weekly therapy. No toxicities greater than grade 2 were seen with 96-hour infusions, while peripheral neuropathy (up to grade 3) was most common with postprotocol weekly infusions. Paclitaxel appears to be the only agent with significant clinical systemic activity against anaplastic thyroid carcinoma; however, it is not capable of altering the lethality of this malignancy, suggesting the need for additional therapeutic innovations. Decreased time intervals between paclitaxel infusions may be more efficacious.
A large kindred from eastern Kentucky, with extensive history of recurrent venous thrombosis and pulmonary embolism, was studied. Low antithrombin III titers, ranging from 26% to 49% of normal values, were found in plasma of nine members in three consecutive generations; another five members, four of whom were not available for study, are suspected of having the biochemical defect. There was a good correlation between clinical symptoms and antithrombin III deficiency, although three of the younger members with the defect still remained free of thrombosis. In serum of the affected subjects antithrombin III was almost completely utilized, which indicates that stoichiometric binding to coagulation enzymes dominates under biological conditions. Antithrombin and antifactor Xa activities residing in the macroglobulin region of plasma and serum remained unchanged. The responsiveness to heparin in vitro and in vivo confirmed the evidence that antithrombin III is the sole blood component through which heparin exerts its anticoagulant effect. In five affected members therapy with oral anticoagulants increased very significantly the level of antithrombin III in plasma and contributed to a remarkable increase of residual antithrombin III in serum. This objective improvement after warfarin therapy may create significant difficulties in the laboratory diagnosis of antithrombin III deficiency.
Total systemic exposure of ICA-17043 after a single oral dose, as measured by AUC(0-infinity), increased nearly proportionally with the dose. The rate of absorption, however, appeared to be delayed at doses greater than 100 mg. With the long half-life of ICA-17043 demonstrated in this study, once-daily dosing is probably adequate to maintain steady-state plasma concentrations. In addition, single doses of ICA-17043 were well tolerated.
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