Variable effects of nonsteroidal antiinflammatory agents on thyroid test results.

To investigate the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on thyroid tests, 25 healthy subjects underwent a single-dose study and/or a 1-wk study. In the single-dose study, subjects received a single dose of one of six NSAIDs (aspirin, salsalate, meclofenamate, ibuprofen, naproxen, or indomethacin) at 0800 h. Total and free thyroid hormones and TSH were analyzed 0, 1, 2, 3, 4, and 8 h later. In the 1-wk study, subjects received one of six NSAIDs for 7 d. Thyroid hormones and TSH were analyzed at 0800 h each day. Total T(4) and total T(3) were measured by RIA, free T(4) and free T(3) were measured by equilibrium dialysis, and TSH was measured by immunometric assay. There were no changes in any hormones after a single dose or 1 wk of ibuprofen, naproxen, or indomethacin. Single-dose aspirin or salsalate decreased, whereas meclofenamate increased, various total and free thyroid hormone measurements. One week of aspirin or salsalate decreased total T(4), free T(4) (salsalate only), total T(3), free T(3), and TSH. These data confirm that aspirin, salsalate, and meclofenamate affect total and free thyroid hormone measurements and identify three NSAIDs that did not change thyroid tests. TSH remained within the normal range during acute or 1-wk administration of all of the NSAIDs.

Sequential dacarbazine/cisplatin and interleukin-2 in metastatic melanoma: immunological effects of therapy.

Thirteen previously untreated patients with metastatic melanoma entered into a phase II chemo-immunotherapy trial were monitored immunologically during treatment. Treatment consisted of dacarbazine (DTIC) 750 mg/m2 and cisplatin 100 mg/m2 on day 1 followed by interleukin-2 (IL-2) 4 x 10(6) U/m2 by daily intravenous bolus on days 12-16 and 19-23. Cycles were repeated every 28 days. On days 1 (pretreatment), 12, 16, and 23 of each cycle, lymphokine-activated killer (LAK) cell and natural killer cell activity as well as total lymphocyte count and CD3, CD4, CD8, and CD56 lymphocyte subsets were analyzed. Despite pretreatment with full-dose cytotoxic chemotherapy, all patients were able to respond immunologically to IL-2. Spontaneous LAK cell activity was generated by the end of each course of IL-2 administration and persisted for at least 5 days thereafter. Lymphocytosis was maximum at 5 days after IL-2 administration and included increased numbers of all measured lymphocyte subsets. IL-2 administration caused a relative increase in CD56+ cells and a relative decrease in CD3+ cells. There was a direct correlation between the increase in LAK cell activity and the increase in CD56+ lymphocytes. Antitumor responses occurred in five patients but these responses did not correlate with any of the measured changes in LAK activity or lymphocyte subsets. DTIC and cisplatin administered in this schedule does not abrogate the immunological effects of IL-2.

Potentiation of 2'-deoxyguanosine cytotoxicity by a novel inhibitor of purine nucleoside phosphorylase, 8-amino-9-benzylguanine.

We have synthesized and evaluated a series of 9-substituted analogues of 8-aminoguanine, a known inhibitor of human purine nucleoside phosphorylase (PNP) activity. The ability of these agents to inhibit PNP has been investigated. All compounds were found to act as competitive (with inosine) inhibitors of PNP, with Ki values ranging from 0.2 to 290 microM. The most potent of these analogues, 8-amino-9-benzylguanine; exhibited a Ki value that was 4-fold lower than that determined for the parent base, 8-aminoguanine. As a metabolically stable compound in human blood, 8-amino-9-benzylguanine was more effective than 8-aminoguanine at potentiating the toxicity of 2'-deoxyguanosine to MOLT-4 T-lymphoblasts in culture. 8-Amino-9-benzylguanine is the most potent base or nucleoside inhibitor of human PNP reported to date, and it is a promising lead compound in the development of more effective PNP inhibitors.