Phase I study of recombinant human CD40 ligand in cancer patients.

PURPOSE: To determine the toxicity, maximum-tolerated dose (MTD), and pharmacokinetics of recombinant human CD40 ligand (rhuCD40L) (Avrend; Immunex Corp, Seattle, WA), suggested in preclinical studies to mediate cytotoxicity against CD40-expressing tumors and immune stimulation. PATIENTS AND METHODS: Patients with advanced solid tumors or intermediate- or high-grade non-Hodgkin's lymphoma (NHL) received rhuCD40L subcutaneously daily for 5 days in a phase I dose-escalation study. Subsequent courses were given until disease progression. RESULTS: Thirty-two patients received rhuCD40L at three dose levels. A total of 65 courses were administered. The MTD was 0.1 mg/kg/d based on dose-related but transient elevations of serum liver transaminases. Grade 3 or 4 transaminase elevations occurred in 14%, 28%, and 57% of patients treated at 0.05, 0.10, and 0.15 mg/kg/d, respectively. Other toxicities were mild to moderate. At the MTD, the half-life of rhuCD40L was calculated at 24.8 +/- 22.8 hours. Two patients (6%) had a partial response on study (one patient with laryngeal carcinoma and one with NHL). For the patient with laryngeal cancer, a partial response was sustained for 12 months before the patient was taken off therapy and observed on no additional therapy. Three months later, the patient was found to have a complete response and remains biopsy-proven free of disease at 24 months. Twelve patients (38%) had stable disease after one course, which was sustained in four patients through four courses. CONCLUSION: The MTD of rhuCD40L when administered subcutaneously daily for 5 days was defined by transient serum elevations in hepatic transaminases. Encouraging antitumor activity, including a long-term complete remission, was observed. Phase II studies are warranted.

A postmarketing evaluation of guanfacine hydrochloride in mild to moderate hypertension.

More than 5,000 primary-care physicians enrolled more than 22,000 patients with mild to moderate hypertension in a postmarketing study in which guanfacine hydrochloride, a centrally acting antihypertensive agent, was given for 28 days. The objectives of the evaluation were: (1) to obtain broad experience with guanfacine for the management of essential hypertension in a clinical practice setting; (2) to obtain information on patient acceptance of guanfacine, 1 mg HS, for the control of essential hypertension; and (3) to obtain more information on the drug's safety in clinical practice. Patients had to be at least 21 years of age, to be receiving a thiazide-type diuretic, and to have a sitting diastolic blood pressure of 95 to 114 mmHg. Women who were pregnant or lactating or planning to become pregnant during the evaluation were excluded. Blood pressure and heart rate were measured before guanfacine was started and at the completion of the study. Adverse on-therapy events were reported at the return visit. The average blood pressure in the general patient population decreased by 17/12 mmHg, that is, from 164/100 to 147/88 mmHg in four weeks. The magnitude of the reduction was not significantly influenced by age, race, sex, duration of hypertension, or the use of concomitant antihypertensive therapy. Adding guanfacine to another antihypertensive regimen resulted in mean reductions of 11 to 15 mmHg diastolic pressure, and the substitution of guanfacine for another antihypertensive agent resulted in mean reductions of 10 to 11 mmHg diastolic pressure. The most common side effect reported was dry mouth in 6% of patients, followed by dizziness, somnolence, fatigue, headache, and nausea, each reported in fewer than 3% of patients. More than 80% of the participants continued to receive guanfacine after the study. Of the total patient population, 7% discontinued guanfacine because of lack of efficacy, 10% because of side effects, and 3% for other reasons. The results of this large postmarketing study confirmed the results of controlled clinical trials conducted prior to marketing.

Freeze-drying of histocompatibility typing sera.

This report describes a unit employed for the freeze-drying of histocompatibility typing sera using a 50-h cycle. The unit will process approximately 3,200 3-ml vials with a final residual moisture content of less than 2%. The system employs dry ice-alcohol cooled circulating baths to maintain the condensers below -60 degrees C, and two shelf-cooling baths to maintain the product at the required temperatures during the freeze-drying process. The results of a recently conducted 5-year study of the effect of residual moisture as a function of time and storage temperature are also included. Studies conducted to date indicate that with residual moistures below 2%, freeze-dried histocompatibility sera can be stored at +4 degrees C without the loss of significant tissue typing factors. Solubility of all serum was lost when samples were stored at +37 degrees C or higher during this same 5-year period. The long-term storage studies are being continued.